Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 3, Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of Dexamethasone Plus MLN9708 or Physician’s Choice of Treatment Administered to Patients With Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis

    Summary
    EudraCT number
    		 2011-005468-10
    Trial protocol
    		 DE   NL   GB   IT   GR   ES   DK   CZ  
    Global end of trial date
    11 Jul 2022

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    C16011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01659658
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, United States, MA 02421
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study is to determine whether dexamethasone plus MLN9708 improves hematologic response and 2-year vital organ (that is, heart or kidney) deterioration and mortality rate versus a physician’s choice of a chemotherapy regimen.
    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
    12 Dec 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    United States: 42
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    China: 6
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 14
    Worldwide total number of subjects
    177
    EEA total number of subjects
    59
    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)
    84
    From 65 to 84 years
    93
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in the study at 66 investigative sites from 12 December 2012 to 11 July 2022. The study was prematurely terminated as it failed to meet the first primary endpoint at the first interim analysis.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of relapsed or refractory (R/R) systemic light chain amyloidosis (AL) were enrolled in the study to receive ixazomib capsules or physician’s choice of therapy, which included dexamethasone tablets alone or in combination with either melphalan, cyclophosphamide, thalidomide or lenalidomide.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Ixazomib + Dexamethasone
    Arm description
    		 Participants received ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone tablets

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    MLN9708
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib capsules

    Arm title
    		 Arm B: Dexamethasone + Melphalan
    Arm description
    		 Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Melphalan tablets

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone tablets

    Arm title
    		 Arm B: Dexamethasone + Cyclophosphamide
    Arm description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8, and 15 of each 28-day cycle for up to a maximum of 72.4 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cyclophosphamide tablets

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone tablets

    Arm title
    		 Arm B: Dexamethasone + Thalidomide
    Arm description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Thalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Thalidomide capsules

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone tablets

    Arm title
    		 Arm B: Dexamethasone + Lenalidomide
    Arm description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide capsules

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone tablets

    Number of subjects in period 1
    		Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Thalidomide Arm B: Dexamethasone + Lenalidomide
    Started
    90
    26
    10
    2
    49
    Completed
    0
    0
    0
    0
    0
    Not completed
    90
    26
    10
    2
    49
         Lost to Follow-up
    2
    -
    -
    -
    -
         Withdrawal by Patient
    18
    4
    2
    -
    11
         Study Terminated by Sponsor
    9
    7
    -
    1
    4
         Reason not Specified
    61
    15
    8
    1
    34

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Ixazomib + Dexamethasone
    Reporting group description
    		 Participants received ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated.

    Reporting group title
    Arm B: Dexamethasone + Melphalan
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months.

    Reporting group title
    Arm B: Dexamethasone + Cyclophosphamide
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8, and 15 of each 28-day cycle for up to a maximum of 72.4 months.

    Reporting group title
    Arm B: Dexamethasone + Thalidomide
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months.

    Reporting group title
    Arm B: Dexamethasone + Lenalidomide
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.

    Reporting group values
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Thalidomide Arm B: Dexamethasone + Lenalidomide Total
    Number of subjects
    		 90 26 10 2 49
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.4 ( 9.83 ) 64.8 ( 8.73 ) 60.0 ( 14.97 ) 65.0 ( 2.83 ) 64.9 ( 8.68 ) -
    Gender categorical
    Units: Subjects
        Female
    		 35 11 4 2 22 74
        Male
    		 55 15 6 0 27 103
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 1 0 0 2 3
        Not Hispanic or Latino
    		 85 25 9 2 40 161
        Unknown or Not Reported
    		 5 0 1 0 7 13
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 16 9 5 1 1 32
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 1 0 0 0 0 1
        White
    		 70 17 5 1 48 141
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 3 0 0 0 0 3
    Region of Enrollment
    Units: Subjects
        Canada
    		 5 0 1 0 3 9
        United States
    		 24 2 3 0 13 42
        Czechia
    		 2 0 0 0 1 3
        Denmark
    		 0 0 0 1 2 3
        France
    		 3 1 0 0 1 5
        Germany
    		 8 5 0 0 3 16
        United Kingdom
    		 10 4 0 0 3 17
        Greece
    		 6 0 2 0 7 15
        Italy
    		 3 0 0 0 4 7
        Netherlands
    		 3 1 0 0 0 4
        Spain
    		 1 1 0 0 3 5
        Turkey
    		 1 0 0 0 0 1
        Australia
    		 8 0 0 0 6 14
        Brazil
    		 0 0 0 1 0 1
        China
    		 4 2 0 0 0 6
        Israel
    		 3 3 0 0 2 8
        Japan
    		 2 5 0 0 0 7
        Korea, Republic of
    		 7 2 4 0 1 14
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 77.33 ( 16.740 ) 70.95 ( 12.476 ) 70.20 ( 21.815 ) 50.10 ( 15.415 ) 75.35 ( 17.144 ) -
    Height
    Height was planned to be analysed for Intent-to-Treat (ITT) Population. Number of subjects analysed for this baseline characteristic is the number of participants with data available for height. Arm-wise number of subjects analysed is 90, 26, 10, 2, and 48.
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    		 170.40 ( 10.507 ) 167.07 ( 8.662 ) 170.65 ( 13.274 ) 160.50 ( 13.435 ) 169.17 ( 10.532 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Arm A: Ixazomib + Dexamethasone
    Reporting group description
    		 Participants received ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated.

