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    Clinical Trial Results:
    Lenalidomide (Revlimid®), Adriamycin and Dexamethasone (RAD) as an Induction Therapy in Newly Diagnosed Multiple Myeloma Followed by a Risk-Defined Transplant Strategy and Lenalidomide Maintenance – A Multicenter Phase II Trial by Deutsche Studiengruppe Multiples Myelom

    Summary
    EudraCT number
    		 2008-000007-28
    Trial protocol
    		 DE  
    Global end of trial date
    20 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jul 2022
    First version publication date
    10 Jul 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DSMMXII
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00925821
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Wuerzburg University Hospital, Dept. of Hematology and Oncology, Center for Internal Medicine (ZIM)
    Sponsor organisation address
    Oberduerrbacher Str. 6, Wuerzburg, Germany, 97080
    Public contact
    Wuerzburg University Hospital Dept. of Hematology and Oncology Center for Internal Medicine (ZIM), Wuerzburg University Hospital Dept. of Hematology and Oncology Center for Internal Medicine (ZIM), +49 93120135156,
    Scientific contact
    Wuerzburg University Hospital Dept. of Hematology and Oncology Center for Internal Medicine (ZIM), Wuerzburg University Hospital Dept. of Hematology and Oncology Center for Internal Medicine (ZIM), +49 93120135156,
    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
    25 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine efficacy of the novel induction regimen (combination of lenalidomide, adriamycin, and dexamethasone; RAD) followed by a risk-defined transplant strategy and subsequent lenalidomide maintenance in patients with symptomatic multiple myeloma
    Protection of trial subjects
    Safety monitoring (adverse events, serious adverse events, adverse drug reactions) and continuous assessment of laboratory values (hematology and biochemistry assessments). Subject insurance according to §40 Article 1 No. 8 and Article 3 German Drug Law had been obtained.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Aug 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 190
    Worldwide total number of subjects
    190
    EEA total number of subjects
    190
    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)
    183
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient (FPFV) was enrolled on 18th August 2009. Last-patient-last visit (LPLV) took place on 20th April 2016. 215 patients were recruited by 17 clincial sites in Germany. 25 patients did not enter the treatment phase, i.e. 190 received treatment. Data are available for these 190 patients.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility. Screning had to take place within 28 days prior to initiation of therapy.

    Period 1
    Period 1 title
    Screening phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All patients enrolled
    Arm description
    		 All screened patients, including n=25 patients not treated.
    Arm type
    		 Screened

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		All patients enrolled
    Started
    190
    Completed
    190
    Period 2
    Period 2 title
    RAD phase
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 RAD chemotherapy
    Arm description
    		 Induction therapy with four 28-day cycles of RAD (lenalidomide, adriamycin, dexamethasone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg / day, day 1-21

    Investigational medicinal product name
    Adriamycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    9 mg/m2 for four consecutive days

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg po, day 1-4 & day 17-20.

    Investigational medicinal product name
    Pegfilgrastim
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    6 mg day 6 (+2), single dose

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Records of all subjects who signed an ICF, i.e. all subjects screened, were kept at the investigational sites. Data were documented in the CRF from the start of the RAD phase only. Complete BL data are therefore available for analysis the FAS/Safety set only.
    Number of subjects in period 2
    		RAD chemotherapy
    Started
    190
    Completed
    157
    Not completed
    33
         Consent withdrawn by subject, Lost to follow-up
    1
         Consent withdrawn by subject
    5
         Adverse event, non-fatal
    11
         Other
    4
         Progression
    11
         Lost to follow-up
    1
    Period 3
    Period 3 title
    Transplantation phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 autograft-allograft arm
    Arm description
    		 An allogeneic stem cell graft was offered to subjects displaying features that have previously been associated with an adverse prognosis for whom a fully HLAidentical sibling or unrelated donor is available.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cyclophosphamide/etoposide stem cell mobilization
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cyclophosphamide 2500 mg/m2 iv, day 1 (3 h infusion) Etoposide 200 mg/m2 iv, days 1-3 (1 h infusion)

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    100 mg/m2/day, day -3 and -2

    Investigational medicinal product name
    Treosulfan/fludarabine conditioning
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Treosulfan 14 g/m2/d, iv, day -6 to -4 Fludarabine 30 mg/m2/d, iv, day -6 to -4

    Arm title
    		 autograft-autograft arm
    Arm description
    		 All patients not displaying risk parameters were assigned to be of “very favorable” risk. They were not offered an allogeneic graft, but received a second cycle of high-dose melphalan and autologous PBPC transplantation together with those of the high-risk patients without a donor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cyclophosphamide/etoposide stem cell mobilization
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cyclophosphamide 2500 mg/m2 iv, day 1 (3 h infusion) Etoposide 200 mg/m2 iv, days 1-3 (1 h infusion)

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    100 mg/m2/day, day -3 and -2

    Arm title
    		 No second SCT
    Arm description
    		 Patients who did not receive a second stem cell transplant (SCT)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		autograft-allograft arm autograft-autograft arm No second SCT
    Started
    49
    84
    24
    Completed
    22
    77
    0
    Not completed
    27
    7
    24
         Consent withdrawn by subject
    1
    -
    3
         Adverse event, Progression, Death
    1
    -
    -
         Adverse event, non-fatal
    2
    1
    1
         Other
    13
    3
    6
         Death
    2
    1
    1
         Progression
    2
    -
    9
         AE, Further criteria for next phase not fulfilled
    1
    -
    -
         Further criteria for next phase not fulfilled
    5
    1
    2
         Protocol deviation
    -
    1
    2
    Period 4
    Period 4 title
    Maintenance phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 autograft-allograft arm
    Arm description
    		 An allogeneic stem cell graft was offered to subjects displaying features that have previously been associated with an adverse prognosis for whom a fully HLAidentical sibling or unrelated donor is available. Lenalidomide maintenance therapy for a maximum duration of 12 months was instituted in all patients completing both transplantations.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In patients with an allogeneic transplant, lenalidomide maintenance was given at a dose of 5 mg once daily continuously (reduced to 5 mg on day 1- day 21 of a 28-day cycle from Amendment 5 onwards). Lenalidomide maintenance therapy was given for a maximum of 12 months or until progression.

    Arm title
    		 autograft-autograft arm
    Arm description
    		 All patients not displaying risk parameters were assigned to be of “very favorable” risk. They were not offered an allogeneic graft, but received a second cycle of high-dose melphalan and autologous PBPC transplantation together with those of the high-risk patients without a donor. Lenalidomide maintenance therapy for a maximum duration of 12 months is instituted in all patients completing both transplantations.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients with a tandem autoSCT received lenalidomide maintenance therapy at a dose of 10 mg continuously once daily. Lenalidomide maintenance therapy was given for a maximum of 12 months or until progression.

    Number of subjects in period 4
    		autograft-allograft arm autograft-autograft arm
    Started
    22
    77
    Completed
    8
    54
    Not completed
    14
    23
         Adverse event, serious fatal
    1
    -
         Adverse event, Other
    -
    2
         Consent withdrawn by subject
    -
    2
         Adverse event, non-fatal
    2
    10
         Death
    1
    2
         Other
    7
    2
         Progression
    3
    4
         Adverse event, Death
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RAD chemotherapy
    Reporting group description
    		 Induction therapy with four 28-day cycles of RAD (lenalidomide, adriamycin, dexamethasone).

    Reporting group values
    		 RAD chemotherapy Total
    Number of subjects
    		 190 190
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 189 189
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 55.0 (30.0 to 66.0) -
    Gender categorical
    Units: Subjects
        Female
    		 64 64
        Male
    		 126 126
    Subject analysis sets

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who have received at least one dose of RAD induction chemotherapy were included in the safety analysis. The safety set was used for all baseline and safety parameters.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis included all patients of the safety set as full analysis set. The full analysis set was used for all efficacy parameters.

    Subject analysis set title
    FAS - Auto-allo SCT
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    An allogeneic stem cell graft was offered to subjects displaying features that have previously been associated with an adverse prognosis for whom a fully HLAidentical sibling or unrelated donor is available.

    Subject analysis set title
    FAS - Auto-auto SCT
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients not displaying risk parameters were assigned to be of “very favorable” risk. They were not offered an allogeneic graft, but received a second cycle of high-dose melphalan and autologous PBPC transplantation together with those of the high-risk patients without a donor.

    Subject analysis set title
    FAS - no second SCT
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who did not receive a second stem cell transplant (SCT)

    Subject analysis set title
    FAS for statistical analysis of primary endpoint.
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    For formal reasons, a second FAS needed to be defined since EudraCT does not support the statistical analysis of single-arm studies, see FAQ 82.

    Subject analysis sets values
    		 Safety Set Full Analysis Set (FAS) FAS - Auto-allo SCT FAS - Auto-auto SCT FAS - no second SCT FAS for statistical analysis of primary endpoint.
    Number of subjects
    190
    190
    49
    84
    57
    190
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    189
        From 65-84 years
    1
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    54.2 (7.2 to )
    Gender categorical
    Units: Subjects
        Female
    64
        Male
    126

    End points

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    End points reporting groups
    Reporting group title
    All patients enrolled
    Reporting group description
    		 All screened patients, including n=25 patients not treated.
    Reporting group title
    RAD chemotherapy
    Reporting group description
    		 Induction therapy with four 28-day cycles of RAD (lenalidomide, adriamycin, dexamethasone).
    Reporting group title
    autograft-allograft arm
    Reporting group description
    		 An allogeneic stem cell graft was offered to subjects displaying features that have previously been associated with an adverse prognosis for whom a fully HLAidentical sibling or unrelated donor is available.

    Reporting group title
    autograft-autograft arm
    Reporting group description
    		 All patients not displaying risk parameters were assigned to be of “very favorable” risk. They were not offered an allogeneic graft, but received a second cycle of high-dose melphalan and autologous PBPC transplantation together with those of the high-risk patients without a donor.

    Reporting group title
    No second SCT
    Reporting group description
    		 Patients who did not receive a second stem cell transplant (SCT)
    Reporting group title
    autograft-allograft arm
    Reporting group description
    		 An allogeneic stem cell graft was offered to subjects displaying features that have previously been associated with an adverse prognosis for whom a fully HLAidentical sibling or unrelated donor is available. Lenalidomide maintenance therapy for a maximum duration of 12 months was instituted in all patients completing both transplantations.

    Reporting group title
    autograft-autograft arm
    Reporting group description
    		 All patients not displaying risk parameters were assigned to be of “very favorable” risk. They were not offered an allogeneic graft, but received a second cycle of high-dose melphalan and autologous PBPC transplantation together with those of the high-risk patients without a donor. Lenalidomide maintenance therapy for a maximum duration of 12 months is instituted in all patients completing both transplantations.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who have received at least one dose of RAD induction chemotherapy were included in the safety analysis. The safety set was used for all baseline and safety parameters.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis included all patients of the safety set as full analysis set. The full analysis set was used for all efficacy parameters.

    Subject analysis set title
    FAS - Auto-allo SCT
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    An allogeneic stem cell graft was offered to subjects displaying features that have previously been associated with an adverse prognosis for whom a fully HLAidentical sibling or unrelated donor is available.

    Subject analysis set title
    FAS - Auto-auto SCT
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients not displaying risk parameters were assigned to be of “very favorable” risk. They were not offered an allogeneic graft, but received a second cycle of high-dose melphalan and autologous PBPC transplantation together with those of the high-risk patients without a donor.

    Subject analysis set title
    FAS - no second SCT
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who did not receive a second stem cell transplant (SCT)

    Subject analysis set title
    FAS for statistical analysis of primary endpoint.
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    For formal reasons, a second FAS needed to be defined since EudraCT does not support the statistical analysis of single-arm studies, see FAQ 82.

    Primary: Response rate (sCR, CR, or VGPR)

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    End point title
    		 Response rate (sCR, CR, or VGPR)
    End point description
    Response rate (sCR, CR, or VGPR) at the start of scheduled lenalidomide maintenance. For patients with NE or missing, e.g. due to termination before the 3rd restaging, the data of the last assessment before restaging 3 were imputed. The reposnse rate without data imputation, i.e. when NE or missing are analysed as non-responder, is 89/190, 46.8% (90%-CI 40.7, 53.1).
    End point type
    Primary
    End point timeframe
    3rd restaging after transplantation phase, at the start of maintenance therapy.
    End point values
    		 Full Analysis Set (FAS) FAS for statistical analysis of primary endpoint.
    Number of subjects analysed
    190
    190
    Units: Response rate (%)
        number (confidence interval 90%)
    62.6 (56.5 to 68.5)
    62.6 (56.5 to 68.5)
    Statistical analysis title
    		 Primary endpoint analysis
    Statistical analysis description
    The primary objective of the study was to demonstrate with a power of 90% and a one-sided type I error rate of α=0.05 that the true response rate was at least 47.5%.
    Comparison groups
    Full Analysis Set (FAS) v FAS for statistical analysis of primary endpoint.
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Confidence interval
    Point estimate
    46.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 40.7
         upper limit
    		 53.1
    Notes
    [1] - The treatment strategy was defined as promising if the lower boundary of the two-sided 90% confidence interval (CI) was equal or above 47.5%.

    Secondary: Other efficacy: objective response (sCR, CR, VGPR, or PR)

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    End point title
    		 Other efficacy: objective response (sCR, CR, VGPR, or PR)
    End point description
    The objective response rate (ORR) was defined as the proportion of patients with response sCR, CR, VGPR or PR at the respective restaging .
    End point type
    Secondary
    End point timeframe
    At the first restaging after RAD induction treatment; at the third restaging (before the start of scheduled maintenance therapy).
    End point values
    		 autograft-allograft arm autograft-autograft arm No second SCT RAD chemotherapy Full Analysis Set (FAS)
    Number of subjects analysed
    49
    84
    24 [2]
    190
    190
    Units: ORR (%)
        number (confidence interval 90%)
    65.3 (52.6 to 76.5)
    94.1 (87.9 to 97.6)
    0.0 (0 to 0)
    74.2 (68.5 to 79.4)
    58.4 (52.2 to 64.4)
    Notes
    [2] - Over all, n=57 non-responders, including NE and missing; n=24 patients received CE mobilisation.
    No statistical analyses for this end point

    Secondary: Other efficacy: progression-free survival (PFS)

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    End point title
    		 Other efficacy: progression-free survival (PFS)
    End point description
    PFS was defined as the time from day 1 of the first RAD cycle to the date of first progression or death of any cause, whichever occurred first. Patients without event were censored with the last date known to be progression-free.
    End point type
    Secondary
    End point timeframe
    From day 1 of the first RAD cycle to the date of first progression or death of any cause, whichever occurred first.
    End point values
    		 Full Analysis Set (FAS) FAS - Auto-allo SCT FAS - Auto-auto SCT FAS - no second SCT
    Number of subjects analysed
    190
    49
    84
    57
    Units: PFS (months)
        median (confidence interval 90%)
    47.0 (38.9 to 54.6)
    46.0 (28.4 to 58.1)
    9999 (55.5 to 9999)
    10.9 (6.5 to 18.1)
    No statistical analyses for this end point

    Secondary: Other efficacy: overall survival (OS)

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    End point title
    		 Other efficacy: overall survival (OS)
    End point description
    Overall survival was defined as the time from first day of administration of the study drugs to the date of death of any cause. All patients without event were censored with the last date known to be alive.
    End point type
    Secondary
    End point timeframe
    From first day of administration of the study drugs to the date of death of any cause.
    End point values
    		 Full Analysis Set (FAS) FAS - Auto-allo SCT FAS - Auto-auto SCT FAS - no second SCT
    Number of subjects analysed
    190
    49
    84
    57
    Units: OS (months)
        median (confidence interval 90%)
    83.9 (76.6 to 9999)
    0000 (0000 to 9999)
    83.9 (76.6 to 9999)
    50.8 (40.5 to 9999)
    No statistical analyses for this end point

    Secondary: Other efficacy: time to next anti-myeloma therapy (TTNT)

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    End point title
    		 Other efficacy: time to next anti-myeloma therapy (TTNT)
    End point description
    Time to next anti-myeloma therapy was defined as the time from last treatment during study treatment to start of subsequent anti-myeloma therapy. All patients without event were censored with the last date known to be alive.
    End point type
    Secondary
    End point timeframe
    From last treatment during study treatment to start of subsequent anti-myeloma therapy.
    End point values
    		 Full Analysis Set (FAS) FAS - Auto-allo SCT FAS - Auto-auto SCT FAS - no second SCT
    Number of subjects analysed
    190
    49
    84
    57
    Units: TTNT (months)
        median (confidence interval 90%)
    9999 (35.5 to 9999)
    9999 (24.5 to 9999)
    9999 (0000 to 9999)
    4.1 (2.3 to 22.5)
    No statistical analyses for this end point

    Secondary: Adverse events

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    End point title
    		 Adverse events
    End point description
    Incidence of adverse events taking into account type, severity, and relationship to study Treatment.
    End point type
    Secondary
    End point timeframe
    AEs were recorded continuously from the first day of administration of study medication during RAD induction therapy until 28 days after the last administration of the study drugs.
    End point values
    		 Safety Set
    Number of subjects analysed
    190
    Units: Patients
        TEAEs total
    190
        TEAEs related to RAD/lenalidomide
    189
        TEAEs NCI-CTCAE grade 3-5
    175
        TEAEs grade 3-5 related to RAD/lenalidomide
    126
        TEAEs NCI-CTCAE grade 5
    8
        TEAEs grade 5 related to RAD/lenalidomide
    3
        TESAEs total
    122
        TESAEs related to RAD/lenalidomide
    83
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reporting started with screening and ended with the final safety assessment which took place about 28 days after last study drug administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Safety set
    Reporting group description
    		 All patients who have received at least one dose of RAD induction chemotherapy were included in the safety analysis.

    Serious adverse events
    		 Safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    122 / 190 (64.21%)
         number of deaths (all causes)
    8
         number of deaths resulting from adverse events
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Lymphoproliferative disorder
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    6 / 190 (3.16%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Inguinal hernia repair
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    19 / 190 (10.00%)
         occurrences causally related to treatment / all
    17 / 25
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Granuloma
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Chest pain
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    Acute graft versus host disease in skin
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute graft versus host disease in liver
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute graft versus host disease in intestine
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute psychosis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcus test positive
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Simplex virus test positive
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy test positive
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac output decreased
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Myopericarditis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Paresis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Epilepsy
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    10 / 190 (5.26%)
         occurrences causally related to treatment / all
    6 / 11
         deaths causally related to treatment / all
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 190 (2.63%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 190 (2.63%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic fibrosis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Purpura
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure acute
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 190 (2.11%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Varicella
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 190 (1.58%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 190 (2.63%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    1 / 2
    Respiratory tract infection
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia primary atypical
         subjects affected / exposed
    5 / 190 (2.63%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    14 / 190 (7.37%)
         occurrences causally related to treatment / all
    6 / 16
         deaths causally related to treatment / all
    0 / 1
    Pertussis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    7 / 190 (3.68%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    5 / 190 (2.63%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    2 / 190 (1.05%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    5 / 190 (2.63%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    4 / 190 (2.11%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    188 / 190 (98.95%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    16 / 190 (8.42%)
         occurrences all number
    21
    Hypertension
         subjects affected / exposed
    27 / 190 (14.21%)
         occurrences all number
    40
    Flushing
         subjects affected / exposed
    22 / 190 (11.58%)
         occurrences all number
    31
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    100 / 190 (52.63%)
         occurrences all number
    200
    Pain
         subjects affected / exposed
    12 / 190 (6.32%)
         occurrences all number
    17
    Oedema peripheral
         subjects affected / exposed
    84 / 190 (44.21%)
         occurrences all number
    186
    Oedema
         subjects affected / exposed
    30 / 190 (15.79%)
         occurrences all number
    52
    Mucosal inflammation
         subjects affected / exposed
    68 / 190 (35.79%)
         occurrences all number
    123
    Influenza like illness
         subjects affected / exposed
    20 / 190 (10.53%)
         occurrences all number
    29
    Feeling cold
         subjects affected / exposed
    15 / 190 (7.89%)
         occurrences all number
    18
    Fatigue
         subjects affected / exposed
    123 / 190 (64.74%)
         occurrences all number
    345
    Face oedema
         subjects affected / exposed
    12 / 190 (6.32%)
         occurrences all number
    14
    Chills
         subjects affected / exposed
    27 / 190 (14.21%)
         occurrences all number
    40
    Chest pain
         subjects affected / exposed
    22 / 190 (11.58%)
         occurrences all number
    23
    Catheter site pain
         subjects affected / exposed
    11 / 190 (5.79%)
         occurrences all number
    14
    Catheter site erythema
         subjects affected / exposed
    18 / 190 (9.47%)
         occurrences all number
    23
    Asthenia
         subjects affected / exposed
    25 / 190 (13.16%)
         occurrences all number
    32
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    12 / 190 (6.32%)
         occurrences all number
    15
    Oropharyngeal pain
         subjects affected / exposed
    45 / 190 (23.68%)
         occurrences all number
    61
    Hiccups
         subjects affected / exposed
    20 / 190 (10.53%)
         occurrences all number
    35
    Epistaxis
         subjects affected / exposed
    26 / 190 (13.68%)
         occurrences all number
    32
    Dyspnoea exertional
         subjects affected / exposed
    21 / 190 (11.05%)
         occurrences all number
    28
    Dyspnoea
         subjects affected / exposed
    30 / 190 (15.79%)
         occurrences all number
    41
    Dysphonia
         subjects affected / exposed
    14 / 190 (7.37%)
         occurrences all number
    14
    Cough
         subjects affected / exposed
    68 / 190 (35.79%)
         occurrences all number
    120
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    23 / 190 (12.11%)
         occurrences all number
    36
    Restlessness
         subjects affected / exposed
    20 / 190 (10.53%)
         occurrences all number
    26
    Depression
         subjects affected / exposed
    14 / 190 (7.37%)
         occurrences all number
    16
    Investigations
    Weight increased
         subjects affected / exposed
    36 / 190 (18.95%)
         occurrences all number
    117
    Weight decreased
         subjects affected / exposed
    32 / 190 (16.84%)
         occurrences all number
    39
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    32 / 190 (16.84%)
         occurrences all number
    53
    C-reactive protein increased
         subjects affected / exposed
    42 / 190 (22.11%)
         occurrences all number
    94
    Body temperature increased
         subjects affected / exposed
    18 / 190 (9.47%)
         occurrences all number
    21
    Blood pressure increased
         subjects affected / exposed
    29 / 190 (15.26%)
         occurrences all number
    56
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 190 (11.05%)
         occurrences all number
    46
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    13 / 190 (6.84%)
         occurrences all number
    15
    Nervous system disorders
    Tremor
         subjects affected / exposed
    29 / 190 (15.26%)
         occurrences all number
    44
    Somnolence
         subjects affected / exposed
    16 / 190 (8.42%)
         occurrences all number
    18
    Polyneuropathy
         subjects affected / exposed
    25 / 190 (13.16%)
         occurrences all number
    30
    Paraesthesia
         subjects affected / exposed
    33 / 190 (17.37%)
         occurrences all number
    42
    Hypoaesthesia
         subjects affected / exposed
    19 / 190 (10.00%)
         occurrences all number
    24
    Headache
         subjects affected / exposed
    81 / 190 (42.63%)
         occurrences all number
    200
    Dysgeusia
         subjects affected / exposed
    46 / 190 (24.21%)
         occurrences all number
    59
    Dizziness
         subjects affected / exposed
    66 / 190 (34.74%)
         occurrences all number
    107
    Ageusia
         subjects affected / exposed
    10 / 190 (5.26%)
         occurrences all number
    11
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    61 / 190 (32.11%)
         occurrences all number
    197
    Neutropenia
         subjects affected / exposed
    57 / 190 (30.00%)
         occurrences all number
    147
    Lymphopenia
         subjects affected / exposed
    11 / 190 (5.79%)
         occurrences all number
    34
    Leukopenia
         subjects affected / exposed
    79 / 190 (41.58%)
         occurrences all number
    278
    Febrile neutropenia
         subjects affected / exposed
    34 / 190 (17.89%)
         occurrences all number
    45
    Anaemia
         subjects affected / exposed
    84 / 190 (44.21%)
         occurrences all number
    248
    Eye disorders
    Visual impairment
         subjects affected / exposed
    15 / 190 (7.89%)
         occurrences all number
    17
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    78 / 190 (41.05%)
         occurrences all number
    192
    Tongue coated
         subjects affected / exposed
    10 / 190 (5.26%)
         occurrences all number
    14
    Stomatitis
         subjects affected / exposed
    23 / 190 (12.11%)
         occurrences all number
    36
    Oedema mouth
         subjects affected / exposed
    13 / 190 (6.84%)
         occurrences all number
    17
    Nausea
         subjects affected / exposed
    124 / 190 (65.26%)
         occurrences all number
    377
    Gastrointestinal pain
         subjects affected / exposed
    24 / 190 (12.63%)
         occurrences all number
    31
    Dysphagia
         subjects affected / exposed
    25 / 190 (13.16%)
         occurrences all number
    31
    Dyspepsia
         subjects affected / exposed
    48 / 190 (25.26%)
         occurrences all number
    61
    Dry mouth
         subjects affected / exposed
    12 / 190 (6.32%)
         occurrences all number
    16
    Diarrhoea
         subjects affected / exposed
    129 / 190 (67.89%)
         occurrences all number
    307
    Constipation
         subjects affected / exposed
    96 / 190 (50.53%)
         occurrences all number
    189
    Abdominal pain upper
         subjects affected / exposed
    31 / 190 (16.32%)
         occurrences all number
    49
    Abdominal pain
         subjects affected / exposed
    28 / 190 (14.74%)
         occurrences all number
    32
    Abdominal distension
         subjects affected / exposed
    28 / 190 (14.74%)
         occurrences all number
    37
    Abdominal discomfort
         subjects affected / exposed
    37 / 190 (19.47%)
         occurrences all number
    45
    Skin and subcutaneous tissue disorders
    Rash pruritic
         subjects affected / exposed
    20 / 190 (10.53%)
         occurrences all number
    24
    Rash
         subjects affected / exposed
    73 / 190 (38.42%)
         occurrences all number
    113
    Pruritus
         subjects affected / exposed
    50 / 190 (26.32%)
         occurrences all number
    63
    Petechiae
         subjects affected / exposed
    21 / 190 (11.05%)
         occurrences all number
    23
    Night sweats
         subjects affected / exposed
    56 / 190 (29.47%)
         occurrences all number
    86
    Hyperhidrosis
         subjects affected / exposed
    36 / 190 (18.95%)
         occurrences all number
    50
    Erythema
         subjects affected / exposed
    56 / 190 (29.47%)
         occurrences all number
    88
    Dry skin
         subjects affected / exposed
    42 / 190 (22.11%)
         occurrences all number
    48
    Alopecia
         subjects affected / exposed
    29 / 190 (15.26%)
         occurrences all number
    31
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    10 / 190 (5.26%)
         occurrences all number
    10
    Nocturia
         subjects affected / exposed
    13 / 190 (6.84%)
         occurrences all number
    23
    Dysuria
         subjects affected / exposed
    21 / 190 (11.05%)
         occurrences all number
    26
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    36 / 190 (18.95%)
         occurrences all number
    57
    Myalgia
         subjects affected / exposed
    19 / 190 (10.00%)
         occurrences all number
    20
    Musculoskeletal pain
         subjects affected / exposed
    27 / 190 (14.21%)
         occurrences all number
    35
    Musculoskeletal chest pain
         subjects affected / exposed
    12 / 190 (6.32%)
         occurrences all number
    13
    Muscle spasms
         subjects affected / exposed
    53 / 190 (27.89%)
         occurrences all number
    90
    Bone pain
         subjects affected / exposed
    77 / 190 (40.53%)
         occurrences all number
    137
    Back pain
         subjects affected / exposed
    79 / 190 (41.58%)
         occurrences all number
    117
    Arthralgia
         subjects affected / exposed
    34 / 190 (17.89%)
         occurrences all number
    58
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    17 / 190 (8.95%)
         occurrences all number
    20
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 190 (12.11%)
         occurrences all number
    41
    Staphylococcal infection
         subjects affected / exposed
    12 / 190 (6.32%)
         occurrences all number
    12
    Sinusitis
         subjects affected / exposed
    12 / 190 (6.32%)
         occurrences all number
    15
    Respiratory tract infection
         subjects affected / exposed
    22 / 190 (11.58%)
         occurrences all number
    32
    Oral herpes
         subjects affected / exposed
    20 / 190 (10.53%)
         occurrences all number
    24
    Oral candidiasis
         subjects affected / exposed
    17 / 190 (8.95%)
         occurrences all number
    24
    Nasopharyngitis
         subjects affected / exposed
    57 / 190 (30.00%)
         occurrences all number
    105
    Infection
         subjects affected / exposed
    32 / 190 (16.84%)
         occurrences all number
    42
    Device related infection
         subjects affected / exposed
    36 / 190 (18.95%)
         occurrences all number
    47
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    36 / 190 (18.95%)
         occurrences all number
    53
    Hypocalcaemia
         subjects affected / exposed
    18 / 190 (9.47%)
         occurrences all number
    25
    Hyperglycaemia
         subjects affected / exposed
    31 / 190 (16.32%)
         occurrences all number
    76
    Decreased appetite
         subjects affected / exposed
    80 / 190 (42.11%)
         occurrences all number
    152

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2009
    Clarification / modification of AE/SAE reporting requirements. Modification of lenalidomide reduction schedule in maintenance therapy. Modification of additional inclusion criteria for lenalidomide maintenance phase. Reduction of fludarabine dosage in the conditioning regimen. Time points of ATG and calcium folinate administration adapted according to common clinical practice. Mycophenolate mofetil may replace MTX/calcium folinate according to local protocols of participating centers. Additional restaging between the 1st and 2nd cycle of stem cell transplantation. Additional determination of uric acid. Clarification of the required donor HLA-identity for allogeneic SCT: In case no HLAidentical donor (10 out of 10 gene loci) is available, one antigen disparity (class I) and/or one allele disparity (class II) between patient and donor is acceptable. Lenalidomide maintenance treatment starts 8 to 20 weeks after an allogeneic SCT. Permanent discontinuation of lenalidomide maintenance treatment, if patients develop acute GvHD ≥ grade III. Administrative changes.
    19 Oct 2010
    Myocardial infarction, myocarditis, perimyocarditis added as exclusion criteria. Clarification of respective inclusion criterion: If DLCO cannot be determined, pO2 [art.] as a substitute has to be ≥70 mm Hg. No other experimental drugs are allowed during the entire study in addition to being not permitted within 28 days before baseline. Adaption of the time frame for the administration of pegfilgrastim during RAD cycles. Modification of the administration of ciclosporin A during conditioning for allogeneic SCT according to common clinical practice. Maximum permitted delay of three weeks for start of next RAD cycles, if conditions for initiation of a new cycle are not fulfilled. Lenalidomide maintenance therapy must start two weeks after the restaging assessments prior to lenalidomide maintenance therapy. Update of required dose modifications for lenalidomide in relation to creatinine clearance in accordance with updated SmPC for lenalidomide. Separate dose reductions for neutropenia and thrombocytopenia during the RAD cycles. Both interim analyses will be exploratory only.
    19 Jan 2011
    Permitted interruption of lenalidomide maintenance therapy limited to max. 1 month. Monthly assessments of response, urine protein electrophoresis, immunofixation (serum and 24-h-urine specimen), serum immunoglobulins, and serum free light chain assay during lenalidomide maintenance instead of assessments every three months.
    03 May 2011
    Continuous daily administration of 10 mg lenalidomide maintenance therapy only in patients who received tandem autoSCT. Dose reduction for patients who received auto-allo transplantation to 5 mg daily on day 1-21 of a 28-day cycle after a reduced starting dose of 5 mg lenalidomide every other day on day 1-21 of cycle 1. Start of maintenance therapy in patients after auto-alloSCT 10-22 weeks after end of alloSCT instead after 8-20 weeks. Modified additional inclusion and exclusion criteria for lenalidomide maintenance: ▪ Inclusion of patients with neutrophil count ≥ 1.5 x 109 /L permitted ▪ Exclusion of patients with acute GvHD ≥ grade II or extensive chronic GvHD ▪ Restriction of allowed steroid medication to ≤ 1mg/kg BW methylprednisolone or equivalent, only ciclosporin and MMF permitted as immunosuppressants ▪ At least three-week interval from last taper of ciclosporin and MMF required GvHD needs to be reported as SAE when it occurred after the start of lenalidomide maintenance therapy. Long-term follow up for two years after last administration of lenalidomide maintenance (including explicit follow up with regard to second primary malignancies).
    15 Jul 2011
    Sample size increased from 146 to 190 patients due to drop-out rate of 23 % nonevaluable patients in the first interim analysis. Extension of the recruitment period to 2.5 years.
    07 Nov 2011
    Due to availability of 2.5 mg lenalidomide capsules, the application schedule of lenalidomide maintenance in cycle 1 of lenalidomide maintenance (starting dose) after alloSCT was modified to 2.5 mg daily on day 1-21 of this cycle.
    03 Jun 2013
    Modification of the study protocol according to the updated Pregnancy Prevention Program for lenalidomide. Among others modifications, females of childbearing potential requirement must use two contraceptives measures simultaneously.

    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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