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    Clinical Trial Results:
    A PHASE 3, MULTICENTRE, RANDOMIZED, CONTROLLED STUDY TO DETERMINE THE EFFICACY AND SAFETY OF CYCLOPHOSPHAMIDE, LENALIDOMIDE AND DEXAMETHASONE (CRD) versus MELPHALAN (200 mg/m2) FOLLOWED BY STEM CELL TRANSPLANT IN NEWLY DIAGNOSED MULTIPLE MYELOMA SUBJECTS

    Summary
    EudraCT number
    2008-008599-15
    Trial protocol
    IT   CZ   SK   HU  
    Global end of trial date
    01 Jul 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Feb 2025
    First version publication date
    16 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RV-MM-EMN-441
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01091831
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Fondazione EMN Italy Onlus
    Sponsor organisation address
    Via Saluzzo I/A, Turin, Italy, 10125
    Public contact
    Clinical Trial Office, Fondazione EMN Italy Onlus , 0039 0110243236, clinicaltrialoffice@emnitaly.org
    Scientific contact
    Clinical Trial Office, Fondazione EMN Italy Onlus , 0039 0110243236 , clinicaltrialoffice@emnitaly.org
    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
    23 Jan 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of the combination of lenalidomide with low-dose alkylating agents versus high-dose melphalan in newly diagnosed, symptomatic MM patients.
    Protection of trial subjects
    The protocol for this study has been designed in accordance with the general ethical principles outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC and the performance of all aspects of the study, including the methods used for obtaining informed consent, must also be in accordance with principles enunciated in the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Jan 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Czechia: 54
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Italy: 258
    Country: Number of subjects enrolled
    Australia: 64
    Country: Number of subjects enrolled
    New Zealand: 1
    Worldwide total number of subjects
    389
    EEA total number of subjects
    324
    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)
    368
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Multicenter, randomized, open label study designed to compare the efficacy and safety of lenalidomide with low-dose alkylating agents vs high-dose melphalan followed by stem cell support in newly diagnosed symptomatic MM patients who are 65 years or younger. It consists of 4 phases for each study subject: Pre-treatment, Treatment, Extension and FU.

    Pre-assignment
    Screening details
    The pre-treatment period includes screening visits, performed at study entry. After providing written informed consent to participate in the study, patients will be evaluated for study eligibility. The screening period includes the availability of inclusion criteria.

    Period 1
    Period 1 title
    Induction
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    RD Induction
    Arm description
    Patients will start induction treatment with lenalidomide and dexamethasone (RD) for 4 cycles every 28 days: - Lenalidomide will be given orally at the dose of 25 mg/d for 21 days followed by a 7 days rest period (day 22 to 28), - Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15, 22. After 1-2 months from the completion of the last RD cycle, i.v. cyclophosphamide (CY) will be given at the dose of 3 g/m2 followed by G-CSF (5-10 ug/kg/day starting at day 5 until completion of PBSC collection) to collect an adequate number of PBSC (≥ 4 to 10 x 106/kg CD34+ cells). Patients who fail to collect the minimum of 4 x 106/kg CD34+ cells will receive either a second course of CY with higher dose of or G-CSF or it is allowed the association of G-CSF with Plerixafor, as per standard practice of every single institution, for a second mobilization according to physician willing. Patients who fail to collect a minimum of 4 x 106/kg CD34+ will be withdrawn from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be given orally at the dose of 25 mg/d for 21 days followed by a 7 days rest period (day 22 to 28)

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15, 22

    Arm title
    CY infusion
    Arm description
    After 1-2 months from the completion of the last RD cycle, i.v. cyclophosphamide (CY) will be given at the dose of 3 g/m2 followed by G-CSF (5-10 ug/kg/day starting at day 5 until completion of PBSC collection) to collect an adequate number of PBSC (≥ 4 to 10 x 106/kg CD34+ cells). Patients who fail to collect the minimum of 4 x 106/kg CD34+ cells will receive either a second course of CY with higher dose of or G-CSF or it is allowed the association of G-CSF with Plerixafor, as per standard practice of every single institution, for a second mobilization according to physician willing. Patients who fail to collect a minimum of 4 x 106/kg CD34+ will be withdrawn from the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 g/m2

    Number of subjects in period 1
    RD Induction CY infusion
    Started
    387
    315
    Completed
    315
    256
    Not completed
    72
    59
         Adverse event, serious fatal
    3
    -
         Consent withdrawn by subject
    5
    13
         Physician decision
    -
    2
         Adverse event, non-fatal
    14
    2
         Other
    9
    13
         Lost to follow-up
    3
    -
         Lack of efficacy
    38
    29
    Period 2
    Period 2 title
    Consolidation
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ARM A (CRd)
    Arm description
    Patients will start consolidation treatment with the association lenalidomide, cyclophosphamide and dexamethasone (CRD) for 6 cycles every 28 days: - Lenalidomide will be given orally at the dose of 25 mg/d for 21 days followed by a 7 days rest period (day 22 to 28) - Cyclophosphamide will be given orally at the dose of 300 mg/m2 on days 1, 8, 15 - Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15, 22.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be given orally at the dose of 25 mg/d for 21 days followed by a 7 days rest period (day 22 to 28)

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide will be given orally at the dose of 300 mg/m2 on days 1, 8, 15

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15, 22.

    Arm title
    ARM B (MEL200)
    Arm description
    Patients will start consolidation treatment with melphalan 200 mg/m2 followed by stem cell support (MEL200) for 1 cycle (if at least VGPR was achieved after the 1st MEL200) or 2 cycles (if ≤ PR was achieved after the 1st MEL200) - Melphalan will be given iv at the dose of 200 mg/m2 for 1 day followed by stem cell support. The second MEL200 was performed 120 days after the first if ≤ PR was achieved after the 1st MEL200.
    Arm type
    Experimental

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Melphalan will be given iv at the dose of 200 mg/m2 for 1 day followed by stem cell support. The second MEL200 was performed 120 days after the first if ≤ PR was achieved after the 1st MEL200.

    Number of subjects in period 2
    ARM A (CRd) ARM B (MEL200)
    Started
    129
    127
    Completed
    106
    117
    Not completed
    23
    10
         Adverse event, serious fatal
    2
    1
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    4
    1
         Other
    2
    1
         Lost to follow-up
    -
    1
         Lack of efficacy
    14
    4
    Period 3
    Period 3 title
    Maintenance
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ARM A1 and B1
    Arm description
    Arms A1 and B1 will receive lenalidomide at dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28) and Prednisone 50 mg every other day, until relapse.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide at dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28)

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 50 mg every other day, until relapse.

    Arm title
    ARM A2 and B2
    Arm description
    Arms A2 and B2 will receive lenalidomide at dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), until relapse.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide at dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), until relapse.

    Number of subjects in period 3
    ARM A1 and B1 ARM A2 and B2
    Started
    117
    106
    Completed
    0
    0
    Not completed
    117
    106
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    3
    2
         Physician decision
    1
    -
         Adverse event, non-fatal
    20
    16
         Other
    4
    3
         Lost to follow-up
    9
    3
         Lack of efficacy
    72
    75
         Treatment will be continued outside the scope of t
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction
    Reporting group description
    -

    Reporting group values
    Induction Total
    Number of subjects
    389 389
    Age categorical
    Units: Subjects
        <= 60
    248 248
        > 60
    141 141
    Age continuous
    Units: months
        median (full range (min-max))
    57 (18 to 69) -
    Gender categorical
    Units: Subjects
        Female
    193 193
        Male
    196 196
    ISS Stage
    Units: Subjects
        ISS I
    171 171
        ISS II
    152 152
        ISS III
    66 66
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    ITT population

    Subject analysis sets values
    ITT
    Number of subjects
    389
    Age categorical
    Units: Subjects
        <= 60
    248
        > 60
    141
    Age continuous
    Units: months
        median (full range (min-max))
    57 (18 to 69)
    Gender categorical
    Units: Subjects
        Female
    193
        Male
    196
    ISS Stage
    Units: Subjects
        ISS I
    171
        ISS II
    152
        ISS III
    66

    End points

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    End points reporting groups
    Reporting group title
    RD Induction
    Reporting group description
    Patients will start induction treatment with lenalidomide and dexamethasone (RD) for 4 cycles every 28 days: - Lenalidomide will be given orally at the dose of 25 mg/d for 21 days followed by a 7 days rest period (day 22 to 28), - Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15, 22. After 1-2 months from the completion of the last RD cycle, i.v. cyclophosphamide (CY) will be given at the dose of 3 g/m2 followed by G-CSF (5-10 ug/kg/day starting at day 5 until completion of PBSC collection) to collect an adequate number of PBSC (≥ 4 to 10 x 106/kg CD34+ cells). Patients who fail to collect the minimum of 4 x 106/kg CD34+ cells will receive either a second course of CY with higher dose of or G-CSF or it is allowed the association of G-CSF with Plerixafor, as per standard practice of every single institution, for a second mobilization according to physician willing. Patients who fail to collect a minimum of 4 x 106/kg CD34+ will be withdrawn from the study.

    Reporting group title
    CY infusion
    Reporting group description
    After 1-2 months from the completion of the last RD cycle, i.v. cyclophosphamide (CY) will be given at the dose of 3 g/m2 followed by G-CSF (5-10 ug/kg/day starting at day 5 until completion of PBSC collection) to collect an adequate number of PBSC (≥ 4 to 10 x 106/kg CD34+ cells). Patients who fail to collect the minimum of 4 x 106/kg CD34+ cells will receive either a second course of CY with higher dose of or G-CSF or it is allowed the association of G-CSF with Plerixafor, as per standard practice of every single institution, for a second mobilization according to physician willing. Patients who fail to collect a minimum of 4 x 106/kg CD34+ will be withdrawn from the study.
    Reporting group title
    ARM A (CRd)
    Reporting group description
    Patients will start consolidation treatment with the association lenalidomide, cyclophosphamide and dexamethasone (CRD) for 6 cycles every 28 days: - Lenalidomide will be given orally at the dose of 25 mg/d for 21 days followed by a 7 days rest period (day 22 to 28) - Cyclophosphamide will be given orally at the dose of 300 mg/m2 on days 1, 8, 15 - Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15, 22.

    Reporting group title
    ARM B (MEL200)
    Reporting group description
    Patients will start consolidation treatment with melphalan 200 mg/m2 followed by stem cell support (MEL200) for 1 cycle (if at least VGPR was achieved after the 1st MEL200) or 2 cycles (if ≤ PR was achieved after the 1st MEL200) - Melphalan will be given iv at the dose of 200 mg/m2 for 1 day followed by stem cell support. The second MEL200 was performed 120 days after the first if ≤ PR was achieved after the 1st MEL200.
    Reporting group title
    ARM A1 and B1
    Reporting group description
    Arms A1 and B1 will receive lenalidomide at dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28) and Prednisone 50 mg every other day, until relapse.

    Reporting group title
    ARM A2 and B2
    Reporting group description
    Arms A2 and B2 will receive lenalidomide at dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), until relapse.

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    ITT population

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    Defined as time from start of treatment to the first documentation of progressive disease based on the International Uniform Response Criteria, Appendix IV or death due to any cause during the treatment phase.
    End point type
    Primary
    End point timeframe
    from R1 and R2
    End point values
    ARM A (CRd) ARM B (MEL200) ARM A1 and B1 ARM A2 and B2
    Number of subjects analysed
    129
    127
    117
    106
    Units: month
        median (confidence interval 95%)
    23.7 (18.2 to 30)
    36.9 (30.9 to 51.6)
    29.7 (23.5 to 47.6)
    24.3 (18.9 to 38.5)
    Statistical analysis title
    R1 Analysis
    Comparison groups
    ARM A (CRd) v ARM B (MEL200)
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0075
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    0.9
    Variability estimate
    Standard deviation
    Dispersion value
    0.1449
    Statistical analysis title
    R2 Analysis
    Comparison groups
    ARM A1 and B1 v ARM A2 and B2
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1908
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.1
    Variability estimate
    Standard deviation
    Dispersion value
    0.150797

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    Defined as time from start of treatment to death due to any cause.
    End point type
    Secondary
    End point timeframe
    7 years probability
    End point values
    ARM A (CRd) ARM B (MEL200) ARM A1 and B1 ARM A2 and B2
    Number of subjects analysed
    129
    127
    117
    106
    Units: month
        number (confidence interval 95%)
    0.57 (0.48 to 0.67)
    0.67 (0.59 to 0.77)
    0.6 (0.51 to 0.71)
    0.64 (0.55 to 0.76)
    Statistical analysis title
    R1 Analysis
    Comparison groups
    ARM A (CRd) v ARM B (MEL200)
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.035
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    0.97
    Variability estimate
    Standard deviation
    Dispersion value
    0.201867
    Statistical analysis title
    R2 Analysis
    Comparison groups
    ARM A1 and B1 v ARM A2 and B2
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.301
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.95
    Variability estimate
    Standard deviation
    Dispersion value
    0.222775

    Secondary: Time to progression (TTP)

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    End point title
    Time to progression (TTP)
    End point description
    Defined as time from start of treatment to the first documentation of progressive disease or death due to progressive disease during the treatment phase.
    End point type
    Secondary
    End point timeframe
    For R1 and R2
    End point values
    ARM A (CRd) ARM B (MEL200) ARM A1 and B1 ARM A2 and B2
    Number of subjects analysed
    129
    127
    117
    106
    Units: month
        median (confidence interval 95%)
    23.8 (19.2 to 30.6)
    37.2 (30.9 to 51.6)
    29.7 (23.5 to 47.6)
    25 (19.1 to 39.3)
    Statistical analysis title
    R1 Analysis
    Comparison groups
    ARM A (CRd) v ARM B (MEL200)
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0073
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    0.9
    Variability estimate
    Standard deviation
    Dispersion value
    0.146255
    Statistical analysis title
    R2 Analysis
    Comparison groups
    ARM A1 and B1 v ARM A2 and B2
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2012
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.11
    Variability estimate
    Standard deviation
    Dispersion value
    0.151661

    Secondary: VGPR rate

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    End point title
    VGPR rate
    End point description
    Objective overall Response rate (including complete response [CR] and VGPR using the International Uniform Response Criteria, Appendix IV).
    End point type
    Secondary
    End point timeframe
    Overall
    End point values
    ARM A (CRd) ARM B (MEL200)
    Number of subjects analysed
    129
    127
    Units: patients
        >= VGPR
    66
    31
        < VGPR
    63
    96
    Statistical analysis title
    Log rank test
    Comparison groups
    ARM A (CRd) v ARM B (MEL200)
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Fisher exact
    Confidence interval

    Secondary: Time to the next anti-myeloma therapy

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    End point title
    Time to the next anti-myeloma therapy
    End point description
    Time to the next anti-myeloma therapy (defined as time from start of treatment to start of next therapy)
    End point type
    Secondary
    End point timeframe
    from R1 and R2
    End point values
    ARM A (CRd) ARM B (MEL200) ARM A1 and B1 ARM A2 and B2
    Number of subjects analysed
    129
    127
    117
    106
    Units: month
        median (confidence interval 95%)
    30.4 (23.4 to 39.5)
    48.4 (42.8 to 63.3)
    41.6 (32.6 to 63)
    40.6 (27.3 to 48.6)
    Statistical analysis title
    R1 Analysis
    Comparison groups
    ARM A (CRd) v ARM B (MEL200)
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.007
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    0.9
    Variability estimate
    Standard deviation
    Dispersion value
    0.149977
    Statistical analysis title
    R2 Analysis
    Comparison groups
    ARM A1 and B1 v ARM A2 and B2
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4195
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.2
    Variability estimate
    Standard deviation
    Dispersion value
    0.157613

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Per protocol population
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    27
    Reporting groups
    Reporting group title
    Per protocol
    Reporting group description
    -