    Reporting group title
    Arm B: Dexamethasone + Melphalan
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months.

    Reporting group title
    Arm B: Dexamethasone + Cyclophosphamide
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8, and 15 of each 28-day cycle for up to a maximum of 72.4 months.

    Reporting group title
    Arm B: Dexamethasone + Thalidomide
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months.

    Reporting group title
    Arm B: Dexamethasone + Lenalidomide
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.

    Subject analysis set title
    ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months OR dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8, and 15 of each 28-day cycle for up to a maximum of 72.4 months OR dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months OR dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.

    Primary: Percentage of Participants With Overall Hematologic Response

    		 Close Top of page
    End point title
    		 Percentage of Participants With Overall Hematologic Response
    End point description
    Overall hematologic response was defined as the percentage of participants with complete response (CR), very good partial response (VGPR) and partial response (PR) based on central laboratory results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria as assessed by an adjudication committee. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalisation of free light chain (FLC) ratio. VGPR: differential free light chain (difference between involved and uninvolved FLC levels; dFLC) < 40 mg/L. PR: ≥50% reduction in dFLC. Percentages were rounded off to the nearest decimal. ITT Population included all participants who were randomised. Number of subjects analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
    End point values
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Thalidomide Arm B: Dexamethasone + Lenalidomide
    Number of subjects analysed
    85
    24
    10
    2
    47
    Units: percentage of participants
        number (confidence interval 95%)
    53 (41.8 to 63.9)
    58 (36.6 to 77.9)
    30 (6.7 to 65.2)
    50 (1.3 to 98.7)
    51 (36.1 to 65.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Statistical analysis was planned to be collected and analyzed in a combined manner for the non-ixazomib arm groups versus ixazomib group in this outcome measure.
    Comparison groups
    Arm A: Ixazomib + Dexamethasone v Arm B: Dexamethasone + Melphalan v Arm B: Dexamethasone + Thalidomide v Arm B: Dexamethasone + Cyclophosphamide v Arm B: Dexamethasone + Lenalidomide
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.7623 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 2.01
    Notes
    [1] - Odds ratio was derived from a logistic regression model with treatment and 95% confidence interval (CI) for the odds ratio was based on the Wald approximation.
    [2] - P-value was calculated from the unstratified Cochran-Mantel-Haenszel (CMH) test to compare hematologic response rate between the treatment arms.

    Primary: 2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate

    		 Close Top of page
    End point title
    		 2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate [3]
    End point description
    Cardiac (Heart) deterioration was defined as the need for hospitalisation for heart failure. Kidney deterioration was defined as progression to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal transplantation. Vital organ deterioration was evaluated by an adjudication committee. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised. Number of subjects analysed is the number of participants with data available for analyses.
    End point type
    Primary
    End point timeframe
    Up to 2 years
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    85
    83
    Units: percentage of participants
        number (confidence interval 95%)
    47 (36.1 to 58.2)
    54 (41.7 to 64.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ixazomib + Dexamethasone v ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.351 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.38
    Notes
    [4] - Odds ratio was derived from a logistic regression model with treatment and 95% CI for the odds ratio was based on the Wald approximation.
    [5] - P-value was calculated from the unstratified CMH test to make comparisons between the 2 treatment arms.

    Secondary: Percentage of Participants With Complete Hematologic Response

    		 Close Top of page
    End point title
    		 Percentage of Participants With Complete Hematologic Response [6]
    End point description
    Complete hematologic response was defined as the percentage of participants with CR based on central laboratory results and the 2010 ISA Consensus Criteria as assessed by the investigator. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalisation of FLC ratio. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    90
    87
    Units: percentage of participants
        number (confidence interval 95%)
    30 (20.8 to 40.6)
    17 (10.0 to 26.8)
    No statistical analyses for this end point

    Secondary: Overall Survival

    		 Close Top of page
    End point title
    		 Overall Survival [7]
    End point description
    Overall survival was defined as the time from the date of randomisation to the date of death. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    90
    87
    Units: months
        median (full range (min-max))
    69.55 (0.8 to 95.5)
    43.17 (0.0 to 82.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ixazomib + Dexamethasone v ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.389 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.29
    Notes
    [8] - Unadjusted stratified Cox regression model was used to estimate the hazard ratio and its 95% CIs for the treatment effect using the stratification factors.
    [9] - P-value was calculated using log-rank test stratified by the stratification factors.

    Secondary: Progression Free Survival (PFS)

    		 Close Top of page
    End point title
    		 Progression Free Survival (PFS) [10]
    End point description
    PFS was defined as the time from the date of randomisation to the date of first documentation of hematologic disease progression, or organ (cardiac or renal) progression, or death due to any cause, whichever occurred first according to central laboratory results and ISA criteria as evaluated by the investigator. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    90
    87
    Units: months
        median (full range (min-max))
    11.86 (0.8 to 72.0)
    7.62 (0.0 to 71.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ixazomib + Dexamethasone v ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.135 [12]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.09
    Notes
    [11] - Unadjusted stratified Cox regression model was used to estimate the hazard ratio and its 95% CIs for the treatment effect using the stratification factors.
    [12] - P-value was calculated using stratified log-rank test with stratification factors.

    Secondary: Hematologic Disease Progression Free Survival

    		 Close Top of page
    End point title
    		 Hematologic Disease Progression Free Survival
    End point description
    Hematologic disease PFS was defined as the time from the date of randomisation to the date of first documentation of hematologic PD according to central laboratory results and ISA criteria as evaluated by an adjudication committee, or death due to any cause, whichever occurred first. As the study failed to meet the first primary endpoint per Sponsor’s specification at the first interim analysis, it was decided to terminate the study early without proceeding with the protocol-specified sequence of analyses. Owing to the same, data for this endpoint was not collected.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
    End point values
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Thalidomide Arm B: Dexamethasone + Lenalidomide
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    0 [17]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [13] - The data for this outcome measure was not collected due to study termination.
    [14] - The data for this outcome measure was not collected due to study termination.
    [15] - The data for this outcome measure was not collected due to study termination.
    [16] - The data for this outcome measure was not collected due to study termination.
    [17] - The data for this outcome measure was not collected due to study termination.
    No statistical analyses for this end point

    Secondary: Time to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate

    		 Close Top of page
    End point title
    		 Time to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate [18]
    End point description
    Time to vital organ deterioration or death was assessed by the investigator and defined as the time from randomisation to vital organ (heart or kidney) deterioration or death, whichever occurs first. Cardiac deterioration is defined as the need for hospitalisation for heart failure. Kidney deterioration is defined as progression to ESRD with the need for maintenance dialysis or renal transplantation. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    From randomisation to time of vital organ deterioration or death (up to 115 months)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    90
    87
    Units: months
        median (full range (min-max))
    38.67 (0.0 to 70.5)
    26.09 (0.0 to 71.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ixazomib + Dexamethasone v ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.036 [20]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.97
    Notes
    [19] - Unadjusted stratified Cox regression model was used to estimate the hazard ratio and its 95% CIs for the treatment effect using the stratification factors.
    [20] - P-value was calculated using log-rank test stratified by the stratification factors.

    Secondary: Percentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response

    		 Close Top of page
    End point title
    		 Percentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response [21]
    End point description
    Vital organ (heart and kidney) response rate was defined as the percentage of participants who achieved vital organ response according to central laboratory results and ISA criteria as evaluated by an adjudication committee. A vital organ response was defined as response of 1 or 2 of the involved vital organs with no change from Baseline in the rest of involved vital organs. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised. Number of subjects analysed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    85
    83
    Units: percentage of participants
        number (confidence interval 95%)
    19 (11.2 to 28.8)
    12 (5.9 to 21.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ixazomib + Dexamethasone v ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.226 [23]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 3.99
    Notes
    [22] - Odds ratio was calculated from a logistic regression model with treatment and 95% CI for the odds ratio was based on the Wald approximation.
    [23] - P-value was calculated from the unstratified CMH test to compare vital organ response rate between the 2 treatment arms.

    Secondary: Vital Organ Progression Free Survival

    		 Close Top of page
    End point title
    		 Vital Organ Progression Free Survival [24]
    End point description
    Vital organ PFS is defined as the time from the date of randomisation to the date of first documentation of progression of vital organ (heart or kidney) according to central laboratory results and ISA criteria as evaluated by an adjudication committee, or death due to any cause, whichever occurs first. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    90
    87
    Units: months
        median (full range (min-max))
    15.77 (0.0 to 72.0)
    11.01 (0.0 to 71.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ixazomib + Dexamethasone v ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.163 [26]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.12
    Notes
    [25] - Unadjusted stratified Cox regression model was used to estimate the hazard ratio and its 95% CIs for the treatment effect using the stratification factors.
    [26] - P-value was calculated using stratified log-rank test with stratification factors.

    Secondary: Duration of Hematologic Response

    		 Close Top of page
    End point title
    		 Duration of Hematologic Response [27]
    End point description
    Duration of hematologic response (DOR) was defined as the time from the date of first documentation of a hematologic response to the date of first documented hematologic disease progression as determined by the investigator. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised. Number of subjects analysed is the number of hematologic responders. 9.999=Median was not estimable due to excess amount of censoring among the participants for the analysis.
    End point type
    Secondary
    End point timeframe
    From time of first documented response to disease progression (up to 115 months)
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    49
    45
    Units: months
        median (full range (min-max))
    9.999 (1.8 to 71.1)
    21.19 (0.0 to 69.0)
    No statistical analyses for this end point

    Secondary: Time To Subsequent Anticancer Treatment

    		 Close Top of page
    End point title
    		 Time To Subsequent Anticancer Treatment [28]
    End point description
    Time to subsequent anticancer therapy was defined as the time from randomisation to the first date of subsequent anticancer therapy. Participants without subsequent anticancer therapy were censored at the date of death or last known to be alive. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until subsequent anticancer treatment (up to 115 months)
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    90
    87
    Units: months
        median (full range (min-max))
    26.48 (0.8 to 95.5)
    12.45 (0.0 to 72.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ixazomib + Dexamethasone v ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.01 [30]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.88
    Notes
    [29] - Unadjusted stratified Cox regression model was used to estimate the hazard ratio and its 95% CIs for the treatment effect using the stratification factors.
    [30] - P-value was calculated using stratified log-rank test with stratification factors.

