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    Clinical Trial Results:
    A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib Maintenance Therapy After Initial Therapy in Patients With Newly Diagnosed Multiple Myeloma Not Treated With Stem Cell Transplantation

    Summary
    EudraCT number
    2014-001394-13
    Trial protocol
    DE   BE   CZ   AT   PT   DK   ES   SE   HU   FR   HR   PL   GR   IT  
    Global end of trial date
    26 Aug 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Sep 2023
    First version publication date
    08 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C16021
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02312258
    WHO universal trial number (UTN)
    U1111-1160-1702
    Other trial identifiers
    REec: REec-2015-1414, JapicCTI: JapicCTI-152873, RNEC: 153300410A0048, TCTIN: 1046003327, SNCTP: SNCTP000001745, NRES: 15/NE/0167, HC-CTD: 182602, CRS: MOH_2017-06-15_000529
    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
    26 Aug 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine the effect of ixazomib maintenance therapy on progression free survival (PFS) compared with placebo, in subjects with newly diagnosed multiple myeloma (NDMM) who have had a major response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to initial therapy and who have not undergone stem-cell transplantation (SCT).
    Protection of trial subjects
    Each subject signed an informed consent form before participating in the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Apr 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    40 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Chile: 11
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Singapore: 12
    Country: Number of subjects enrolled
    United Kingdom: 66
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Brazil: 43
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    China: 9
    Country: Number of subjects enrolled
    Czechia: 69
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Greece: 113
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Italy: 52
    Country: Number of subjects enrolled
    Japan: 32
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Serbia: 24
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Spain: 48
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Thailand: 10
    Country: Number of subjects enrolled
    Turkey: 12
    Worldwide total number of subjects
    706
    EEA total number of subjects
    370
    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)
    68
    From 65 to 84 years
    617
    85 years and over
    21

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study from 09 April 2015 to 26 August 2022.

    Pre-assignment
    Screening details
    Participants with newly diagnosed multiple myeloma not treated with stem cell transplantation (SCT) were enrolled and randomised in a 3:2 ratio to receive ixazomib or placebo respectively.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Ixazomib placebo-matching capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 through 26.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib placebo-matching capsule, was administered orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 through 26.

    Arm title
    Ixazomib
    Arm description
    Ixazomib 3 mg, capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 to 4 that may have been escalated to 4 mg thereafter up to Cycle 26.
    Arm type
    Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib 3 mg, capsule, was administered orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 to 4 that may have been escalated to 4 mg thereafter up to Cycle 26.

    Number of subjects in period 1
    Placebo Ixazomib
    Started
    281
    425
    Completed
    0
    0
    Not completed
    281
    425
         Adverse event, serious fatal
    115
    181
         Withdrawal by Patient
    49
    76
         Lost to follow-up
    8
    8
         Missing
    2
    1
         Reason not Specified
    107
    159

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Ixazomib placebo-matching capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 through 26.

    Reporting group title
    Ixazomib
    Reporting group description
    Ixazomib 3 mg, capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 to 4 that may have been escalated to 4 mg thereafter up to Cycle 26.

    Reporting group values
    Placebo Ixazomib Total
    Number of subjects
    281 425
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    72.8 ± 6.77 72.3 ± 6.87 -
    Gender categorical
    Units: Subjects
        Male
    155 222 377
        Female
    126 203 329
    Race
    Units: Subjects
        American Indian or Alaska Native
    1 1 2
        Asian
    39 63 102
        Native Hawaiian or Other Pacific Islander
    0 1 1
        Black or African American
    5 15 20
        White
    227 330 557
        Unknown or Not Reported
    9 15 24
    Region of Enrollment
    Units: Subjects
        Australia
    11 9 20
        China
    3 6 9
        Japan
    15 17 32
        Singapore
    4 8 12
        Korea, Republic Of
    10 17 27
        Taiwan, Province Of China
    3 5 8
        Thailand
    2 8 10
        Austria
    2 3 5
        Belgium
    0 1 1
        Czech Republic
    31 38 69
        Denmark
    1 5 6
        France
    10 6 16
        Germany
    5 6 11
        Greece
    50 63 113
        Hungary
    5 7 12
        Israel
    5 11 16
        Italy
    18 34 52
        Poland
    2 13 15
        Portugal
    6 10 16
        Russia
    2 6 8
        Serbia
    11 13 24
        South Africa
    2 5 7
        Spain
    23 25 48
        Sweden
    3 3 6
        Switzerland
    1 1 2
        Turkey
    4 8 12
        United Kingdom
    20 46 66
        Argentina
    2 2 4
        Brazil
    16 27 43
        Chile
    4 7 11
        Colombia
    1 2 3
        Canada
    4 3 7
        Mexico
    2 4 6
        United States
    3 6 9
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    36 46 82
        Not Hispanic or Latino
    237 366 603
        Unknown or Not Reported
    8 13 21

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Ixazomib placebo-matching capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 through 26.

    Reporting group title
    Ixazomib
    Reporting group description
    Ixazomib 3 mg, capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 to 4 that may have been escalated to 4 mg thereafter up to Cycle 26.