    Serious adverse events
    Per protocol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    174 / 387 (44.96%)
         number of deaths (all causes)
    176
         number of deaths resulting from adverse events
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute lymphocytic leukaemia
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Adenocarcinoma
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Basosquamous carcinoma
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal cancer
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    6 / 387 (1.55%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Sweat gland tumour
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 387 (0.78%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    5 / 387 (1.29%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    3 / 387 (0.78%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
         subjects affected / exposed
    4 / 387 (1.03%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    7 / 387 (1.81%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    8 / 387 (2.07%)
         occurrences causally related to treatment / all
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 387 (1.03%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 387 (1.29%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression suicidal
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 387 (1.29%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    17 / 387 (4.39%)
         occurrences causally related to treatment / all
    19 / 19
         deaths causally related to treatment / all
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Leukopenia
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 387 (1.03%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    3 / 387 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    3 / 387 (0.78%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Rash macular
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 387 (1.03%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Greater trochanteric pain syndrome
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 387 (0.52%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    7 / 387 (1.81%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 387 (3.36%)
         occurrences causally related to treatment / all
    6 / 13
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Sinobronchitis
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 387 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Per protocol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    354 / 387 (91.47%)
    Investigations
    Transaminases increased
         subjects affected / exposed
    25 / 387 (6.46%)
         occurrences all number
    25
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    84 / 387 (21.71%)
         occurrences all number
    84
    Neutropenia
         subjects affected / exposed
    61 / 387 (15.76%)
         occurrences all number
    61
    Thrombocytopenia
         subjects affected / exposed
    35 / 387 (9.04%)
         occurrences all number
    35
    Leukopenia
         subjects affected / exposed
    31 / 387 (8.01%)
         occurrences all number
    31
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    32 / 387 (8.27%)
         occurrences all number
    32
    Fatigue
         subjects affected / exposed
    29 / 387 (7.49%)
         occurrences all number
    29
    Pyrexia
         subjects affected / exposed
    22 / 387 (5.68%)
         occurrences all number
    22
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    32 / 387 (8.27%)
         occurrences all number
    32
    Nausea
         subjects affected / exposed
    21 / 387 (5.43%)
         occurrences all number
    21
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 387 (5.68%)
         occurrences all number
    22
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    20 / 387 (5.17%)
         occurrences all number
    20

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2010
    Change of sponsor's legal representative.
    30 Sep 2010
    Amendment 1: The request for amendment was made necessary by new evidence emerging regarding the mobilization of peripheral stem cells, the definition of measurable disease, the doses of lenalidomide to be administered to patients with renal insufficiency, and the follow-up of patients with asymptomatic myeloma.
    10 Jan 2011
    Amendment 2: The amendment request was necessary because a substudy was introduced that will evaluate the outcome of minimal residual disease in patients who achieve at least one VGPR after consolidation therapy.
    02 May 2011
    Urgent Amendment ICF v. 2: the urgent substantial amendment regarding the modification to the information sheet/informed consent, for an update on the risks related to the use of Lenalidomide, following the AIFA communication of 6 April 2011 on the “Safety Lenalidomde” emergency.
    25 Jul 2013
    Amendment 3: The request for this amendment was necessary because there was an error in the definition of the parameters needed to size the study. The correction of these parameters did not change the final sizing of the study.
    15 May 2018
    Amendment 4: It was necessary to update the contacts of the Sponsor, the Principal Investigator of the study, pharmacovigilance, as well as update the criteria for evaluating the response of the disease. With this Amendment, the side effects of the drug Lenalidomide, the risks for the fetus and fertility (male and female), the confidentiality of the data and the appendix on the protection of confidentiality were also updated on the Information Sheet and Informed Consent Form.
    28 Jan 2019
    Amendment 5_AC CEC: Adding new drug depot.
    13 Dec 2019
    Amendment 6: It was made because a new version of the IB of the drug Lenalidomide was released; consequently, the updated Informed Consent is transmitted with the new side effects related to the drug Lenalidomide.
    20 Mar 2020
    Urgent Amendment 1: COVID updates.
    27 Oct 2020
    Amendment 7: The request for a substantial amendment was made necessary because a new version of the Investigator’s Brochure for the drug Lenalidomide was released; consequently, the updated Informed Consent with the new side effects related to the drug Lenalidomide is being transmitted. In addition, following the change of name of the Foundation, the drug labels, the SAE and the Pregnancy Form have been updated.
    05 Sep 2023
    Amendment CEC-CET: Change from CEC to CET.
    27 Feb 2024
    Amendment 8: Central laboratory change, study duration updates, and drug information.

    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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