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

    Summary
    EudraCT number
    		 2007-001610-16
    Trial protocol
    		 IT  
    Global end of trial date
    30 Jun 2024

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RV-MM-PI-209
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00551928
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fondazione EMN Italy Onlus
    Sponsor organisation address
    Via Saluzzo 1/A, Torino, Italy, 10126
    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
    04 Dec 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 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 melphalan 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
    20 Nov 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 355
    Country: Number of subjects enrolled
    Israel: 44
    Worldwide total number of subjects
    399
    EEA total number of subjects
    355
    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)
    386
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This is a multicenter, randomized, open label, 2x2 factorial design, study aimed at comparing the efficacy and safety of lenalidomide in combination with low-dose melphalan versus high-dose melphalan followed by stem cell support in newly diagnosed symptomatic MM patients who are 65 years of age or younger.

    Pre-assignment
    Screening details
    		 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 evaluation of inclusion criteria. Subjects who meet all the inclusion criteria will be enrolled.

    Period 1
    Period 1 title
    Induction
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    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/day 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 and 22 every 28 days.
    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/day for 21 days followed by a 7 days rest period (day 22 to 28) for 4 cycles every 28 days

    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 and 22 every 28 days, for 4 cycles every 28 days

    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 4 g/m2 followed by G-CSF (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 CD 34+ cells). Patients who fail to collect the minimum of 4 x 106/kg CD 34+ cells will receive a second course of CY for a second mobilization attempt. Patients who fails to collect a minimum of 4 x 106/kg CD 34+ 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
    4 g/m2

    Number of subjects in period 1
    		Rd Induction CY infusion
    Started
    399
    332
    Completed
    332
    274
    Not completed
    67
    58
         Adverse event, serious fatal
    6
    -
         Consent withdrawn by subject
    4
    7
         Physician decision
    8
    16
         Adverse event, non-fatal
    16
    2
         Lost to follow-up
    2
    -
         Lack of efficacy
    30
    16
         Protocol deviation
    1
    17
    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 (MPR)
    Arm description
    		 Patients will start consolidation treatment with the association of lenalidomide, melphalan and prednisone (MPR) for 6 cycles every 28 days: • Lenalidomide will be given orally at the dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), • Melphalan will be given orally at the dose of 0.18 mg/Kg for 4 days, followed by a 24 days rest period (day 5 to 28) • Prednisone will be given orally at the dose of 2 mg/Kg for 4 days followed by a 24 day rest period (days 5 to 28),
    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 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), for 6 cycles every 28 days

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Melphalan will be given orally at the dose of 0.18 mg/Kg for 4 days, followed by a 24 days rest period (day 5 to 28), for 6 cycles every 28 days

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone will be given orally at the dose of 2 mg/Kg for 4 days followed by a 24 day rest period (days 5 to 28), for 6 cycles every 28 days

    Arm title
    		 ARM B (MEL200)
    Arm description
    		 Patients will start consolidation treatment with melphalan 200 mg/m2 followed by stem cell support (MEL200) for 2 cycles every 4 months (only 1 cycle if the patient reached almost a VGPR after the 1st MEL200): • Melphalan will be given iv at the dose of 200 mg/m2 for 1 day followed by stem cell support and 120 days rest period.
    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 and 120 days rest period.

    Number of subjects in period 2
    		ARM A (MPR) ARM B (MEL200)
    Started
    133
    141
    Completed
    115
    134
    Not completed
    18
    7
         Consent withdrawn by subject
    1
    -
         Physician decision
    1
    -
         Adverse event, non-fatal
    5
    -
         Lost to follow-up
    -
    1
         Lack of efficacy
    10
    6
         Protocol deviation
    1
    -
    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 (no Maint)
    Arm description
    		 No therapy
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 ARM A2 and B2 (R)
    Arm description
    		 Lenalidomide will be given at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period. Each cycle will be repeated every 28 days, until any sign of disease progression (PD).
    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 at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period. Each cycle will be repeated every 28 days, until any sign of disease progression (PD).

    Number of subjects in period 3
    		ARM A1 and B1 (no Maint) ARM A2 and B2 (R)
    Started
    124
    125
    Completed
    3
    4
    Not completed
    121
    121
         Adverse event, serious fatal
    1
    1
         Physician decision
    19
    18
         Consent withdrawn by subject
    8
    15
         Adverse event, non-fatal
    1
    13
         Lost to follow-up
    2
    2
         Lack of efficacy
    89
    68
         Protocol deviation
    1
    4

    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
    		 399 399
    Age categorical
    Units: Subjects
        <=60
    		 194 194
        >60
    		 205 205
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 57 (51 to 61) -
    Gender categorical
    Units: Subjects
        Female
    		 194 194
        Male
    		 205 205
    ISS Stage
    Units: Subjects
        ISS Stage I
    		 204 204
        ISS Stage II
    		 119 119
        ISS Stage III
    		 76 76
    Subject analysis sets

    Subject analysis set title
    ITT R1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat population from Random 1

    Subject analysis set title
    ITT R2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to Treat from R2

    Subject analysis sets values
    		 ITT R1 ITT R2
    Number of subjects
    274
    249
    Age categorical
    Units: Subjects
        <=60
    205
    187
        >60
    69
    62
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    56 (50 to 61)
    56 (49 to 60)
    Gender categorical
    Units: Subjects
        Female
    131
    119
        Male
    143
    130
    ISS Stage
    Units: Subjects
        ISS Stage I
    150
    141
        ISS Stage II
    83
    75
        ISS Stage III
    41
    33

    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/day 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 and 22 every 28 days.

    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 4 g/m2 followed by G-CSF (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 CD 34+ cells). Patients who fail to collect the minimum of 4 x 106/kg CD 34+ cells will receive a second course of CY for a second mobilization attempt. Patients who fails to collect a minimum of 4 x 106/kg CD 34+ will be withdrawn from the study.
    Reporting group title
    ARM A (MPR)
    Reporting group description
    		 Patients will start consolidation treatment with the association of lenalidomide, melphalan and prednisone (MPR) for 6 cycles every 28 days: • Lenalidomide will be given orally at the dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), • Melphalan will be given orally at the dose of 0.18 mg/Kg for 4 days, followed by a 24 days rest period (day 5 to 28) • Prednisone will be given orally at the dose of 2 mg/Kg for 4 days followed by a 24 day rest period (days 5 to 28),

    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 2 cycles every 4 months (only 1 cycle if the patient reached almost a VGPR after the 1st MEL200): • Melphalan will be given iv at the dose of 200 mg/m2 for 1 day followed by stem cell support and 120 days rest period.
    Reporting group title
    ARM A1 and B1 (no Maint)
    Reporting group description
    		 No therapy

    Reporting group title
    ARM A2 and B2 (R)
    Reporting group description
    		 Lenalidomide will be given at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period. Each cycle will be repeated every 28 days, until any sign of disease progression (PD).

    Subject analysis set title
    ITT R1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat population from Random 1

    Subject analysis set title
    ITT R2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to Treat from R2

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    End point type
    Primary
    End point timeframe
    End of trial
    End point values
    		 ARM A (MPR) ARM B (MEL200) ARM A1 and B1 (no Maint) ARM A2 and B2 (R)
    Number of subjects analysed
    133
    141
    124
    125
    Units: month
        median (inter-quartile range (Q1-Q3))
    17 (15 to 21)
    33 (29 to 42)
    15 (12 to 20)
    25 (20 to 42)
    Statistical analysis title
    		 Log rank test
    Comparison groups
    ARM B (MEL200) v ARM A (MPR)
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.74
    Variability estimate
    Standard deviation
    Dispersion value
    0.13
    Statistical analysis title
    		 Log rank test
    Comparison groups
    ARM A1 and B1 (no Maint) v ARM A2 and B2 (R)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.86
    Variability estimate
    Standard deviation
    Dispersion value
    0.14

    Secondary: time to progression (TTP)

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    End point title
    		 time to progression (TTP)
    End point description
    End point type
    Secondary
    End point timeframe
    End of trial
    End point values
    		 ARM A (MPR) ARM B (MEL200) ARM A1 and B1 (no Maint) ARM A2 and B2 (R)
    Number of subjects analysed
    133
    141
    124
    125
    Units: month
        median (confidence interval 95%)
    17 (16 to 21)
    36 (30 to 47)
    15 (12 to 21)
    26 (21 to 43)
    Statistical analysis title
    		 Log rank test
    Comparison groups
    ARM A (MPR) v ARM B (MEL200)
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.71
    Variability estimate
    Standard deviation
    Dispersion value
    0.13
    Statistical analysis title
    		 Log rank test
    Comparison groups
    ARM A1 and B1 (no Maint) v ARM A2 and B2 (R)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.84
    Variability estimate
    Standard deviation
    Dispersion value
    0.14

    Secondary: time to next therapy (TNT)

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    End point title
    		 time to next therapy (TNT)
    End point description
    End point type
    Secondary
    End point timeframe
    End of trial
    End point values
    		 ARM A (MPR) ARM B (MEL200) ARM A1 and B1 (no Maint) ARM A2 and B2 (R)
    Number of subjects analysed
    133
    141
    124
    125
    Units: month
        median (confidence interval 95%)
    23 (21 to 29)
    42 (36 to 56)
    22 (17 to 28)
    37 (26 to 54)
    Statistical analysis title
    		 Log rank test
    Comparison groups
    ARM A (MPR) v ARM B (MEL200)
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.74
    Variability estimate
    Standard deviation
    Dispersion value
    0.14
    Statistical analysis title
    		 Log rank test
    Comparison groups
    ARM A1 and B1 (no Maint) v ARM A2 and B2 (R)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.79
    Variability estimate
    Standard deviation
    Dispersion value
    0.15

    Secondary: overall survival (OS)

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    End point title
    		 overall survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    End of trial - Probability at 96 months
    End point values
    		 ARM A (MPR) ARM B (MEL200) ARM A1 and B1 (no Maint) ARM A2 and B2 (R)
    Number of subjects analysed
    133
    141
    124
    125
    Units: month
        number (confidence interval 95%)
    0.47 (0.37 to 0.59)
    0.58 (0.49 to 0.68)
    0.56 (0.47 to 0.68)
    0.53 (0.44 to 0.65)
    Statistical analysis title
    		 Log rank test
    Comparison groups
    ARM A (MPR) v ARM B (MEL200)
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.054
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.01
    Variability estimate
    Standard deviation
    Dispersion value
    0.19
    Statistical analysis title
    		 Log rank test
    Comparison groups
    ARM A2 and B2 (R) v ARM A1 and B1 (no Maint)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.73
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.4
    Variability estimate
    Standard deviation
    Dispersion value
    0.21

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Per protocol
    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
    		 Per protocol

    Serious adverse events
    		 Per protocol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 399 (9.52%)
         number of deaths (all causes)
    176
         number of deaths resulting from adverse events
    19
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Basal cell carcinoma
         subjects affected / exposed
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    4 / 399 (1.00%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Colon cancer
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Colorectal adenocarcinoma
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal carcinoma
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Metastases to liver
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    2 / 2
    Ovarian adenoma
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour flare
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Uterine cancer
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Superficial vein thrombosis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Coronary artery bypass
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileostomy
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incisional hernia repair
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Jaw operation
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meniscus removal
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal stabilisation
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroidectomy
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Umbilical hernia repair
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vertebroplasty
         subjects affected / exposed
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyrexia
         subjects affected / exposed
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Obstructive sleep apnoea syndrome
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Respiratory failure
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood pressure diastolic increased
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Acute myocardial infarction
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cardiac arrest
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 399 (0.25%)
         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
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cholecystitis
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Renal failure
         subjects affected / exposed
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholangitis infective
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Enterobacter pneumonia
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster cutaneous disseminated
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    17 / 399 (4.26%)
         occurrences causally related to treatment / all
    10 / 18
         deaths causally related to treatment / all
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 2
    Staphylococcal infection
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Tooth abscess
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 399 (0.25%)
         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
    379 / 399 (94.99%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 399 (5.26%)
         occurrences all number
    21
    Blood creatinine increased
         subjects affected / exposed
    21 / 399 (5.26%)
         occurrences all number
    21
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    29 / 399 (7.27%)
         occurrences all number
    29
    Neuropathy peripheral
         subjects affected / exposed
    22 / 399 (5.51%)
         occurrences all number
    22
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    331 / 399 (82.96%)
         occurrences all number
    331
    Anaemia
         subjects affected / exposed
    309 / 399 (77.44%)
         occurrences all number
    309
    Thrombocytopenia
         subjects affected / exposed
    290 / 399 (72.68%)
         occurrences all number
    290
    Febrile neutropenia
         subjects affected / exposed
    28 / 399 (7.02%)
         occurrences all number
    28
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    149 / 399 (37.34%)
         occurrences all number
    149
    Fatigue
         subjects affected / exposed
    94 / 399 (23.56%)
         occurrences all number
    94
    Asthenia
         subjects affected / exposed
    69 / 399 (17.29%)
         occurrences all number
    69
    Mucosal inflammation
         subjects affected / exposed
    57 / 399 (14.29%)
         occurrences all number
    57
    Pain
         subjects affected / exposed
    37 / 399 (9.27%)
         occurrences all number
    37
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    87 / 399 (21.80%)
         occurrences all number
    87
    Nausea
         subjects affected / exposed
    81 / 399 (20.30%)
         occurrences all number
    81
    Leukopenia
         subjects affected / exposed
    60 / 399 (15.04%)
         occurrences all number
    60
    Vomiting
         subjects affected / exposed
    60 / 399 (15.04%)
         occurrences all number
    60
    Constipation
         subjects affected / exposed
    43 / 399 (10.78%)
         occurrences all number
    43
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    32 / 399 (8.02%)
         occurrences all number
    32
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    62 / 399 (15.54%)
         occurrences all number
    62
    Erythema
         subjects affected / exposed
    42 / 399 (10.53%)
         occurrences all number
    42
    Pruritus
         subjects affected / exposed
    25 / 399 (6.27%)
         occurrences all number
    25
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    27 / 399 (6.77%)
         occurrences all number
    27
    Bone pain
         subjects affected / exposed
    27 / 399 (6.77%)
         occurrences all number
    27
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    23 / 399 (5.76%)
         occurrences all number
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2008
    Amendment 1: Update to examinations, risks and benefits, and informed consent.
    30 Nov 2009
    Amendment 2: Update on protocol procedures and drug risks.
    27 Jul 2010
    Amendment Sponsor: Change of sponsor's legal representative.
    27 Apr 2011
    Amendment ICF v.4: Urgent drug side effects update.
    30 Apr 2013
    Amendment 3: Statistical updates.
    16 May 2017
    Amendment 4: Updates: Sponsor contacts, disease assessment, and drug side effects.
    05 Feb 2019
    Amendment 5: Adding new drug depot and implementing pregnancy prevention program.
    18 Jun 2019
    Amendment 6: Side effects update.
    20 Mar 2020
    Urgent Amendment 1: COVID updates.
    03 Aug 2020
    Amendment 7: Side effects update and Sponsor name.
    30 Oct 2023
    Amendment CEC-CET: Change from CEC to CET.
    05 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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/17785703
    http://www.ncbi.nlm.nih.gov/pubmed/21637283
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