    Subject analysis set title
    Ixazomib
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    test

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS) [1]
    End point description
    PFS is defined as time from date of randomisation to date of first documentation of progressive disease (PD) or death from any cause, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first. Per IMWG criteria, PD is defined as, increase of 25% of lowest response value in one or more of following criteria: serum M-component (absolute increase ≥0.5 g/ deciliter (dL)); or urine M-component (absolute increase ≥200 mg/24-hour); difference between involved and uninvolved free light chains (FLC) levels (absolute increase >10 mg/dL); or bone marrow plasma cell percentage (absolute plasma cell percentage ≥10%); development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma; or development of hypercalcemia (corrected serum calcium >11.5mg/dL). Intent-to-treat (ITT) Population included all participants who were randomised and had post-randomisation data.
    End point type
    Primary
    End point timeframe
    From randomisation until PD or death (up to 52 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned to be analysed for this endpoint.
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    281
    425
    Units: months
        median (confidence interval 95%)
    9.4 (8.51 to 11.47)
    17.4 (14.78 to 20.30)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was measured as the time from the date of randomisation to the date of death. ITT Population included all participants who were randomised and had post-randomisation data.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation every 12 weeks after PD on next-line therapy until death (up to 88 months)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    281
    425
    Units: months
        median (confidence interval 95%)
    69.5 (56.67 to 75.17)
    64.8 (54.87 to 74.84)
    Statistical analysis title
    Overall Survival (OS)
    Statistical analysis description
    P-value comparing OS between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), International Staging System (ISS) stage before initial therapy (stage I or II vs stage III), age (<75 versus [vs] >=75 years) at randomisation, and best response to initial therapy (complete response (CR) or very good partial response (VGPR) vs partial response (PR)).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.473
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.861
         upper limit
    1.381
    Notes
    [2] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.

    Secondary: Percentage of Participants Who Achieve or Maintain Any Best Response Category During the Treatment Period

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    End point title
    Percentage of Participants Who Achieve or Maintain Any Best Response Category During the Treatment Period
    End point description
    Response was assessed according to IMWG criteria based on IRC assessment. Best response included PR, VGPR and CR. PR= >=50% reduction of serum M protein and >=90% or <200 mg reduction urinary M protein in 24-hour, or >50% decrease in difference between involved and uninvolved FLC levels, or >50% reduction in bone marrow plasma cells, if bone marrow plasma cells >30% and >50% reduction in size of soft tissue plasmacytomas at baseline. VGPR= >90% reduction (<100 mg/24-hour) in serum M-protein + urine M-protein detectable by immunofixation but not on electrophoresis. Complete response= >5% plasma cells in myelogram with absence of paraprotein in serum and urine according to immunofixation. ITT Population included all participants who were randomised and had post-randomisation data. The percentages are rounded off to the single nearest decimal point.
    End point type
    Secondary
    End point timeframe
    Up to 27 months
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    281
    425
    Units: percentage of participants
    number (not applicable)
        PR
    29
    25
        VGPR
    37
    34
        CR
    28
    31
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    TTP is defined as the time from the date of randomisation to the date of first documentation of PD, using IMWG criteria. ITT Population included all participants who were randomised and had post-randomisation data.
    End point type
    Secondary
    End point timeframe
    From randomisation until PD or death (up to 52 months)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    281
    425
    Units: months
        median (confidence interval 95%)
    9.6 (8.67 to 11.99)
    17.8 (15.67 to 20.63)
    Statistical analysis title
    Time to Progression (TTP)
    Statistical analysis description
    P-value comparing TTP between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.655
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.537
         upper limit
    0.799
    Notes
    [3] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.

    Secondary: Time to Next Line Therapy (TTNT)

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    End point title
    Time to Next Line Therapy (TTNT)
    End point description
    TTNT is defined as the time from the date of randomisation to the date of the first dose of next-line antineoplastic therapy. ITT Population included all participants who were randomised and had post-randomisation data.
    End point type
    Secondary
    End point timeframe
    From randomisation until PD or death (up to 52 months)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    281
    425
    Units: months
        median (confidence interval 95%)
    16.1 (13.54 to 19.35)
    22.1 (19.55 to 25.89)
    Statistical analysis title
    Time to Next Line Therapy (TTNT)
    Statistical analysis description
    P-value comparing TTNT between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.018
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.777
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.631
         upper limit
    0.957
    Notes
    [4] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.

    Secondary: Duration of Next-line Therapy

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    End point title
    Duration of Next-line Therapy
    End point description
    Duration of next-line therapy is defined as the time from the date of the first dose of the line of antineoplastic therapy coming after study treatment to the date of the last dose. ITT Population included all participants who were randomised and had post-randomisation data. Number of subjects analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    From randomisation until PD or death (up to 52 months)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    164
    215
    Units: months
        median (confidence interval 95%)
    14.0 (10.41 to 16.82)
    8.7 (7.85 to 10.87)
    Statistical analysis title
    Duration of Next-line Therapy
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.293
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.968
         upper limit
    1.727
    Notes
    [5] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.

    Secondary: Progression Free Survival 2 (PFS2)

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    End point title
    Progression Free Survival 2 (PFS2)
    End point description
    PFS2 is defined as the time from the date of randomisation to objective PD on next-line treatment using IMWG criteria, or death due to any cause, whichever occurred first. ITT Population included all participants who were randomised and had post-randomisation data.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation to every 12 weeks until second PD or death (up to 88 months)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    281
    425
    Units: months
        median (confidence interval 95%)
    50.3 (40.05 to 62.46)
    51.3 (44.91 to 63.41)
    Statistical analysis title
    Progression Free Survival 2 (PFS2)
    Statistical analysis description
    P-value comparing PFS2 between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.893
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.984
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.777
         upper limit
    1.246
    Notes
    [6] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.

    Secondary: Correlation of MRD Status With PFS and OS

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    End point title
    Correlation of MRD Status With PFS and OS
    End point description
    PFS is defined as the time from the date of randomisation to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurred first, assessed for up to 52 months in this endpoint. OS was measured as the time from the date of randomisation to the date of death, assessed for up to 52 months in this endpoint. Participants with various types of known MRD status were pooled together for analysis of overall survival in this outcome measure. ITT Population included all participants who were randomised and had post-randomisation data. Number of subjects analysed is the number of participants with data available for analyses. 'n'=number analysed is the number of participants with data available for analyses for the specified category. The percentages are rounded off to the nearest single decimal point. '9999' indicates that the value was not estimable due to censoring.
    End point type
    Secondary
    End point timeframe
    From randomisation up to 52 months
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    151
    213
    Units: months
    median (confidence interval 95%)
        PFS for Participants with Known MRD+ (n=125,169)
    9.3 (7.75 to 11.99)
    16.9 (13.47 to 21.29)
        PFS for Participants with Known MRD- (n=26,44)
    9999 (23.69 to 9999)
    40.5 (26.94 to 9999)
        OS for Participants:Known MRDStatus(n=151,213)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    PFS for Known MRD+ at Study Entry
    Statistical analysis description
    P-value comparing PFS between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Ixazomib v Placebo
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.582
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.425
         upper limit
    0.796
    Notes
    [7] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.
    Statistical analysis title
    PFS for Known MRD- at Study Entry
    Statistical analysis description
    P-value comparing PFS between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.398
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.537
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.563
         upper limit
    4.194
    Notes
    [8] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.
    Statistical analysis title
    OS:MRD-,Known MRD+,Known MRD Status at Study Entry
    Statistical analysis description
    P-value comparing OS between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Ixazomib v Placebo
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.012
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    10.173
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.194
         upper limit
    86.649
    Notes
    [9] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.

    Secondary: Percentage of Participants Who Develop a New Primary Malignancy

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    End point title
    Percentage of Participants Who Develop a New Primary Malignancy [10]
    End point description
    Safety Population included all participants who received at least 1 dose of ixazomib or placebo. Three placebo participants who erroneously received a single dose of ixazomib were included in the ixazomib arm of the safety population. The percentages are rounded off to the single nearest decimal point.
    End point type
    Secondary
    End point timeframe
    From randomisation until PD or death (up to 52 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: This endpoint is applicable only for participants in the safety population.
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    276
    426
    Units: percentage of subjects
        number (not applicable)
    6.2
    5.2
    No statistical analyses for this end point

    Secondary: Time to End of Next-line of Therapy

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    End point title
    Time to End of Next-line of Therapy
    End point description
    Time to end of the next line of therapy is defined as the time from the date of randomisation to the date of last dose of the next line of antineoplastic therapy following study treatment. ITT Population included all participants who were randomised and had post-randomisation data. Number of subjects analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    From randomisation until PD or death (up to 52 months)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    164
    215
    Units: months
        median (confidence interval 95%)
    25.6 (22.70 to 28.48)
    23.1 (20.93 to 26.05)
    Statistical analysis title
    Time to End of Next-line of Therapy
    Statistical analysis description
    P-value comparing Time to End of Next Line Therapy between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.111
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.839
         upper limit
    1.47
    Notes
    [11] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.

    Secondary: Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

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    End point title
    Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
    End point description
    ECOG assesses participant’s performance status on 6-point scale:0=fully active/able to carry on all pre-disease activities without restriction;1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work;2=ambulatory (>50% of waking hours),capable of all self-care,unable to carry out any work activities;3=capable of only limited self-care,confined to bed/chair >50% of waking hours;4=completely disabled,cannot carry on any self-care,totally confined to bed/chair;5=dead. Lower grades indicate improvement.Safety Population=all participants who received atleast 1 dose of ixazomib or placebo.3 placebo participants who erroneously received a single dose of ixazomib were included in ixazomib arm of safety population.Number of participants analysed=number of participants with data available for analysis. '9999'=standard deviation was not estimable for a single participant.'999'=data was not available as no participants were available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2 to 26, progression free survival follow-up (PFSFU)- Visit 37 and progressive disease follow-up (PDFU)- Visit 26 (cycle length=28 days)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    271
    415
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n=271, 415)
    -0.0 ± 0.36
    -0.0 ± 0.42
        Cycle 3 Day 1 (n=263, 396)
    -0.0 ± 0.36
    -0.0 ± 0.42
        Cycle 4 Day 1 (n=251, 379)
    -0.0 ± 0.39
    -0.1 ± 0.42
        Cycle 5 Day 1 (n=235, 355)
    -0.0 ± 0.44
    -0.0 ± 0.44
        Cycle 6 Day 1 (n=219, 332)
    -0.0 ± 0.46
    -0.0 ± 0.43
        Cycle 7 Day 1 (n=204, 305)
    -0.0 ± 0.49
    -0.0 ± 0.42
        Cycle 8 Day 1 (n=188, 287)
    -0.1 ± 0.48
    -0.0 ± 0.42
        Cycle 9 Day 1 (n=175, 279)
    -0.1 ± 0.47
    -0.0 ± 0.45
        Cycle 10 Day 1 (n=163, 261)
    -0.1 ± 0.52
    -0.0 ± 0.47
        Cycle 11 Day 1 (n=151, 246)
    -0.1 ± 0.51
    -0.0 ± 0.43
        Cycle 12 Day 1 (n=151, 246)
    -0.1 ± 0.56
    -0.0 ± 0.43
        Cycle 13 Day 1 (n=129, 219)
    -0.0 ± 0.54
    -0.0 ± 0.46
        Cycle 14 Day 1 (n=115, 204)
    0.0 ± 0.53
    -0.0 ± 0.44
        Cycle 15 Day 1 (n=104, 185)
    -0.0 ± 0.53
    -0.0 ± 0.49
        Cycle 16 Day 1 (n=96, 177)
    -0.0 ± 0.51
    -0.0 ± 0.49
        Cycle 17 Day 1 (n=84, 164)
    -0.0 ± 0.54
    -0.0 ± 0.50
        Cycle 18 Day 1 (n=74, 159)
    0.0 ± 0.51
    -0.0 ± 0.51
        Cycle 19 Day 1 (n=65, 148)
    0.0 ± 0.47
    -0.0 ± 0.49
        Cycle 20 Day 1 (n=57, 133)
    0.0 ± 0.46
    -0.0 ± 0.49
        Cycle 21 Day 1 (n=52, 122)
    0.0 ± 0.48
    -0.0 ± 0.52
        Cycle 22 Day 1 (n=51, 111)
    0.1 ± 0.51
    -0.0 ± 0.52
        Cycle 23 Day 1 (n=42, 101)
    0.0 ± 0.44
    -0.0 ± 0.48
        Cycle 24 Day 1 (n=41, 91)
    0.1 ± 0.54
    -0.0 ± 0.47
        Cycle 25 Day 1 (n=35, 79)
    0.0 ± 0.42
    -0.0 ± 0.47
        Cycle 26 Day 1 (n=28, 68)
    0.0 ± 0.47
    -0.0 ± 0.47
        PFSFU- Visit 37 (n=0, 1)
    999 ± 999
    1.0 ± 9999
        PDFU- Visit 26 (n=0, 1)
    999 ± 999
    1.0 ± 9999
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative

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    End point title
    Percentage of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative
    End point description
    Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry. MRD negativity was defined as absence of MRD and MRD positivity was defined as presence of MRD. MRD was assessed by 8-color flow cytometry with the IMWG recommended sensitivity of 10^-5. ITT Population included all participants who were randomised and had post-randomisation data. Number of subjects analysed is the number of participants with data available for analyses. The percentages are rounded off to the nearest single decimal point.
    End point type
    Secondary
    End point timeframe
    Up to 52 months
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    125
    169
    Units: percentage of participants
        number (not applicable)
    3
    6
    No statistical analyses for this end point

    Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) as Measured by the Global Health Status

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    End point title
    Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) as Measured by the Global Health Status
    End point description
    ECOG assesses participant’s performance status on 5-point scale:0=fully active/able to carry on all pre-disease activities without restriction;1=restricted in physically strenuous activity, ambulatory/able to carry out light/sedentary work;2=ambulatory(>50%of waking hours),capable of all self-care,unable to carry out any work activities;3=capable of only limited self-care,confined to bed/chair>50%of waking hours;4=completely disabled,cannot carry on self-care,totally confined to bed/chair;5=dead.Lower grades=improvement.Safety Population=all participants with 1 dose of ixazomib/placebo.3placebo participants who erroneously received single ixazomib dose were included in ixazomib arm of safety.Number of subjects analysed=participants with data available for analysis.'9999'=standard deviation was not estimable for single subject.'999'=data was not available as no participants were available for analyses.'n'=number of participants with data available for analysis for the given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycles 2 through 26 (cycle length=28 days)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    270
    407
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 (n=257, 391)
    1.7 ± 16.63
    -0.1 ± 16.77
        Cycle 3 (n=257, 375)
    2.1 ± 15.74
    -1.2 ± 17.14
        Cycle 4 (n=245, 360)
    1.5 ± 16.80
    -0.6 ± 16.53
        Cycle 5 (n=227, 340)
    1.8 ± 15.79
    0.6 ± 16.33
        Cycle 6 (n=213, 307)
    1.0 ± 18.33
    -1.5 ± 16.56
        Cycle 7 (n=202, 292)
    3.1 ± 16.32
    -0.7 ± 17.28
        Cycle 8 (n= 186, 273)
    0.9 ± 18.07
    -0.4 ± 17.44
        Cycle 9 (n=173, 258)
    1.4 ± 16.67
    0.1 ± 16.57
        Cycle 10 (n=163, 245)
    2.0 ± 16.38
    -1.6 ± 17.82
        Cycle 11 (n=152, 233)
    3.9 ± 17.37
    0.2 ± 17.75
        Cycle 12 (n=143, 228)
    3.9 ± 14.53
    0.3 ± 16.26
        Cycle 13 (n=132, 218)
    4.2 ± 16.13
    -0.5 ± 16.85
        Cycle 14 (n=126, 204)
    3.1 ± 16.99
    -1.1 ± 17.45
        Cycle 15 (n=115, 194)
    2.2 ± 16.74
    -0.7 ± 17.65
        Cycle 16 (n=104, 184)
    2.5 ± 15.57
    0.5 ± 17.03
        Cycle 17 (n=100, 182)
    2.4 ± 15.09
    -0.2 ± 18.09
        Cycle 18 (n=91, 182)
    0.5 ± 18.40
    1.7 ± 16.87
        Cycle 19 (n=82, 172)
    1.6 ± 18.07
    1.1 ± 17.24
        Cycle 20 (n=74, 161)
    1.1 ± 17.95
    0.4 ± 16.13
        Cycle 21 (n=72, 153)
    1.5 ± 16.39
    1.3 ± 16.19
        Cycle 22 (n=72, 147)
    1.6 ± 15.55
    1.0 ± 17.13
        Cycle 23 (n=68, 137)
    2.1 ± 19.01
    0.9 ± 16.96
        Cycle 24 (n=64, 132)
    -0.3 ± 20.46
    2.3 ± 15.65
        Cycle 25 (n=56, 125)
    0.0 ± 18.80
    0.3 ± 17.52
        Cycle 26 (n=47, 106)
    2.8 ± 17.49
    0.9 ± 17.26
    No statistical analyses for this end point

    Secondary: PFS in a High-risk Population

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    End point title
    PFS in a High-risk Population
    End point description
    High-risk population included but not be limited to participants carrying del17, t(4;14), t(14;16). PFS was defined as the time from the date of randomisation to the date of first documentation of PD or death from any cause. ITT Population included all participants who were randomised and had post-randomisation data. Number of subjects analysed is the number of participants present in the high-risk group.
    End point type
    Secondary
    End point timeframe
    From randomisation until PD or death (up to 52 months)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    48
    74
    Units: months
        median (confidence interval 95%)
    9.6 (5.62 to 13.90)
    10.1 (6.01 to 17.02)
    Statistical analysis title
    PFS in a High-risk Population
    Statistical analysis description
    P-value comparing PFS between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    = 0.963
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.631
         upper limit
    1.621
    Notes
    [12] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.

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

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    End point title
    Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [13]
    End point description
    An adverse event(AE)=any untoward medical occurrence in participant administered a drug;not necessarily having causal relationship with this treatment.An AE can be any unfavorable,unintended sign(e.g.,clinically significant abnormal laboratory finding),symptom,disease temporally associated with use of drug,whether or not considered related to drug.TEAEs=events occurring post administration of first ixazomib/placebo dose through 30days post last ixazomib/placebo dose.SAE=any untoward medical occurrence resulting in death,was life-threatening,required in-patient hospitalization/prolongation of existing hospitalization,resulted in persistent/significant disability/incapacity,congenital anomaly/birth defect or considered medically significant.Safety Population=all participants receiving 1 ixazomib/placebo dose.3placebo participants who erroneously received single ixazomib dose were included in ixazomib arm of safety population.Percentages were rounded off to nearest single decimal point.
    End point type
    Secondary
    End point timeframe
    First dose of study drug through 30 days after last dose of study drug (up to 88 months)
    Notes
    [13] - 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: This endpoint is applicable only for participants in the safety population.
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    276
    426
    Units: percentage of participants
    number (not applicable)
        SAE
    17
    24
        TEAE
    82
    92
    No statistical analyses for this end point

    Secondary: OS in a High-risk Population

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    End point title
    OS in a High-risk Population
    End point description
    High-risk population included but not be limited to participants carrying cytogenetic deletion (del)17, translocation [t](4;14), t(14;16). OS was measured as the time from the date of randomisation to the date of death. ITT Population included all participants who were randomised and had post-randomisation data. Number of subjects analysed is the number of participants present in the high-risk group.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation and every 12 weeks after PD on next-line therapy until death (up to 88 months)
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    48
    74
    Units: months
        median (confidence interval 95%)
    48.3 (29.70 to 74.48)
    37.3 (26.05 to 47.44)
    No statistical analyses for this end point

    Secondary: Correlation Between Frailty Status and PFS and OS

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    End point title
    Correlation Between Frailty Status and PFS and OS
    End point description
    Participant’s frailty status is classified as fit, unfit or frail on bases of 4 components: age, Charlson comorbidity scoring system without age weighting, Katz index of independence in activities of daily living,and Lawton instrumental activities of daily living scale. Sum of 4 frailty scores is total frailty score. Total frailty score of 0=frailty status of fit;of 1 to unfit;and of 2/more to frail. PFS=time from date of randomisation to date of first documentation of PD/death from any cause, evaluated by IRC according to IMWG criteria, or death due to any cause,whichever occurs first. OS=time from date of randomisation to date of death. ITT Population=all participants who were randomised and had post-randomisation data. Number of subjects analysed is number of participants with data available for analysis. 'n'=number of participants with data available for analysis for the specified category. '9999' indicates median, upper, and lower limit of CI were not estimable due to censoring.
    End point type
    Secondary
    End point timeframe
    From randomisation up to 52 months
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    112
    172
    Units: months
    median (confidence interval 95%)
        PFS Based on Frailty Status of Fit (n=112, 172)
    8.5 (7.39 to 10.41)
    18.6 (12.75 to 25.63)
        PFS Based on Frailty Status of Unfit (n=98, 147)
    10.6 (7.39 to 14.23)
    17.6 (13.17 to 21.78)
        PFS Based on Frailty Status of Frail (n=68, 102)
    11.1 (8.44 to 15.67)
    15.4 (11.10 to 23.75)
        OS Based on Frailty Status of Fit (n=112, 172)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
        OS Based on Frailty Status of Unfit (n= 98, 147)
    9999 (9999 to 9999)
    9999 (39.59 to 9999)
        OS Based on Frailty Status of Frail (n=68, 102)
    42.5 (29.93 to 9999)
    46.5 (34.30 to 46.52)
    Statistical analysis title
    PFS Based on Frailty Status of Fit
    Statistical analysis description
    P-value comparing PFS between treatment groups was based on Log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), and age (<75 vs >=75 years) at randomisation.
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.387
         upper limit
    0.727
    Notes
    [14] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), and age (<75 vs >=75 years) at randomisation, comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.
    Statistical analysis title
    OS Based on Frailty Status of Frail
    Statistical analysis description
    P-value comparing OS between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.63
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.854
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.448
         upper limit
    1.627
    Notes
    [15] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.
    Statistical analysis title
    PFS Based on Frailty Status of Frail
    Statistical analysis description
    P-value comparing PFS between treatment groups was based on Log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), and age (<75 vs >=75 years) at randomisation.
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    superiority [16]
    P-value
    = 0.147
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.733
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.481
         upper limit
    1.117
    Notes
    [16] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), and age (<75 vs >=75 years) at randomisation, comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.
    Statistical analysis title
    OS Based on Frailty Status of Unfit
    Statistical analysis description
    P-value comparing OS between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.124
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    3.601
    Notes
    [17] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.
    Statistical analysis title
    PFS Based on Frailty Status of Unfit
    Statistical analysis description
    P-value comparing PFS between treatment groups was based on Log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), and age (<75 vs >=75 years) at randomisation.
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    P-value
    = 0.098
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.746
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.526
         upper limit
    1.058
    Notes
    [18] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), and age (<75 vs >=75 years) at randomisation, comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.
    Statistical analysis title
    OS Based on Frailty Status of Fit
    Statistical analysis description
    P-value comparing OS between treatment groups was based on log-rank test stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR).
    Comparison groups
    Placebo v Ixazomib
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.714
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.897
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.502
         upper limit
    1.602
    Notes
    [19] - Hazard ratio was based on an unadjusted Cox’s proportional hazard regression model stratified by initial therapy (proteasome inhibitor-containing or not), ISS stage before initial therapy (stage I or II vs stage III), age (<75 vs >=75 years) at randomisation, and best response to initial therapy (CR or VGPR vs PR), comparing the hazard rate of ixazomib arm over the hazard rate of placebo arm. A less than 1 hazard ratio was to be considered statistically significant.

    Secondary: Pharmacokinetic Parameter: Plasma Concentration of Ixazomib

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    End point title
    Pharmacokinetic Parameter: Plasma Concentration of Ixazomib [20]
    End point description
    Plasma concentrations of the complete hydrolysis product of ixazomib citrate (ixazomib) were measured using a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay. Pharmacokinetic Analysis Population included all participants with at least one pharmacokinetic (PK) sample that was collected and analysed.'n'=number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (1 and 4 hours post-dose Day 1, Days 8 and 15 pre-dose); Cycle 2 and 5 (Days 1 and 8 pre-dose) and Cycles 3, 4, 6 to 10 (Day 1 pre-dose) (Cycle length=28 days)
    Notes
    [20] - 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: This endpoint is applicable only for participants in the ixazomib arm group of the pharmacokinetic analysis population.
    End point values
    Ixazomib
    Number of subjects analysed
    423
    Units: nanogram per millilitre (ng/ml)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 - 1 Hour Post-dose (n=413)
    19.353 ± 89.2568
        Cycle 1 Day 1 - 4 Hours Post-dose (n=403)
    12.698 ± 67.8350
        Cycle 1 Day 8 - Pre-dose (n=409)
    1.683 ± 162.3947
        Cycle 1 Day 15 - Pre-dose (n=411)
    2.828 ± 86.7699
        Cycle 2 Day 1 - Pre-dose (n=410)
    1.958 ± 170.8938
        Cycle 2 Day 8 - Pre-dose (n=394)
    3.217 ± 188.6379
        Cycle 3 Day 1 - Pre-dose (n=391)
    2.252 ± 56.2869
        Cycle 4 Day 1 - Pre-dose (n=372)
    2.363 ± 52.9781
        Cycle 5 Day 1 - Pre-dose (n=348)
    2.328 ± 53.0909
        Cycle 5 Day 8 - Pre-dose (n=257)
    4.547 ± 224.4312
        Cycle 6 Day 1 - Pre-dose (n=320)
    2.503 ± 52.9349
        Cycle 7 Day 1 - Pre-dose (n=298)
    2.585 ± 57.9514
        Cycle 8 Day 1 - Pre-dose (n=281)
    2.606 ± 58.5109
        Cycle 9 Day 1 - Pre-dose (n=269)
    2.566 ± 58.1094
        Cycle 10 Day 1 - Pre-dose (n=250)
    2.686 ± 50.2494
    No statistical analyses for this end point

    Secondary: Time to Improvement of PN Events

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    End point title
    Time to Improvement of PN Events
    End point description
    PN is defined as the event in the high-level term of peripheral neuropathies NEC according to the MedDRA. A PN event was considered as resolved if its final outcome was resolved with no subsequent PN event of the same preferred term occurring on the improvement date or the day before and after. Time to improvement was defined as the time from the initial onset date (inclusive) to the improvement of event. Safety Population included all subjects who received at least 1 dose of ixazomib or placebo. Number of subjects analysed are the number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to 52 months
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    30
    83
    Units: days
        median (confidence interval 95%)
    81.0 (15.0 to 280.0)
    64.0 (29.0 to 393.0)
    No statistical analyses for this end point

    Secondary: Time to Resolution of Peripheral Neuropathy (PN) Events

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    End point title
    Time to Resolution of Peripheral Neuropathy (PN) Events
    End point description
    PN is defined as the event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the medical dictionary for regulatory activities (MedDRA). A PN event was considered as resolved if its final outcome was resolved with no subsequent PN event of the same preferred term occurring on the resolution date or the day before and after. Time to resolution was defined as the time from the initial onset date (inclusive) to the resolution date for resolved events. Safety Population included all subjects who received at least 1 dose of ixazomib or placebo. Number of subjects analysed are the number of participants with events. '9999' indicates that upper limit of confidence interval (CI) was not estimable due to censoring.
    End point type
    Secondary
    End point timeframe
    Up to 52 months
    End point values
    Placebo Ixazomib
    Number of subjects analysed
    30
    83
    Units: days
        median (confidence interval 95%)
    196.0 (43.0 to 331.0)
    451.0 (98.0 to 9999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug through 30 days after last dose of study drug (up to 88 months)
    Adverse event reporting additional description
    Serious and Other Adverse Events: Safety population included all participants who received at least 1 dose of ixazomib or placebo. Three participants assigned to placebo arm each received a single 3 mg dose of ixazomib. These participants were excluded from the placebo arm and included in the ixazomib arm in the safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Ixazomib
    Reporting group description
    Ixazomib 3 mg, capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 to 4 that may have been escalated to 4 mg thereafter up to Cycle 26.

    Reporting group title
    Placebo
    Reporting group description
    Ixazomib placebo-matching capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 through 26.

    Serious adverse events
    Ixazomib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    101 / 426 (23.71%)
    48 / 276 (17.39%)
         number of deaths (all causes)
    184
    115
         number of deaths resulting from adverse events
    11
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    5 / 426 (1.17%)
    2 / 276 (0.72%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Plasmacytoma
         subjects affected / exposed
    2 / 426 (0.47%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell cancer of the renal pelvis and ureter
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    3 / 426 (0.70%)
    4 / 276 (1.45%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 426 (0.47%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic pleural effusion
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 426 (0.00%)
    2 / 276 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 426 (0.00%)
    2 / 276 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    3 / 426 (0.70%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis radiation
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 426 (0.00%)
    2 / 276 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 426 (0.47%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 426 (0.00%)
    3 / 276 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    3 / 426 (0.70%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chilaiditi's syndrome
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 426 (0.70%)
    2 / 276 (0.72%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 426 (1.17%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcapsular renal haematoma
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 426 (0.00%)
    2 / 276 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    3 / 426 (0.70%)
    2 / 276 (0.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Varicella
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    16 / 426 (3.76%)
    2 / 276 (0.72%)
         occurrences causally related to treatment / all
    4 / 17
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    5 / 426 (1.17%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 426 (0.70%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 426 (0.94%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    6 / 426 (1.41%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 276 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 276 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ixazomib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    340 / 426 (79.81%)
    188 / 276 (68.12%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 426 (6.10%)
    16 / 276 (5.80%)
         occurrences all number
    32
    22
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    66 / 426 (15.49%)
    25 / 276 (9.06%)
         occurrences all number
    91
    30
    Headache
         subjects affected / exposed
    23 / 426 (5.40%)
    11 / 276 (3.99%)
         occurrences all number
    33
    14
    Dizziness
         subjects affected / exposed
    27 / 426 (6.34%)
    16 / 276 (5.80%)
         occurrences all number
    34
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 426 (7.28%)
    19 / 276 (6.88%)
         occurrences all number
    42
    26
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    49 / 426 (11.50%)
    28 / 276 (10.14%)
         occurrences all number
    59
    32
    Pyrexia
         subjects affected / exposed
    44 / 426 (10.33%)
    13 / 276 (4.71%)
         occurrences all number
    60
    15
    Asthenia
         subjects affected / exposed
    25 / 426 (5.87%)
    17 / 276 (6.16%)
         occurrences all number
    33
    21
    Oedema peripheral
         subjects affected / exposed
    37 / 426 (8.69%)
    16 / 276 (5.80%)
         occurrences all number
    48
    20
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    36 / 426 (8.45%)
    21 / 276 (7.61%)
         occurrences all number
    50
    26
    Diarrhoea
         subjects affected / exposed
    102 / 426 (23.94%)
    35 / 276 (12.68%)
         occurrences all number
    209
    43
    Dyspepsia
         subjects affected / exposed
    24 / 426 (5.63%)
    7 / 276 (2.54%)
         occurrences all number
    26
    8
    Nausea
         subjects affected / exposed
    119 / 426 (27.93%)
    23 / 276 (8.33%)
         occurrences all number
    202
    32
    Vomiting
         subjects affected / exposed
    102 / 426 (23.94%)
    11 / 276 (3.99%)
         occurrences all number
    187
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 426 (7.28%)
    19 / 276 (6.88%)
         occurrences all number
    38
    22
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    24 / 426 (5.63%)
    12 / 276 (4.35%)
         occurrences all number
    31
    14
    Rash maculo-papular
         subjects affected / exposed
    36 / 426 (8.45%)
    2 / 276 (0.72%)
         occurrences all number
    47
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    26 / 426 (6.10%)
    12 / 276 (4.35%)
         occurrences all number
    27
    12
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    25 / 426 (5.87%)
    13 / 276 (4.71%)
         occurrences all number
    30
    14
    Myalgia
         subjects affected / exposed
    22 / 426 (5.16%)
    8 / 276 (2.90%)
         occurrences all number
    26
    8
    Back pain
         subjects affected / exposed
    62 / 426 (14.55%)
    33 / 276 (11.96%)
         occurrences all number
    67
    40
    Arthralgia
         subjects affected / exposed
    61 / 426 (14.32%)
    30 / 276 (10.87%)
         occurrences all number
    78
    37
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    36 / 426 (8.45%)
    18 / 276 (6.52%)
         occurrences all number
    50
    27
    Upper respiratory tract infection
         subjects affected / exposed
    69 / 426 (16.20%)
    32 / 276 (11.59%)
         occurrences all number
    104
    44
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    36 / 426 (8.45%)
    13 / 276 (4.71%)
         occurrences all number
    48
    15

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2018
    The following major changes were implemented based on Amendment 5: 1. Reduced the number of participants be enrolled from 761 to 700. 2. Modified the statistical to change the timing of the first interim analysis (IA), allocate statistical power to a subgroup analysis, and updated the PFS assumptions and type I error allocation. 3. Modified the statistical design to adopt an adaptive design to test OS at the second IA. 5. Moved the details of analysis of the secondary endpoint, duration of the next line of therapy, to correct section. 6. Described how adjustment for potential effects of subsequent therapy used after study discontinuation may be analysed. 7. Changed the duration of the study to accommodate other changes to the statistical design. 8. Listed 2 secondary objectives in the Protocol Summary that were accidentally not yet listed there: “To determine the effect of ixazomib maintenance therapy on duration of next-line therapy”; and “To assess the correlation between MRD status (detected using 8-color flow cytometry) and PFS and OS, using bone marrow aspirates.” 9. Update details about storage of study drug.
    23 Sep 2020
    The following major changes were implemented based on Amendment 7: 1. Discontinued a number of efficacy response assessments, including central laboratory assessments of efficacy for protocol purposes and IRC evaluations, and clarified safety laboratory evaluation. 2. Updated the estimated study duration. 3. Updated language about the management of clinical events in participants receiving ixazomib. 4. Required all participants to reconsent. 5. Added flexibility in study conduct in unavoidable circumstances (e.g., the coronavirus disease-2019 [COVID-19] pandemic). 6. Updated the procedures for SAE reporting. 7. Added information about alternative monitoring approaches, such as remote source data verification, in the event a monitor cannot visit the site in a timely manner due to the COVID-19 pandemic.
    15 Nov 2021
    The following major changes were implemented based on Amendment 9: 1. Changed the legal entity name of the sponsor. 2. Clarified language regarding procedures for reporting product complaints or medication errors and for study conduct regarding the coronavirus disease 2019 (COVID-19) pandemic. 3. Clarified local laboratory assessment recordings.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

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