    Secondary: Time To Treatment Failure (TTF)

    		 Close Top of page
    End point title
    		 Time To Treatment Failure (TTF) [31]
    End point description
    TTF was defined as the time from randomisation to the date of first documented treatment failure. Treatment failure was defined as: 1) death due to any cause; 2) hematologic progression or major organ progression according to central laboratory results and ISA criteria as evaluated by the investigator; 3) clinically morbid organ disease requiring additional therapy; or 4) withdrawn for any reason. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    90
    87
    Units: months
        median (confidence interval 95%)
    10.32 (7.52 to 14.82)
    5.32 (4.14 to 7.82)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ixazomib + Dexamethasone v ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.025 [33]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.96
    Notes
    [32] - Unadjusted stratified Cox regression model was used to estimate the hazard ratio and its 95% CIs for the treatment effect using the stratification factors.
    [33] - P-value was calculated using stratified log-rank test with stratification factors.

    Secondary: Number of Participants With Serious Adverse Events (SAEs)

    		 Close Top of page
    End point title
    		 Number of Participants With Serious Adverse Events (SAEs)
    End point description
    A SAE is defined as any untoward medical occurrence that at any dose which results in death, is life-threatening, requires inpatient hospitalisation or prolongation of an existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or medically important event. Safety Population included all participants who received at least 1 dose of any treatment drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through 30 days after administration of the last dose of study drug (up to 115 months)
    End point values
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Thalidomide Arm B: Dexamethasone + Lenalidomide
    Number of subjects analysed
    90
    26
    10
    1
    47
    Units: participants
    44
    11
    2
    0
    17
    No statistical analyses for this end point

    Secondary: Change From Baseline in 36-item Short Form General Health Survey (SF-36) General Health Survey Score

    		 Close Top of page
    End point title
    		 Change From Baseline in 36-item Short Form General Health Survey (SF-36) General Health Survey Score
    End point description
    SF-36 Version 2 is a multipurpose, participant completed, short-form health survey with 36 questions that consists of an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Physical component summary(PCS) is mostly contributed by physical function(PF), role physical(RP), bodily pain(BP), and general health(GH). Mental component summary(MCS) is mostly contributed by mental health(MH), role emotional(RE), social function(SF), and vitality(VT). Each component on the on the SF-36 item health survey is scored from 0(best) to 100(worst). As the study failed to meet the first primary endpoint per Sponsor’s specification at the first interim analysis, it was decided to terminate the study early without proceeding with the protocol-specified sequence of analyses. Owing to the same, data for this endpoint was not collected.
    End point type
    Secondary
    End point timeframe
    At screening (Baseline); Cycle 1, Day 1; Cycle 3, Day 1; Day 1 of every 3 cycles until disease progression (up to 115 months) [cycle length=28 days]
    End point values
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Thalidomide Arm B: Dexamethasone + Lenalidomide
    Number of subjects analysed
    0 [34]
    0 [35]
    0 [36]
    0 [37]
    0 [38]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [34] - The data for this outcome measure was not collected due to study termination.
    [35] - The data for this outcome measure was not collected due to study termination.
    [36] - The data for this outcome measure was not collected due to study termination.
    [37] - The data for this outcome measure was not collected due to study termination.
    [38] - The data for this outcome measure was not collected due to study termination.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score

    		 Close Top of page
    End point title
    		 Change From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score
    End point description
    The FACT/GOG-Ntx is a participant completed questionnaire that comprises 11 individual items evaluating symptoms of neurotoxicity on a 5-point scale where: 0=not at all (best) to 4=very much for a total possible score of 0 to 44. As the study failed to meet the first primary endpoint per Sponsor’s specification at the first interim analysis, it was decided to terminate the study early without proceeding with the protocol-specified sequence of analyses. Owing to the same, data for this endpoint was not collected.
    End point type
    Secondary
    End point timeframe
    At screening (Baseline); Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Day 1 of every 3 cycles until disease progression (up to 115 months) [cycle length=28 days]
    End point values
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Thalidomide Arm B: Dexamethasone + Lenalidomide
    Number of subjects analysed
    0 [39]
    0 [40]
    0 [41]
    0 [42]
    0 [43]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [39] - The data for this outcome measure was not collected due to study termination.
    [40] - The data for this outcome measure was not collected due to study termination.
    [41] - The data for this outcome measure was not collected due to study termination.
    [42] - The data for this outcome measure was not collected due to study termination.
    [43] - The data for this outcome measure was not collected due to study termination.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Amyloidosis Symptom Scale Score

    		 Close Top of page
    End point title
    		 Change From Baseline in Amyloidosis Symptom Scale Score
    End point description
    The amyloidosis symptom scale questionnaire is a participant completed questionnaire that evaluates symptom severity of 3 symptoms: Swelling, Shortness of Breath and Dizziness, each rated on an 11-point scale where: 0=no symptoms to 10=very severe symptoms. Higher scores indicate worsening of symptoms. As the study failed to meet the first primary endpoint per Sponsor’s specification at the first interim analysis, it was decided to terminate the study early without proceeding with the protocol-specified sequence of analyses. Owing to the same, data for this endpoint was not collected.
    End point type
    Secondary
    End point timeframe
    At screening (Baseline); Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Day 1 of every 3 cycles until disease progression (up to 115 months) [cycle length=28 days]
    End point values
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Thalidomide Arm B: Dexamethasone + Lenalidomide
    Number of subjects analysed
    0 [44]
    0 [45]
    0 [46]
    0 [47]
    0 [48]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [44] - The data for this outcome measure was not collected due to study termination.
    [45] - The data for this outcome measure was not collected due to study termination.
    [46] - The data for this outcome measure was not collected due to study termination.
    [47] - The data for this outcome measure was not collected due to study termination.
    [48] - The data for this outcome measure was not collected due to study termination.
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Ixazomib

    		 Close Top of page
    End point title
    		 Plasma Concentration of Ixazomib [49]
    End point description
    As prespecified in the protocol, data for this outcome measure was planned to be collected for ixazomib arm group only. Pharmacokinetic (PK) Analysis Population included participants with at least one PK sample that was collected and analysed. Number analysed (n) is the number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 1: 1, 4 hours postdose, Day 14: 144 hours postdose; Cycle 2, Day 1: predose, Day 14: 144 hours postdose; Cycles 3 to 10, Day 1: predose (cycle length=28 days)
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone
    Number of subjects analysed
    78
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1: 1 Hour Post-dose(n=77)
    16.518 ( 97.0462 )
        Cycle 1 Day 14: 4 Hours Post-dose(n=78)
    10.652 ( 121.7231 )
        Cycle 1 Day 14: 144 Hours Post-dose(n=73)
    3.875 ( 100.3055 )
        Cycle 2 Day 1: Pre-dose(n=70)
    2.000 ( 59.4061 )
        Cycle 2 Day 14: 144 Hours Post-dose(n=60)
    4.726 ( 115.5653 )
        Cycle 3 Day 1: Pre-dose(n=65)
    2.187 ( 59.1378 )
        Cycle 4 Day 1 Pre-dose(n=59)
    2.276 ( 59.3690 )
        Cycle 5 Day 1 Pre-dose(n=56)
    2.264 ( 54.8881 )
        Cycle 6 Day 1: Pre-dose(n=54)
    2.235 ( 60.4723 )
        Cycle 7 Day 1: Pre-dose(n=45)
    2.299 ( 53.7147 )
        Cycle 8 Day 1: Pre-dose(n=43)
    2.038 ( 58.6811 )
        Cycle 9 Day 1: Pre-dose(n=42)
    2.143 ( 55.0715 )
        Cycle 10 Day 1: Pre-dose(n=42)
    2.232 ( 57.4067 )
    No statistical analyses for this end point

    Secondary: Number of Participants in Each Category of the EuroQol 5-Dimensional (EQ-5D) Questionnaire Score

    		 Close Top of page
    End point title
    		 Number of Participants in Each Category of the EuroQol 5-Dimensional (EQ-5D) Questionnaire Score [50]
    End point description
    The European Quality of Life (EuroQOL) 5-Dimensional (EQ-5D) is a patient completed questionnaire consisting of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 3 possible choices: no problems to extreme problems. Higher scores=worsening of the quality of life. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised. Number of subjects analysed is the number of participants with data available for analyses. UA=Usual Activities.
    End point type
    Secondary
    End point timeframe
    At Week 28 of the OS follow-up
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    0 [51]
    1
    Units: participants
        Mobility: No Problems in Walking About
    0
        Mobility: Some Problem in Walking About
    1
        Mobility: Confined to Bed
    0
        Self-Care: No Problems With Self- Care
    0
        Self-Care: Some Problems Washing or Dressing
    1
        Self-Care: Unable to Wash or Dress
    0
        Usual Activities: No Problems With Performing UA
    0
        Usual Activities: Some Problem With Performing UA
    1
        Usual Activities: Unable to Performing UA
    0
        Pain/Discomfort: No Pain or Discomfort
    0
        Pain/Discomfort: Moderate Pain or Discomfort
    1
        Pain/Discomfort: Extreme Pain or Discomfort
    0
        Anxiety/Depression: Not Anxious or Depressed
    0
        Anxiety/Depression: Moderately Anxious or Depresse
    0
        Anxiety/Depression: Extremely Anxious or Depressed
    1
    Notes
    [51] - No participants were available for analysis in this arm.
    No statistical analyses for this end point

    Secondary: EuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score

    		 Close Top of page
    End point title
    		 EuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score [52]
    End point description
    The EQ visual analogue scale (VAS) records the participant's self-rated health on a 20 centimeter vertical VAS that ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Baseline is defined as the value collected at the time closest to, but prior to, the start of study drug administration. As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this outcome measure. ITT Population included all participants who were randomised. Number of subjects analysed is the number of participants with data available for analyses. 99999=Standard Deviation (SD) was not estimable for 1 participant.
    End point type
    Secondary
    End point timeframe
    At Week 28 of the OS follow-up
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the protocol, data was planned to be collected and analysed in a combined way for non-ixazomib arm groups in this endpoint.
    End point values
    		 Arm A: Ixazomib + Dexamethasone ArmB:Dex + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
    Number of subjects analysed
    0 [53]
    1
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    23.0 ( 99999 )
    Notes
    [53] - No participants were available for analysis in this arm.
    No statistical analyses for this end point

    Secondary: Number of Medical Encounters Participants Experience

    		 Close Top of page
    End point title
    		 Number of Medical Encounters Participants Experience
    End point description
    Medical encounters were planned to be recorded as the number of admissions to an inpatient and outpatient setting for any reason (including length of stay, inpatient, outpatient and reason), number of missing days from work or other activities by participant or care-giver. As the study failed to meet the first primary endpoint per Sponsor’s specification at the first interim analysis, it was decided to terminate the study early without proceeding with the protocol-specified sequence of analyses. Owing to the same, data for this endpoint was not collected.
    End point type
    Secondary
    End point timeframe
    At screening; Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Day 1 of every 3 cycles until disease progression (up to 115 months) [cycle length=28 days]
    End point values
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Thalidomide Arm B: Dexamethasone + Lenalidomide
    Number of subjects analysed
    0 [54]
    0 [55]
    0 [56]
    0 [57]
    0 [58]
    Units: participants
    Notes
    [54] - The data for this outcome measure was not collected due to study termination.
    [55] - The data for this outcome measure was not collected due to study termination.
    [56] - The data for this outcome measure was not collected due to study termination.
    [57] - The data for this outcome measure was not collected due to study termination.
    [58] - The data for this outcome measure was not collected due to study termination.
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through 30 days after administration of the last dose of study drug (up to 115 months)
    Adverse event reporting additional description
    All-cause mortality: ITT Population included all participants who were randomized. Serious and other adverse events: Safety Population included all participants who received at least 1 dose of any treatment drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Arm A: Ixazomib + Dexamethasone
    Reporting group description
    		 Participants received ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated.

    Reporting group title
    Arm B: Dexamethasone + Cyclophosphamide
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8, and 15 of each 28-day cycle for up to a maximum of 72.4 months.

    Reporting group title
    Arm B: Dexamethasone + Lenalidomide
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.

    Reporting group title
    Arm B: Dexamethasone + Melphalan
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months.

    Reporting group title
    Arm B: Dexamethasone + Thalidomide
    Reporting group description
    		 Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months.

    Serious adverse events
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Lenalidomide Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Thalidomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 90 (48.89%)
    2 / 10 (20.00%)
    17 / 47 (36.17%)
    11 / 26 (42.31%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    40
    4
    22
    14
    0
         number of deaths resulting from adverse events
    6
    1
    3
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal adenoma
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Prostate cancer
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Plasma cell myeloma
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Chest pain
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Asthenia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Sudden cardiac death
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Oedema peripheral
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Pleural effusion
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypoxia
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Dyspnoea
         subjects affected / exposed
    4 / 90 (4.44%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Pulmonary embolism
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Body temperature increased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Femoral neck fracture
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Craniocerebral injury
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Accidental overdose
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin laceration
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Overdose
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Atrial fibrillation
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac amyloidosis
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 90 (3.33%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery dissection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac arrest
         subjects affected / exposed
    3 / 90 (3.33%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    4 / 90 (4.44%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Spinal cord infarction
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Syncope
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Gastritis erosive
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastric ulcer
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastric antral vascular ectasia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Diarrhoea
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Constipation
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Vomiting
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Subileus
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Rectal haemorrhage
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Nausea
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Intestinal obstruction
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Rash maculo-papular
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Acute kidney injury
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Jaw cyst
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal pain
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Muscular weakness
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Cellulitis
         subjects affected / exposed
    4 / 90 (4.44%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Abscess limb
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Herpes zoster cutaneous disseminated
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Influenza
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    2 / 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
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
    4 / 26 (15.38%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    2 / 3
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia chlamydial
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia fungal
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Sepsis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Steroid diabetes
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Dehydration
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Ixazomib + Dexamethasone Arm B: Dexamethasone + Cyclophosphamide Arm B: Dexamethasone + Lenalidomide Arm B: Dexamethasone + Melphalan Arm B: Dexamethasone + Thalidomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    86 / 90 (95.56%)
    9 / 10 (90.00%)
    46 / 47 (97.87%)
    24 / 26 (92.31%)
    1 / 1 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 10 (10.00%)
    4 / 47 (8.51%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    5
    1
    0
    Hypertension
         subjects affected / exposed
    11 / 90 (12.22%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    15
    0
    1
    1
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Orthostatic hypotension
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    8
    0
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 90 (7.78%)
    0 / 10 (0.00%)
    7 / 47 (14.89%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    14
    0
    11
    0
    0
    Peripheral swelling
         subjects affected / exposed
    5 / 90 (5.56%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    6
    1
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    41 / 90 (45.56%)
    3 / 10 (30.00%)
    17 / 47 (36.17%)
    7 / 26 (26.92%)
    0 / 1 (0.00%)
         occurrences all number
    66
    8
    29
    8
    0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    2 / 26 (7.69%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    4
    0
    Malaise
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    8 / 90 (8.89%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    9
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    40 / 90 (44.44%)
    3 / 10 (30.00%)
    24 / 47 (51.06%)
    7 / 26 (26.92%)
    1 / 1 (100.00%)
         occurrences all number
    62
    4
    47
    10
    2
    Chills
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    Asthenia
         subjects affected / exposed
    8 / 90 (8.89%)
    0 / 10 (0.00%)
    6 / 47 (12.77%)
    2 / 26 (7.69%)
    0 / 1 (0.00%)
         occurrences all number
    11
    0
    7
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    3
    0
    0
    Haemoptysis
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    10 / 90 (11.11%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    13
    1
    2
    1
    0
    Dyspnoea
         subjects affected / exposed
    19 / 90 (21.11%)
    0 / 10 (0.00%)
    12 / 47 (25.53%)
    3 / 26 (11.54%)
    1 / 1 (100.00%)
         occurrences all number
    34
    0
    14
    5
    3
    Cough
         subjects affected / exposed
    13 / 90 (14.44%)
    2 / 10 (20.00%)
    4 / 47 (8.51%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    17
    2
    5
    0
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 90 (4.44%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    1
    1
    0
    0
    Anxiety
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    1
    0
    0
    Nightmare
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Mood swings
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Mood altered
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    2
    0
    0
    Irritability
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    Insomnia
         subjects affected / exposed
    32 / 90 (35.56%)
    2 / 10 (20.00%)
    8 / 47 (17.02%)
    3 / 26 (11.54%)
    1 / 1 (100.00%)
         occurrences all number
    39
    2
    8
    4
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    6 / 47 (12.77%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    7
    1
    0
    Platelet count decreased
         subjects affected / exposed
    4 / 90 (4.44%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    2 / 26 (7.69%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    0
    4
    0
    Weight decreased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    4 / 47 (8.51%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    4
    0
    0
    Weight increased
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    6
    0
    1
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0
    3
    0
    0
    Fall
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    9
    0
    2
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    8
    0
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    4 / 90 (4.44%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    1
    0
    0
    0
    Palpitations
         subjects affected / exposed
    5 / 90 (5.56%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    6
    1
    2
    1
    0
    Nervous system disorders
    Dizziness postural
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    1
    0
    0
    Dizziness
         subjects affected / exposed
    14 / 90 (15.56%)
    1 / 10 (10.00%)
    7 / 47 (14.89%)
    3 / 26 (11.54%)
    0 / 1 (0.00%)
         occurrences all number
    17
    1
    8
    3
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Dysaesthesia
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    10 / 90 (11.11%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    14
    0
    5
    1
    0
    Paraesthesia
         subjects affected / exposed
    7 / 90 (7.78%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    10
    0
    4
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    20 / 90 (22.22%)
    0 / 10 (0.00%)
    10 / 47 (21.28%)
    0 / 26 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    22
    0
    18
    0
    4
    Syncope
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    4
    1
    0
    Taste disorder
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    Dysgeusia
         subjects affected / exposed
    6 / 90 (6.67%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    2 / 26 (7.69%)
    0 / 1 (0.00%)
         occurrences all number
    8
    1
    0
    2
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    5 / 90 (5.56%)
    1 / 10 (10.00%)
    3 / 47 (6.38%)
    2 / 26 (7.69%)
    0 / 1 (0.00%)
         occurrences all number
    6
    3
    6
    5
    0
    Neutropenia
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 10 (20.00%)
    4 / 47 (8.51%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    6
    0
    0
    Anaemia
         subjects affected / exposed
    7 / 90 (7.78%)
    2 / 10 (20.00%)
    9 / 47 (19.15%)
    4 / 26 (15.38%)
    0 / 1 (0.00%)
         occurrences all number
    11
    3
    15
    7
    0
    Leukopenia
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 90 (4.44%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    3 / 26 (11.54%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    1
    3
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    7 / 90 (7.78%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    9
    0
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Lacrimation increased
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    Myopia
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    32 / 90 (35.56%)
    1 / 10 (10.00%)
    22 / 47 (46.81%)
    4 / 26 (15.38%)
    0 / 1 (0.00%)
         occurrences all number
    66
    1
    34
    5
    0
    Dyspepsia
         subjects affected / exposed
    7 / 90 (7.78%)
    1 / 10 (10.00%)
    3 / 47 (6.38%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    10
    1
    3
    1
    0
    Flatulence
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    18 / 90 (20.00%)
    4 / 10 (40.00%)
    13 / 47 (27.66%)
    3 / 26 (11.54%)
    1 / 1 (100.00%)
         occurrences all number
    30
    4
    22
    3
    2
    Anal haemorrhage
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    7 / 90 (7.78%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    3 / 26 (11.54%)
    0 / 1 (0.00%)
         occurrences all number
    7
    1
    1
    4
    0
    Abdominal pain
         subjects affected / exposed
    9 / 90 (10.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    13
    1
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    10 / 90 (11.11%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
    2 / 26 (7.69%)
    0 / 1 (0.00%)
         occurrences all number
    12
    0
    2
    4
    0
    Haemorrhoids
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    Nausea
         subjects affected / exposed
    23 / 90 (25.56%)
    3 / 10 (30.00%)
    5 / 47 (10.64%)
    4 / 26 (15.38%)
    0 / 1 (0.00%)
         occurrences all number
    35
    3
    6
    4
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    2 / 26 (7.69%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Stomatitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    2 / 26 (7.69%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Vomiting
         subjects affected / exposed
    13 / 90 (14.44%)
    2 / 10 (20.00%)
    6 / 47 (12.77%)
    3 / 26 (11.54%)
    0 / 1 (0.00%)
         occurrences all number
    35
    2
    8
    3
    0
    Tongue haemorrhage
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    7 / 90 (7.78%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    4 / 90 (4.44%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    1 / 26 (3.85%)
    1 / 1 (100.00%)
         occurrences all number
    5
    0
    1
    1
    1
    Erythema
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    12 / 90 (13.33%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    13
    2
    7
    1
    0
    Rash macular
         subjects affected / exposed
    3 / 90 (3.33%)
    0 / 10 (0.00%)
    4 / 47 (8.51%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    4
    0
    0
    Pruritus
         subjects affected / exposed
    5 / 90 (5.56%)
    2 / 10 (20.00%)
    4 / 47 (8.51%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    6
    2
    4
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 10 (20.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    2
    0
    0
    Rash pruritic
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    2 / 26 (7.69%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Pollakiuria
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 90 (12.22%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    19
    1
    5
    0
    0
    Back pain
         subjects affected / exposed
    15 / 90 (16.67%)
    1 / 10 (10.00%)
    5 / 47 (10.64%)
    3 / 26 (11.54%)
    0 / 1 (0.00%)
         occurrences all number
    19
    1
    6
    4
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    9 / 90 (10.00%)
    0 / 10 (0.00%)
    7 / 47 (14.89%)
    1 / 26 (3.85%)
    1 / 1 (100.00%)
         occurrences all number
    10
    0
    9
    1
    1
    Muscular weakness
         subjects affected / exposed
    12 / 90 (13.33%)
    0 / 10 (0.00%)
    4 / 47 (8.51%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    13
    0
    6
    1
    0
    Pain in extremity
         subjects affected / exposed
    10 / 90 (11.11%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    12
    0
    2
    0
    0
    Myalgia
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 10 (0.00%)
    4 / 47 (8.51%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    6
    0
    5
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 90 (8.89%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    9
    0
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    3
    0
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 10 (10.00%)
    4 / 47 (8.51%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    1
    8
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 90 (24.44%)
    1 / 10 (10.00%)
    10 / 47 (21.28%)
    3 / 26 (11.54%)
    0 / 1 (0.00%)
         occurrences all number
    31
    1
    19
    4
    0
    Tooth abscess
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    7
    1
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    8 / 90 (8.89%)
    4 / 10 (40.00%)
    3 / 47 (6.38%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    15
    6
    3
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 10 (0.00%)
    4 / 47 (8.51%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    8
    0
    5
    1
    0
    Influenza
         subjects affected / exposed
    7 / 90 (7.78%)
    1 / 10 (10.00%)
    3 / 47 (6.38%)
    1 / 26 (3.85%)
    1 / 1 (100.00%)
         occurrences all number
    8
    1
    3
    1
    1
    Herpes zoster
         subjects affected / exposed
    8 / 90 (8.89%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    8
    0
    3
    1
    0
    Conjunctivitis
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    6
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    3 / 90 (3.33%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
    0 / 26 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    3
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 90 (12.22%)
    2 / 10 (20.00%)
    4 / 47 (8.51%)
    3 / 26 (11.54%)
    0 / 1 (0.00%)
         occurrences all number
    14
    2
    4
    3
    0
    Fluid retention
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    3
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 90 (3.33%)
    0 / 10 (0.00%)
    4 / 47 (8.51%)
    1 / 26 (3.85%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    4
    2
    0
    Hypokalaemia
         subjects affected / exposed
    5 / 90 (5.56%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    1
    3
    0
    0
    Iron deficiency
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
    0 / 26 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    0
    2
    0
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jan 2020
    Following updates were made as per Amendment 6: -Added primary study results from the first interim analysis (IA)-Defined the ongoing safety assessments. -Discontinued all disease and efficacy response assessments, including central laboratory assessments of efficacy and safety, for protocol purposes. -Discontinued pharmacokinetic (PK) sampling, health utilisation assessments and collection of concomitant medications and procedures for ongoing participants. -Specified that no further adjudication committee (AC) reviews were needed. -Updated the number of participants in the study and the estimated study duration. -Discontinued the PFS and OS follow-up periods. -Defined overdose. -Removed mention of the Safety Management Attachment (SMA). -Updated the procedures for SAE reporting. -Specified that no further independent data monitoring committee reviews of safety and efficacy were needed.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Jul 2022
    The study was terminated based on Sponsor’s decision as it failed to meet the first primary endpoint at the first interim analysis.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri May 02 05:49:56 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA