Flag of the European Union EU Clinical Trials Register Help

Clinical trials

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

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


    The EU Clinical Trials Register currently displays   43884   clinical trials with a EudraCT protocol, of which   7296   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Randomized, Open-label, Phase 3 Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (A.R.R.O.W.2)

    Summary
    EudraCT number
    2018-000665-36
    Trial protocol
    SE   DE   NL   ES   CZ   FR   BG   SK   FI   LT   AT   RO  
    Global end of trial date
    31 Mar 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Apr 2024
    First version publication date
    10 Apr 2024
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    20180015
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03859427
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    31 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study is to compare the efficacy of carfilzomib, lenalidomide, and dexamethasone (KRd) 56 mg/m^2 once weekly to KRd 27 mg/m^2 twice weekly in participants with relapsed or refractory multiple myeloma (RRMM) with 1 to 3 prior lines of therapy.
    Protection of trial subjects
    The study was conducted in accordance with International Council for Harmonisation Good Clinical Practice regulations/guidelines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 May 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    Czechia: 71
    Country: Number of subjects enrolled
    Finland: 13
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Greece: 90
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Romania: 58
    Country: Number of subjects enrolled
    Russian Federation: 44
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Sweden: 20
    Country: Number of subjects enrolled
    Türkiye: 35
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    454
    EEA total number of subjects
    350
    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)
    223
    From 65 to 84 years
    230
    85 years and over
    1

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Participants were enrolled at 80 study centers in Europe, Japan, and the United States, and participated from 08 May 2019 to 31 March 2023.

    Pre-assignment
    Screening details
    Participants with RRMM were randomized in a 1:1 ratio to receive once-weekly or twice-weekly carfilzomib, stratified by original International Staging System (ISS) stage at the time of study entry (stage 1 or 2 vs stage 3), prior lenalidomide treatment (yes vs no), proteasome inhibitor treatment (yes vs no), and anti-CD38 exposure (yes vs no).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Twice-weekly KRd 20/27 mg/m^2
    Arm description
    Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m^2 on Days 1 and 2 of Cycle 1 and 27 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Kyprolis®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Twice-weekly IV infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m^2 on Days 1 and 2 of Cycle 1 and 27 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Dexamethasone 40 mg weekly by IV infusion.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 40 mg weekly orally.

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide 25 mg daily orally on Days 1 to 21 of each 28-day cycle

    Arm title
    Once-weekly KRd 20/56 mg/m^2
    Arm description
    Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m^2 on Day 1 of Cycle 1 and 56 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Kyprolis®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Once-weekly IV infusion on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m^2 on Day 1 of Cycle 1 and 56 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Dexamethasone 40 mg weekly by IV infusion.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 40 mg weekly orally.

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide 25 mg daily orally on Days 1 to 21 of each 28-day cycle

    Number of subjects in period 1
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Started
    226
    228
    Received carfilzomib
    226
    228
    Completed 12 cycles of carfilzomib
    152 [1]
    150 [2]
    Received lenalidomide
    226
    228
    Received dexamethasone
    226
    228
    Completed
    197
    191
    Not completed
    29
    37
         Adverse event, serious fatal
    22
    25
         Consent withdrawn by subject
    4
    7
         Lost to follow-up
    3
    2
         Decision by sponsor
    -
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestone represents the numbers of participants in each treatment arm completing 12 cycles of carfilzomib.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestone represents the numbers of participants in each treatment arm completing 12 cycles of carfilzomib.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Twice-weekly KRd 20/27 mg/m^2
    Reporting group description
    Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m^2 on Days 1 and 2 of Cycle 1 and 27 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.

    Reporting group title
    Once-weekly KRd 20/56 mg/m^2
    Reporting group description
    Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m^2 on Day 1 of Cycle 1 and 56 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.

    Reporting group values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2 Total
    Number of subjects
    226 228 454
    Age Categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    107 116 223
        From 65-84 years
    118 112 230
        85 years and over
    1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    64.0 ( 8.2 ) 63.7 ( 8.4 ) -
    Gender Categorical
    Units: participants
        Female
    100 118 218
        Male
    126 110 236
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    9 12 21
        Black or African American
    1 1 2
        Native Hawaiian or Other Pacific Islander
    0 0 0
        White
    209 209 418
        Other
    7 6 13
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    8 8 16
        Not Hispanic or Latino
    213 215 428
        Unknown or Not Reported
    5 5 10
    Prior Lenalidomide Treatment
    Units: Subjects
        Yes
    79 85 164
        No
    147 143 290
    Prior Proteasome Inhibitor Treatment
    Units: Subjects
        Yes
    218 214 432
        No
    8 14 22
    Prior Anti-CD38 Treatment
    Units: Subjects
        Yes
    17 21 38
        No
    209 207 416
    Original ISS Stage at Study Entry
    ISS stage classification at study entry per interactive voice/web response system for randomization. Stage 1: serum beta-2 microglobulin < 3.5 mg/L and serum albumin ≥ 3.5 g/dL; Stage 2: serum beta-2 microglobulin < 3.5 mg/L and serum albumin < 3.5 g/dL or serum beta-2 microglobulin 3.5 - < 5.5 mg/L irrespective of the serum albumin; Stage 3: serum beta-2 microglobulin ≥ 5.5 mg/L.
    Units: Subjects
        Stage 1 or 2
    201 201 402
        Stage 3
    25 27 52

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Twice-weekly KRd 20/27 mg/m^2
    Reporting group description
    Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m^2 on Days 1 and 2 of Cycle 1 and 27 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.

    Reporting group title
    Once-weekly KRd 20/56 mg/m^2
    Reporting group description
    Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m^2 on Day 1 of Cycle 1 and 56 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.

    Subject analysis set title
    Twice-weekly KRd 20/27 mg/m^2: Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants in the safety population were analyzed according to the treatment arm corresponding to the actual treatment received. Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m^2 on Days 1 and 2 of Cycle 1 and 27 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.

    Subject analysis set title
    Once-weekly KRd 20/56 mg/m^2: Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants in the safety population were analyzed according to the treatment arm corresponding to the actual treatment received. Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m^2 on Day 1 of Cycle 1 and 56 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.

    Primary: Overall Response Rate (ORR) per International Myeloma Working Group Uniform Response Criteria (IMWG-URC)

    Close Top of page
    End point title
    Overall Response Rate (ORR) per International Myeloma Working Group Uniform Response Criteria (IMWG-URC)
    End point description
    ORR was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) per IMWG-URC. CR: negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, < 5% plasma cells in bone marrow (BM). sCR: CR and normal serum free light chain ratio and no clonal cells in BM by immunohistochemistry. VGPR: Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level < 100 mg/24-hours). PR: ≥ 50% reduction of serum M-protein and reduction in 24-hours urinary M-protein by ≥ 90% or to < 200 mg/24-hours. The ORR 95% confidence intervals (CIs) were estimated using the Clopper-Pearson method. The intent-to-treat (ITT) population included all randomized participants.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    226
    228
    Units: percentage of participants
        number (confidence interval 95%)
    86.3 (81.1 to 90.5)
    82.5 (76.9 to 87.2)
    Statistical analysis title
    Risk Ratio
    Statistical analysis description
    Risk ratio and 95% CIs were estimated by a stratified analysis using the Cochran-Mantel-Haenszel method. The non-inferiority margin was 0.87 for the estimated ORR risk ratio.
    Comparison groups
    Twice-weekly KRd 20/27 mg/m^2 v Once-weekly KRd 20/56 mg/m^2
    Number of subjects included in analysis
    454
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0666
    Method
    Synthesis approach
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.954
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.882
         upper limit
    1.032

    Secondary: Kaplan-Meier Estimate of Progression-free Survival (PFS) Rate at 12 Months

    Close Top of page
    End point title
    Kaplan-Meier Estimate of Progression-free Survival (PFS) Rate at 12 Months
    End point description
    PFS rate was defined as the percentage of participants without disease progression or death due to any cause at 12 months. The PFS rate at 12 months was estimated using the Kaplan-Meier method by Klein and Moeschberger (1997). 95% CIs were estimated using the method by Kalbfleisch and Prentice (1980). PFS data was censored for participants who met any one of the following: 1. no baseline/no post-baseline disease assessments; 2. starting new anti-myeloma therapy before documentation of progressive disease (PD) or death; 3. PD or death immediately after more than 1 consecutively missed disease assessment visit (PD or death immediately after > 63 days without disease assessment visit); 4. alive without documentation of PD; 5. lost to follow-up or withdrawn consent. The ITT analysis set included all randomized participants.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    226
    228
    Units: percentage of participants
        number (confidence interval 95%)
    79.7 (73.6 to 84.6)
    80.7 (74.7 to 85.4)
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment-emergent Adverse Events (TEAEs)

    Close Top of page
    End point title
    Number of Participants with Treatment-emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs were AEs starting on or after the first dose of any study drug, and up to 30 days of the last dose of any study drug, excluding AEs reported after End of Study date. The safety population included all randomized participants who received at least 1 dose of any study treatment (carfilzomib, lenalidomide, or dexamethasone). Participants were analyzed according to the treatment arm corresponding to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 1 up to end of Cycle 12 + 30 days, where each cycle was 28 days; median treatment duration (any study treatment) was 47.00 weeks in the twice-weekly KRd group and 47.14 weeks in the once-weekly KRd group
    End point values
    Twice-weekly KRd 20/27 mg/m^2: Safety population Once-weekly KRd 20/56 mg/m^2: Safety population
    Number of subjects analysed
    231
    223
    Units: participants
    219
    209
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Reported Convenience as Measured by the Patient-reported Convenience with Carfilzomib-dosing Schedule Question

    Close Top of page
    End point title
    Percentage of Participants who Reported Convenience as Measured by the Patient-reported Convenience with Carfilzomib-dosing Schedule Question
    End point description
    Patient-reported convenience was measured by the Patient-reported Convenience with Carfilzomib-dosing Schedule Question. The items in the questionnaire were categorized as 'Convenient', which included responses of 'Very Convenient' and 'Convenient', and 'Inconvenient' which included responses of 'Inconvenient' and 'Very Inconvenient'. The 95% CIs were estimated using the Clopper-Pearson method. The ITT population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Day 28 of Cycle 4
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    226
    228
    Units: percentage of participants
        number (confidence interval 95%)
    80.5 (74.8 to 85.5)
    81.6 (75.9 to 86.4)
    Statistical analysis title
    Odds Ratio
    Statistical analysis description
    Odds ratio and 95% CIs were estimated by a stratified analysis using the Cochran-Mantel-Haenszel method.
    Comparison groups
    Twice-weekly KRd 20/27 mg/m^2 v Once-weekly KRd 20/56 mg/m^2
    Number of subjects included in analysis
    454
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.049
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.653
         upper limit
    1.683

    Secondary: Time to Response (TTR)

    Close Top of page
    End point title
    Time to Response (TTR)
    End point description
    TTR was defined as the time from randomization to the earliest date when confirmed sCR, CR, VGPR, or PR per IMWG-URC was first achieved. The ITT population included all randomized participants. Data is presented for participants in the ITT population who achieved a confirmed response of PR or better.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    195
    188
    Units: months
        median (full range (min-max))
    1.0 (1 to 12)
    1.0 (1 to 10)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of Duration of Response (DOR)

    Close Top of page
    End point title
    Kaplan-Meier Estimate of Duration of Response (DOR)
    End point description
    For participants who achieved a PR or better, i.e., sCR, CR, VGPR, or PR per IMWG-URC, the DOR was defined as the time from the earliest date when a PR or better was first achieved, and confirmed, to the earliest date of confirmed PD or death due to any cause. Median DOR was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. For those alive and who had not experienced PD by analysis time, DOR was censored for participants who met any one of the following: 1. no baseline/no post-baseline disease assessments; 2. starting new anti-myeloma therapy before documentation of PD or death; 3. PD or death immediately after more than 1 consecutively missed disease assessment visit (PD or death immediately after > 63 days without disease assessment visit); 4. alive without documentation of PD; 5. lost to follow-up or withdrawn consent. 99999=median and 95% CIs could not be estimated due to too few events.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    195
    188
    Units: months
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of Overall Survival (OS)

    Close Top of page
    End point title
    Kaplan-Meier Estimate of Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. Participants still alive or lost to follow-up or withdrawn consent from study by the analysis time were censored at the date on which the participant was last known to be alive. The ITT population included all randomized participants. 99999 = median and 95% CIs could not be estimated due to too few events.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    226
    228
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of Time to Progression (TTP)

    Close Top of page
    End point title
    Kaplan-Meier Estimate of Time to Progression (TTP)
    End point description
    TTP was defined as the duration from randomization for the first documented disease progression per IMWG-UCR. Median TTP was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. TTP was censored for participants who had no confirmed PD at the last non non-evaluable (non-NE), post-baseline disease assessment or the earlier of the following, where applicable: 1. the last non-NE, post-baseline disease assessment prior to start of a new anti-myeloma treatment, or 2. the last non-NE, post-baseline assessment followed > 63 days later by disease progression; otherwise, at randomization. The ITT population included all randomized participants. 99999=median and 95% CIs could not be estimated due to too few events.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    226
    228
    Units: months
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Achieved Minimal Residual Disease Negative Complete Response (MRD[-]CR) by Independent Review Committee (IRC) per IMWG-URC

    Close Top of page
    End point title
    Percentage of Participants who Achieved Minimal Residual Disease Negative Complete Response (MRD[-]CR) by Independent Review Committee (IRC) per IMWG-URC
    End point description
    MRD[-]CR was defined as achievement of CR or better by IRC per IMWG-URC and achievement of MRD negativity as assessed by next generation sequencing method at a 10^-5 threshold over the duration of the study. The 95% CIs for proportions were estimated using the Clopper-Pearson method. The ITT population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    226
    228
    Units: percentage of participants
        number (confidence interval 95%)
    18.1 (13.3 to 23.8)
    21.5 (16.3 to 27.4)
    Statistical analysis title
    Odds Ratio
    Statistical analysis description
    Odds ratio and 95% CIs were estimated by a stratified analysis using the Cochran-Mantel-Haenszel method.
    Comparison groups
    Twice-weekly KRd 20/27 mg/m^2 v Once-weekly KRd 20/56 mg/m^2
    Number of subjects included in analysis
    454
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.235
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.775
         upper limit
    1.97

    Secondary: Percentage of Participants with Minimal Residual Disease Negativity (MRD[-]) by IRC per IMWG-URC at 12 Months

    Close Top of page
    End point title
    Percentage of Participants with Minimal Residual Disease Negativity (MRD[-]) by IRC per IMWG-URC at 12 Months
    End point description
    The percentage of participants with achievement of MRD[-] at 12 months (± 4 weeks) from randomization, as assessed by next generation sequencing method at a 10^-5 threshold. MRD negativity results from BM samples obtained at 8 to 13 months from randomization and prior to new anti-myeloma therapy or disease progression were considered in the calculation. The 95% CIs for proportions were estimated using the Clopper-Pearson method. The ITT population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 up to 12 months (cycle = 28 days)
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    226
    228
    Units: percentage of participants
        number (confidence interval 95%)
    18.1 (13.3 to 23.8)
    18.9 (14.0 to 24.6)
    Statistical analysis title
    Odds Ratio
    Statistical analysis description
    Odds ratio and 95% CIs were estimated by a stratified analysis using the Cochran-Mantel-Haenszel method.
    Comparison groups
    Twice-weekly KRd 20/27 mg/m^2 v Once-weekly KRd 20/56 mg/m^2
    Number of subjects included in analysis
    454
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.657
         upper limit
    1.711

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale

    Close Top of page
    End point title
    Change from Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale
    End point description
    The QLQ-C30 physical function score ranges from 0-100 points, with 100 points indicating the best possible functioning. A positive change from baseline indicated an improvement in functioning. The ITT population included all randomized participants. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose)
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    226
    228
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 3 Day 1 (N=186, 182)
    -2.76 ( 16.84 )
    -0.77 ( 14.95 )
        Cycle 5 Day 1 (N=181, 177)
    -2.65 ( 15.76 )
    0.26 ( 15.59 )
        Cycle 7 Day 1 (N=162, 161)
    -0.82 ( 16.59 )
    0.17 ( 14.62 )
        Cycle 9 Day 1 (N=152, 148)
    -1.05 ( 15.59 )
    2.03 ( 14.75 )
        Cycle 12 Day 1 (N=134, 132)
    -1.89 ( 15.15 )
    1.06 ( 15.63 )
        Safety Follow-up (N=146, 145)
    -1.55 ( 16.32 )
    2.11 ( 18.27 )
    Statistical analysis title
    Least Squares (LS) Mean Treatment Difference
    Statistical analysis description
    Analysis was based on repeated measures analysis of covariance (ANCOVA) model, including arm, baseline scale score, randomization stratification factors and visit as repeated measure.
    Comparison groups
    Twice-weekly KRd 20/27 mg/m^2 v Once-weekly KRd 20/56 mg/m^2
    Number of subjects included in analysis
    454
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    2.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    4.69

    Secondary: Change from Baseline in EORTC QLQ C30 Role Functioning Scale

    Close Top of page
    End point title
    Change from Baseline in EORTC QLQ C30 Role Functioning Scale
    End point description
    The QLQ-C30 role function score ranges from 0-100 points, with 100 points indicating the best possible functioning. A positive change from baseline indicated an improvement in functioning. The ITT population included all randomized participants. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose)
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    226
    228
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 3 Day 1 (N=186, 182)
    -4.30 ( 26.16 )
    -2.47 ( 24.81 )
        Cycle 5 Day 1 (N=181, 177)
    -2.67 ( 25.77 )
    -3.11 ( 24.32 )
        Cycle 7 Day 1 (N=162, 161)
    -3.29 ( 26.19 )
    1.76 ( 24.34 )
        Cycle 9 Day 1 (N=152, 148)
    -0.88 ( 23.24 )
    2.70 ( 24.90 )
        Cycle 12 Day 1 (N=134, 132)
    -0.25 ( 23.21 )
    1.64 ( 28.97 )
        Safety Follow-up (N=146, 145)
    -2.28 ( 24.73 )
    3.68 ( 26.24 )
    Statistical analysis title
    LS Mean Treatment Difference
    Statistical analysis description
    Analysis was based on ANCOVA model, including arm, baseline scale score, randomization stratification factors and visit as repeated measure.
    Comparison groups
    Twice-weekly KRd 20/27 mg/m^2 v Once-weekly KRd 20/56 mg/m^2
    Number of subjects included in analysis
    454
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    1.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.26
         upper limit
    4.72

    Secondary: Patient-reported Treatment Satisfaction as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ)

    Close Top of page
    End point title
    Patient-reported Treatment Satisfaction as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ)
    End point description
    The CTSQ measures treatment satisfaction in individuals with cancer and includes a domain for satisfaction with therapy. The satisfaction with therapy scores ranges from 0 to 100 points, with 100 points indicating greatest satisfaction. Analysis was based on ANCOVA model. The dependent variable of the models were the scale scores measured at each visit. The model included effects of intercept, scale score measured at cycle 2 day 1 visit, treatment arm, and randomization stratification factors. The ITT population included all randomized participants. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 5, Day 1 Cycle 12, and safety follow-up (30 days after last dose)
    End point values
    Twice-weekly KRd 20/27 mg/m^2 Once-weekly KRd 20/56 mg/m^2
    Number of subjects analysed
    169
    165
    Units: score on a scale
    least squares mean (standard error)
        Cycle 5 Day 1 (N=169, 165)
    75.73 ( 1.78 )
    75.47 ( 1.76 )
        Cycle 12 Day 1 (N=128, 122)
    78.39 ( 2.40 )
    77.91 ( 2.40 )
        Safety follow-up (N=138, 134)
    74.55 ( 2.58 )
    75.99 ( 2.49 )
    Statistical analysis title
    Treatment Difference at Cycle 5
    Statistical analysis description
    LS mean treatment difference at Cycle 5.
    Comparison groups
    Twice-weekly KRd 20/27 mg/m^2 v Once-weekly KRd 20/56 mg/m^2
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.54
         upper limit
    2.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.16
    Statistical analysis title
    Treatment Difference at Safety Follow-up
    Statistical analysis description
    LS mean treatment difference at safety follow-up.
    Comparison groups
    Twice-weekly KRd 20/27 mg/m^2 v Once-weekly KRd 20/56 mg/m^2
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    1.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.69
         upper limit
    4.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.59
    Statistical analysis title
    Treatment Difference at Cycle 12
    Statistical analysis description
    LS mean treatment difference at Cycle 12.
    Comparison groups
    Twice-weekly KRd 20/27 mg/m^2 v Once-weekly KRd 20/56 mg/m^2
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.24
         upper limit
    2.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from first dose of study drug to last dose of study drug + 30 days; median treatment duration (any study treatment) was 11.8 months.
    Adverse event reporting additional description
    Serious AEs and other AEs were collected for all participants in the safety population who received at least one dose of study drug. Participants in the safety population were analyzed according to the treatment arm corresponding to the actual treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Twice-weekly KRd 20/27 mg/m^2: Safety population
    Reporting group description
    Participants in the safety population were analyzed according to the treatment arm corresponding to the actual treatment received. Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m^2 on Days 1 and 2 of cycle 1 and 27 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.

    Reporting group title
    Once-weekly KRd 20/56 mg/m^2: Safety population
    Reporting group description
    Participants in the safety population were analyzed according to the treatment arm corresponding to the actual treatment received. Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m^2 on Day 1 of Cycle 1 and 56 mg/m^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.

    Serious adverse events
    Twice-weekly KRd 20/27 mg/m^2: Safety population Once-weekly KRd 20/56 mg/m^2: Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    75 / 231 (32.47%)
    84 / 223 (37.67%)
         number of deaths (all causes)
    24
    24
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cryoglobulinaemia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 231 (1.30%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poor venous access
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 231 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    General physical health deterioration
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 231 (0.87%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 231 (2.60%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    3 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram abnormal
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Autonomic nervous system imbalance
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intensive care unit acquired weakness
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (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 / 231 (0.43%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 231 (0.87%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (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
    1 / 231 (0.43%)
    0 / 223 (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
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 231 (0.43%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 231 (1.30%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (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
    Amplified musculoskeletal pain syndrome
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 231 (0.87%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    11 / 231 (4.76%)
    8 / 223 (3.59%)
         occurrences causally related to treatment / all
    0 / 12
    1 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    COVID-19
         subjects affected / exposed
    3 / 231 (1.30%)
    6 / 223 (2.69%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchitis
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 231 (3.90%)
    12 / 223 (5.38%)
         occurrences causally related to treatment / all
    0 / 10
    9 / 14
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 231 (0.87%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 231 (0.87%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection bacterial
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinobronchitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 231 (0.43%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypocalcaemia
         subjects affected / exposed
    1 / 231 (0.43%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 223 (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
    Twice-weekly KRd 20/27 mg/m^2: Safety population Once-weekly KRd 20/56 mg/m^2: Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    190 / 231 (82.25%)
    182 / 223 (81.61%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    56 / 231 (24.24%)
    48 / 223 (21.52%)
         occurrences all number
    92
    66
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 231 (5.19%)
    9 / 223 (4.04%)
         occurrences all number
    13
    12
    Neuropathy peripheral
         subjects affected / exposed
    11 / 231 (4.76%)
    22 / 223 (9.87%)
         occurrences all number
    16
    26
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    55 / 231 (23.81%)
    56 / 223 (25.11%)
         occurrences all number
    71
    88
    Neutropenia
         subjects affected / exposed
    73 / 231 (31.60%)
    65 / 223 (29.15%)
         occurrences all number
    207
    147
    Thrombocytopenia
         subjects affected / exposed
    31 / 231 (13.42%)
    46 / 223 (20.63%)
         occurrences all number
    80
    105
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    13 / 231 (5.63%)
    26 / 223 (11.66%)
         occurrences all number
    26
    37
    Fatigue
         subjects affected / exposed
    29 / 231 (12.55%)
    24 / 223 (10.76%)
         occurrences all number
    39
    32
    Pyrexia
         subjects affected / exposed
    27 / 231 (11.69%)
    23 / 223 (10.31%)
         occurrences all number
    28
    27
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    17 / 231 (7.36%)
    23 / 223 (10.31%)
         occurrences all number
    20
    26
    Diarrhoea
         subjects affected / exposed
    43 / 231 (18.61%)
    42 / 223 (18.83%)
         occurrences all number
    58
    58
    Nausea
         subjects affected / exposed
    15 / 231 (6.49%)
    19 / 223 (8.52%)
         occurrences all number
    17
    38
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    8 / 231 (3.46%)
    12 / 223 (5.38%)
         occurrences all number
    11
    15
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    20 / 231 (8.66%)
    13 / 223 (5.83%)
         occurrences all number
    32
    27
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    16 / 231 (6.93%)
    21 / 223 (9.42%)
         occurrences all number
    21
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 231 (6.93%)
    21 / 223 (9.42%)
         occurrences all number
    17
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 231 (5.63%)
    8 / 223 (3.59%)
         occurrences all number
    16
    8
    Muscle spasms
         subjects affected / exposed
    21 / 231 (9.09%)
    12 / 223 (5.38%)
         occurrences all number
    27
    17
    Back pain
         subjects affected / exposed
    19 / 231 (8.23%)
    17 / 223 (7.62%)
         occurrences all number
    20
    20
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    33 / 231 (14.29%)
    32 / 223 (14.35%)
         occurrences all number
    44
    47
    Nasopharyngitis
         subjects affected / exposed
    16 / 231 (6.93%)
    16 / 223 (7.17%)
         occurrences all number
    21
    18
    COVID-19
         subjects affected / exposed
    14 / 231 (6.06%)
    22 / 223 (9.87%)
         occurrences all number
    14
    23
    Bronchitis
         subjects affected / exposed
    15 / 231 (6.49%)
    11 / 223 (4.93%)
         occurrences all number
    20
    12
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    18 / 231 (7.79%)
    10 / 223 (4.48%)
         occurrences all number
    22
    21
    Hypocalcaemia
         subjects affected / exposed
    13 / 231 (5.63%)
    10 / 223 (4.48%)
         occurrences all number
    13
    11
    Hyperglycaemia
         subjects affected / exposed
    17 / 231 (7.36%)
    9 / 223 (4.04%)
         occurrences all number
    22
    11

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Oct 2019
    - Added overall survival at 1 year as secondary endpoint. - Added a long-term follow-up period with a duration of 12 months after randomization to separate this period from the safety follow-up period after cessation of treatment.
    24 Aug 2020
    - Added duration to secondary objectives. - Deleted early success from interim analysis.
    12 Aug 2021
    - Updated primary endpoint to overall response (removed “rate”). - Updated inclusion criteria. - Updated exclusion criteria. - Clarified administration of dexamethasone. - Updated planned analysis and methods of analysis.

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

    European Medicines Agency © 1995-2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA