Flag of the European Union EU Clinical Trials Register Help

Clinical trials

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

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

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Efficacy and safety of Rituximab, high-dose ARA-C and Dexamethasone (R-HAD) alone or in combination with Bortezomib in patients with relapsed or refractory mantle cell lymphoma A randomized Phase III Trial of the European MCL Network

    Summary
    EudraCT number
    		 2005-005144-62
    Trial protocol
    		 DE  
    Global end of trial date
    02 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2022
    First version publication date
    25 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MCL2005-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01449344
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LMU Klinikum
    Sponsor organisation address
    Marchioninistr. 15, München, Germany, 81377
    Public contact
    Dr. Burkhard Deuß, ClinAssess GmbH, +49 2171363360, info@clinassess.de
    Scientific contact
    Prof. Dr. Martin Dreyling, Studienzentrale für Hämatologie, +49 440074900 / -01, studyce@med.uni-muenchen.de
    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
    19 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Apr 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study is a prospective, randomized, multicenter, open-label phase III clinical trial to compare the efficacy and safety of Bortezomib in combination with Rituximab, high-dose Ara-C and dexamethasone (R-HAD) to R-HAD alone in patients with relapsed or refractory MCL after or not eligible for myeloablative treatment. The primary endpoint is time to treatment failure (TTF).
    Protection of trial subjects
    The aim of the trial is to compare known standard treatments. Therefore, the therapy of the patients is part of the regular care. To ensure, that only patients with mantle cell lymphoma are included in the trial, the initial diagnosis of all patients enrolled was verified by reference pathologists.
    Background therapy
    		 The objective of this trial is to compare the efficacy and safety of the combination of Rituximab, high-dose Ara-C and dexamethasone (R-HAD) with Bortezomib to R-HAD alone in patients with relapsed or refractory mantle cell lymphoma after 1 to 3 prior lines of therapy and not eligible for myeloablative treatment. The primary trial endpoint is the time to treatment failure (TTF). Study arms will be compared to each other to evaluate the effect of additional Bortezomib. Patients receive two cycles of Rituximab, Cytarabine and Dexamethasone ± Bortezomib every three weeks. Those patients who respond to the treatment, defined as complete (CR) or partial remission (PR) at midterm staging after two cycles, will receive two additional treatment cycles. In case of stable disease (SD), patients may proceed with the treatment at the investigator’s discretion.
    Evidence for comparator
    		 Cytarabine (AraC) has long been proven to be an effective drug in the treatment of many Non Hodgkin lymphomas (NHL), in the treatment of MCL it is used especially in relapsed or refractory situations after a CHOP like regimen. In nearly all MCLs a high expression of CD20 may be detected, but Rituximab monotherapy has documented only moderate activity in MCL. In contrast, a combined immunochemotherapy approach has been proven to be superior in randomized trials. These results also apply in relapsed MCL.
    Actual start date of recruitment
    05 May 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 50
    Country: Number of subjects enrolled
    Germany: 78
    Worldwide total number of subjects
    128
    EEA total number of subjects
    128
    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)
    33
    From 65 to 84 years
    93
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 First patient in (randomized): 5 May 2012 Last patient in (randomized): 20 Dec 2016 Stop criterion: sponsor-decided premature stop due to a low recruitment rate

    Pre-assignment
    Screening details
    		 Each subject must fulfill all of the inclusion and exclusion criteria as defined in the study protocol before enrollment to the study: Confirmed pathological diagnosis of MCL Relapse or progression following 1 to 3 prior lines of anti-neoplastic standard therapy 18 years or older and written informed consent

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 R-HAD (Arm A)
    Arm description
    		 Rituximab, high-dose Ara-C and dexamethasone
    Arm type
    		 No IMP

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 R-HAD+Bortezomib (Arm B)
    Arm description
    		 Rituximab, high-dose Ara-C and dexamethasone in combination with Bortezomib
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade (R)
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Bortezomib 1.5 mg/m² was administered additionally to the chemotherapy R-HAD as a intravenous or subcutaneous injection (subcutaneous through the thighs or abdomen) on day 1 at least one hour prior to Rituximab infusion and similarly on day 4. Treatment course will be repeated in 3-week intervals (day 22 + / - 3 days).

    Number of subjects in period 1
    		R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Started
    64
    64
    Completed
    59
    59
    Not completed
    5
    5
         Consent withdrawn by subject
    1
    1
         Diagnosis of MCL rejected
    -
    1
         Lost to follow-up
    -
    1
         Protocol deviation
    4
    2

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    R-HAD (Arm A)
    Reporting group description
    		 Rituximab, high-dose Ara-C and dexamethasone

    Reporting group title
    R-HAD+Bortezomib (Arm B)
    Reporting group description
    		 Rituximab, high-dose Ara-C and dexamethasone in combination with Bortezomib

    Reporting group values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B) Total
    Number of subjects
    		 64 64 128
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 13 20 33
        From 65-84 years
    		 50 43 93
        85 years and over
    		 1 1 2
    Age continuous
    Units: years
        median (full range (min-max))
    		 71 (41 to 85) 70 (41 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 13 18 31
        Male
    		 51 46 97
    Study group
    Units: Subjects
        LYSA
    		 26 24 50
        GLSG
    		 38 40 78
    Stage
    Units: Subjects
        stage I
    		 4 5 9
        stage II
    		 6 8 14
        stage III
    		 5 9 14
        stage IV
    		 49 42 91
    ECOG
    Units: Subjects
        ECOG 0
    		 29 25 54
        ECOG 1
    		 29 37 66
        ECOG 2
    		 6 2 8
    B-symptoms
    Units: Subjects
        No
    		 50 46 96
        Yes
    		 14 18 32
    Bone marrow involvement
    Units: Subjects
        No
    		 25 23 48
        Yes
    		 39 41 80
    Gastrointestinal involvement
    Units: Subjects
        No
    		 55 55 110
        Yes
    		 9 9 18
    Number of other extranodal involvement
    Units: Subjects
        zero
    		 54 50 104
        one
    		 3 12 15
        two
    		 4 2 6
        three
    		 3 0 3
    MIPI
    Units: Subjects
        Low
    		 11 16 27
        Intermediate
    		 22 25 47
        High
    		 31 23 54
    Previous lines of treatment
    Units: Subjects
        one
    		 40 51 91
        two
    		 17 9 26
        three
    		 7 4 11
    Previous high-dose cytarabine
    Units: Subjects
        No
    		 42 40 82
        Yes
    		 22 24 46
    Previous ASCT
    Units: Subjects
        Yes
    		 24 26 50
        No
    		 40 38 78
    Previous remission
    Units: Subjects
        Yes
    		 61 62 123
        No
    		 3 2 5
    Primary salvage treatment
    Units: Subjects
        Yes
    		 1 2 3
        No
    		 63 62 125
    LDH ratio to ULN
    Units: ratio
        median (full range (min-max))
    		 0.95 (0.51 to 5.79) 0.93 (0.57 to 6.74) -
    Hb
    Units: g/L
        median (full range (min-max))
    		 1.20 (0.64 to 1.66) 1.29 (0.88 to 1.56) -
    Leucocytes
    Units: 10^9/L
        median (full range (min-max))
    		 7.20 (0.050 to 240.60) 6.96 (1.82 to 374.76) -
    Thrombocytes
    Units: 10^9/L
        median (full range (min-max))
    		 150 (20 to 437) 158 (24 to 555) -
    Neutr. Granulocytes
    Units: 10^9/L
        median (full range (min-max))
    		 3.79 (0 to 55.44) 3.83 (0.38 to 44.88) -
    Lymphocytes
    Units: 10^9/L
        median (full range (min-max))
    		 1.94 (0.01 to 233.38) 1.38 (0.15 to 363.52) -
    Number of Extranodal involvement
    Units: count
        median (full range (min-max))
    		 1 (0 to 5) 1 (0 to 4) -
    MIPI score
    Units: score
        median (full range (min-max))
    		 6.15 (4.96 to 8.23) 6.05 (4.92 to 7.86) -
    Time from first diagnosis
    Units: years
        median (full range (min-max))
    		 3.7 (0.1 to 14.2) 3.9 (0 to 11.1) -
    Time from last relapse/progression
    Units: days
        median (full range (min-max))
    		 27 (4 to 1504) 31 (2 to 1136) -
    Subject analysis sets

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intention-to-treat (mITT) analysis set comprises all subjects who are randomized, regardless of which treatment they received and whether further protocol violations have occurred. Patients for whom the diagnosis of MCL is rejected by the central pathology review are excluded from the mITT set. The mITT set applies for primary efficacy analysis, secondary efficacy analysis, and subgroup analyses.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) analysis set comprises all subjects of the mITT set who actually received the treatment they were assigned to by randomization and in whom treatment was not stopped prematurely. Thus, patients with progressive (PD) or stable disease (SD) at the end of therapy have to have received at least two cycles and patients with partial (PR, CRu) or complete remission (CR) have to have received the total number of four cycles of therapy. Patients still belong to the PP analysis set if further protocol violations occur. The PP set applies for secondary efficacy analysis

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety set comprises all randomized subjects who have received at least one cycle of therapy. Patients are evaluated according to the therapy they actually received. The safety set applies for safety analysis.

    Subject analysis sets values
    		 mITT PP Safety
    Number of subjects
    127
    118
    126
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    33
    30
    31
        From 65-84 years
    92
    86
    93
        85 years and over
    2
    2
    2
    Age continuous
    Units: years
        median (full range (min-max))
    70 (41 to 85)
    70 (41 to 85)
    71 (41 to 85)
    Gender categorical
    Units: Subjects
        Female
    31
    29
    30
        Male
    96
    89
    96
    Study group
    Units: Subjects
        LYSA
    50
    47
    50
        GLSG
    77
    71
    76
    Stage
    Units: Subjects
        stage I
    9
    8
    9
        stage II
    14
    14
    14
        stage III
    14
    13
    14
        stage IV
    90
    83
    89
    ECOG
    Units: Subjects
        ECOG 0
    53
    51
    54
        ECOG 1
    66
    60
    64
        ECOG 2
    8
    7
    8
    B-symptoms
    Units: Subjects
        No
    95
    89
    95
        Yes
    32
    29
    31
    Bone marrow involvement
    Units: Subjects
        No
    48
    46
    48
        Yes
    79
    72
    78
    Gastrointestinal involvement
    Units: Subjects
        No
    109
    101
    109
        Yes
    18
    17
    17
    Number of other extranodal involvement
    Units: Subjects
        zero
    100
    94
    100
        one
    18
    16
    17
        two
    6
    5
    6
        three
    3
    3
    3
    MIPI
    Units: Subjects
        Low
    27
    24
    26
        Intermediate
    46
    45
    47
        High
    54
    49
    53
    Previous lines of treatment
    Units: Subjects
        one
    90
    84
    89
        two
    26
    23
    26
        three
    11
    11
    11
    Previous high-dose cytarabine
    Units: Subjects
        No
    81
    75
    81
        Yes
    46
    43
    45
    Previous ASCT
    Units: Subjects
        Yes
    50
    47
    48
        No
    77
    71
    78
    Previous remission
    Units: Subjects
        Yes
    122
    113
    121
        No
    5
    5
    5
    Primary salvage treatment
    Units: Subjects
        Yes
    3
    3
    3
        No
    124
    115
    123
    LDH ratio to ULN
    Units: ratio
        median (full range (min-max))
    0.95 (0.51 to 6.74)
    0.93 (0.51 to 6.74)
    0.94 (0.51 to 6.74)
    Hb
    Units: g/L
        median (full range (min-max))
    1.27 (0.64 to 1.66)
    1.27 (0.78 to 1.66)
    1.27 (0.64 to 1.66)
    Leucocytes
    Units: 10^9/L
        median (full range (min-max))
    6.98 (0.050 to 374.76)
    6.97 (1.82 to 240.60)
    6.96 (0.050 to 240.60)
    Thrombocytes
    Units: 10^9/L
        median (full range (min-max))
    153 (20 to 555)
    155 (24 to 555)
    153 (20 to 555)
    Neutr. Granulocytes
    Units: 10^9/L
        median (full range (min-max))
    3.84 (0 to 55.44)
    3.78 (0.38 to 55.44)
    3.78 (0 to 55.44)
    Lymphocytes
    Units: 10^9/L
        median (full range (min-max))
    1.60 (0.01 to 363.52)
    1.62 (0.15 to 233.38)
    1.58 (0.01 to 233.38)
    Number of Extranodal involvement
    Units: count
        median (full range (min-max))
    1 (0 to 5)
    1 (0 to 5)
    1 (0 to 5)
    MIPI score
    Units: score
        median (full range (min-max))
    6.08 (4.92 to 8.23)
    6.08 (4.92 to 8.23)
    6.08 (4.92 to 8.23)
    Time from first diagnosis
    Units: years
        median (full range (min-max))
    3.8 (0 to 14.2)
    3.8 (0 to 14.2)
    3.8 (0 to 14.2)
    Time from last relapse/progression
    Units: days
        median (full range (min-max))
    28 (2 to 1504)
    29 (2 to 1504)
    29 (2 to 1504)

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    R-HAD (Arm A)
    Reporting group description
    		 Rituximab, high-dose Ara-C and dexamethasone

    Reporting group title
    R-HAD+Bortezomib (Arm B)
    Reporting group description
    		 Rituximab, high-dose Ara-C and dexamethasone in combination with Bortezomib

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intention-to-treat (mITT) analysis set comprises all subjects who are randomized, regardless of which treatment they received and whether further protocol violations have occurred. Patients for whom the diagnosis of MCL is rejected by the central pathology review are excluded from the mITT set. The mITT set applies for primary efficacy analysis, secondary efficacy analysis, and subgroup analyses.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) analysis set comprises all subjects of the mITT set who actually received the treatment they were assigned to by randomization and in whom treatment was not stopped prematurely. Thus, patients with progressive (PD) or stable disease (SD) at the end of therapy have to have received at least two cycles and patients with partial (PR, CRu) or complete remission (CR) have to have received the total number of four cycles of therapy. Patients still belong to the PP analysis set if further protocol violations occur. The PP set applies for secondary efficacy analysis

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety set comprises all randomized subjects who have received at least one cycle of therapy. Patients are evaluated according to the therapy they actually received. The safety set applies for safety analysis.

    Primary: Time to treatment failure (mITT)

    		 Close Top of page
    End point title
    		 Time to treatment failure (mITT)
    End point description
    The primary endpoint is time to treatment failure (TTF) calculated from the date of randomization. Treatment failure is defined as – progressive disease (PD) or stable disease (SD) following induction therapy or – relapse or progression after complete or partial remission (CR, CRu, PR) or – death from any cause, whichever occurred first. Response to therapy is defined as the staging result after the last cycle of therapy. If no treatment failure has been observed until the time of analysis, TTF is censored at the day of the last follow-up staging.
    End point type
    Primary
    End point timeframe
    Midterm staging, end of treatment evaluation, follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B) mITT
    Number of subjects analysed
    64
    60 [1]
    124 [2]
    Units: Months
        median (confidence interval 95%)
    2.6 (1.9 to 7.1)
    12 (6.2 to 21.2)
    6.2 (2.7 to 10.6)
    Attachments
    		 Primary analysis
    Notes
    [1] - 3 patients were excluded from the analysis because of missing staging result.
    [2] - 3 patients from R-HAD+B group were excluded from the analysis because of missing staging result.
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The primary statistical comparison between two treatment arms by the log-rank test was performed as underrunning analysis of the sequential test, as no decision boundary was reached. In this underrunning analysis, the p-value and the adjusted maximum-likelihood estimate for the hazard ratio were calculated correcting for the performed interim analyses.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.045 [4]
    Method
    		 sequential eval. of Logrank stat.
    Parameter type
    		 adjusted mle of hazard ratio
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 99999
    Notes
    [3] - This study was planned as a confirmatory superiority trial. A two-sided log-rank test with a significance level of 5% will be used to compare TTF in two arms. The null hypothesis H0 is TTF(R-HAD)=TTF(R-HAD+B), and the alternative hypothesis H1 is TTF(R-HAD)≠TTF(R-HAD+B).
    [4] - P-value from an underrunning analysis of a sequential test. No valid method for calculation of confidence interval of adjusted mle of hazard ratio is known. Since database does not accept this, (-1 ,999999) was entered for interval.
    Statistical analysis title
    		 Sensitivity analysis for primary endpoint
    Statistical analysis description
    After the clinical cut-off date of 19 April 2021, an unplanned data update was performed and one more event of treatment failure in the R-HAD+B group was documented. The updated data were analyzed for the primary endpoint as a sensitivity analysis for the primary analysis.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    124
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.089 [5]
    Method
    		 sequential eval. of Logrank stat.
    Parameter type
    		 adjusted mle of hazard ratio
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 999999
    Notes
    [5] - p value from unterrunning analysis of sequential test. No valid method for calculation of confidence interval of adjusted mle of hazard ratio is known. Since database does not accept this, (-1 ,999999) was entered for interval.

    Secondary: Complete remission rates (mITT)

    		 Close Top of page
    End point title
    		 Complete remission rates (mITT)
    End point description
    Complete remission rate: the rate of complete remissions (CR) after induction therapy. CR including/excluding CRu will be evaluated separately.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    64
    60 [6]
    Units: patients
        Complete remission (CR)
    8
    17
        Complete remission (CR+CRu)
    12
    25
    Attachments
    		 Response rates (mITT)
    Notes
    [6] - 3 patients from the mITT set were excluded from the analysis because of missing staging results.
    Statistical analysis title
    		 Response rates
    Statistical analysis description
    CR- and OR-rate for each treatment arm were calculated with the corresponding 95% confidence intervals, and compared by two-sided Fisher’s exact test.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043 [7]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [7] - complete remission (CR): P=0.043 complete remission (CR, CRu): P=0.0062

    Secondary: Complete remission rates (PP)

    		 Close Top of page
    End point title
    		 Complete remission rates (PP)
    End point description
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    58 [8]
    58 [9]
    Units: patients
        Complete remission (CR)
    8
    17
        Complete remission (CR+CRu)
    11
    25
    Attachments
    		 Response rates (PP)
    Notes
    [8] - 1 patient was excluded from PP set because of missing staging result.
    [9] - 1 patient was excluded from PP set because of missing staging result.
    Statistical analysis title
    		 Response rates
    Statistical analysis description
    CR- and OR-rate for each treatment arm were calculated with the corresponding 95% confidence intervals, and compared by two-sided Fisher’s exact test.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07 [10]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [10] - Complete remission (CR): p=0.070 Complete remission (CR+CRu): p=0.0086

    Secondary: Time to treatment failure (PP)

    		 Close Top of page
    End point title
    		 Time to treatment failure (PP)
    End point description
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation, follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    58 [11]
    58 [12]
    Units: Months
        median (confidence interval 95%)
    2.6 (1.3 to 6.8)
    12.9 (7.6 to 23.2)
    Attachments
    		 TTF (PP)
    Notes
    [11] - 1 patient was excluded from the PP analysis because of missing staging results during induction.
    [12] - 1 patient was excluded from the PP analysis because of missing staging results during induction.
    Statistical analysis title
    		 TTF (PP)
    Statistical analysis description
    Kaplan-Meier estimates stratified by treatment groups were calculated with 95% confidence intervals at 12, 24, and 36 months. The hazard ratio of Bortezomib+R-HAD to R-HAD with 95% confidence intervals and the corresponding P values will be calculated from both univariate and multivariate Cox proportional hazards models adjusted for the MIPI prognostic score at trial baseline and time from first diagnosis to randomization, without correction for the sequential design.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.91

    Secondary: Progression-free survival (mITT)

    		 Close Top of page
    End point title
    		 Progression-free survival (mITT)
    End point description
    Progression free survival (PFS): time from randomization to first documentation of progression or relapse or death from any cause, whichever occurred first. Patients with no event during follow-up are censored at the day of the last follow-up staging. For per protocol analysis, patients with new lymphoma treatment before progression will be censored additionally or earlier at treatment start.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation, follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    64
    60 [13]
    Units: Months
        median (confidence interval 95%)
    9.2 (6.2 to 14.3)
    15.4 (12.0 to 22.0)
    Attachments
    		 PFS (mITT)
    Notes
    [13] - 3 patients were excluded from the analysis because of missing staging results during induction.
    Statistical analysis title
    		 PFS (mITT)
    Statistical analysis description
    Kaplan-Meier estimates at 12, 24, and 36 months were calculated with 95% confidence intervals. PFS was compared between two treatment arms by log-rank test. Hazard ratios with 95% confidence intervals and the corresponding P values were calculated from multivariate Cox proportional hazards models adjusted for the MIPI prognostic score at baseline and time from first diagnosis.
    Comparison groups
    R-HAD+Bortezomib (Arm B) v R-HAD (Arm A)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.15

    Secondary: Progression-free survival (PP)

    		 Close Top of page
    End point title
    		 Progression-free survival (PP)
    End point description
    Progression free survival (PFS): time from randomization to first documentation of progression or relapse or death from any cause, whichever occurred first. Patients with no event during follow-up are censored at the day of the last follow-up staging. For per protocol analysis, patients with new lymphoma treatment before progression will be censored additionally or earlier at treatment start.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation, follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    58 [14]
    58 [15]
    Units: Months
        median (confidence interval 95%)
    7.4 (6.2 to 18.8)
    16.3 (12.8 to 30.8)
    Attachments
    		 PFS (PP)
    Notes
    [14] - 1 patient was excluded from the analysis because of missing staging results during induction.
    [15] - 1 patient was excluded from the analysis because of missing staging results during induction.
    Statistical analysis title
    		 PFS (PP)
    Statistical analysis description
    Kaplan-Meier estimates at 12, 24, and 36 months were calculated with 95% confidence intervals. PFS was compared between two treatment arms by log-rank test. Hazard ratios with 95% confidence intervals and the corresponding P values were calculated from multivariate Cox proportional hazards models adjusted for the MIPI prognostic score at baseline and time from first diagnosis.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.92

    Secondary: Response duration (mITT)

    		 Close Top of page
    End point title
    		 Response duration (mITT)
    End point description
    Progression free survival of responders (PFS of responders) or response duration (RD): time from end of successful (CR, CRu, PR) trial therapy to first documentation of progression or relapse or death from any cause, whichever occurred first. Patients with no event during follow-up are censored at the day of the last follow-up staging.
    End point type
    Secondary
    End point timeframe
    Follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    29
    38
    Units: Months
        median (confidence interval 95%)
    13.5 (8.2 to 33.7)
    20.7 (12.2 to 30.9)
    Attachments
    		 RD(mITT)
    Statistical analysis title
    		 RD (mITT)
    Statistical analysis description
    Kaplan-Meier estimates at 12, 24, and 36 months were calculated with 95% confidence intervals. RD was compared between two treatment arms by log-rank test. Hazard ratios with 95% confidence intervals and the corresponding P values were calculated from multivariate Cox proportional hazards models adjusted for the MIPI prognostic score at baseline and time from first diagnosis.
    Comparison groups
    R-HAD+Bortezomib (Arm B) v R-HAD (Arm A)
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.52

    Secondary: Response duration (PP)

    		 Close Top of page
    End point title
    		 Response duration (PP)
    End point description
    Progression free survival of responders (PFS of responders) or response duration (RD): time from end of successful (CR, CRu, PR) trial therapy to first documentation of progression or relapse or death from any cause, whichever occurred first. Patients with no event during follow-up are censored at the day of the last follow-up staging. For per-protocol analysis, patients with new lymphoma treatment before progression will be censored additionally or earlier at treatment start. Since upper confidence intervall could not be valid calculated and database does not provide entries like "not reached", the value 999999 was entered.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation, follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    26
    37
    Units: Months
        median (confidence interval 95%)
    17.0 (10.3 to 999999)
    21.2 (13.1 to 40.6)
    Attachments
    		 RD(PP)
    Statistical analysis title
    		 RD (PP)
    Statistical analysis description
    Kaplan-Meier estimates at 12, 24, and 36 months were calculated with 95% confidence intervals. RD was compared between two treatment arms by log-rank test. Hazard ratios with 95% confidence intervals and the corresponding P values were calculated from multivariate Cox proportional hazards models adjusted for the MIPI prognostic score at baseline and time from first diagnosis.
    Comparison groups
    R-HAD+Bortezomib (Arm B) v R-HAD (Arm A)
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.17

    Secondary: Time to next lymphoma treatment (mITT)

    		 Close Top of page
    End point title
    		 Time to next lymphoma treatment (mITT)
    End point description
    Time to next lymphoma treatment: time from treatment start to the start of next lymphoma treatment outside the protocol. Patients in which no further treatment has been started are censored at the day of the last follow-up staging.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation, follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    64
    61 [16]
    Units: events
    19
    12
    Attachments
    		 Next lymphoma treatment (mITT)
    Notes
    [16] - 2 patients were excluded from the mITT analysis because of missing next lymphoma treatment status.
    Statistical analysis title
    		 Next lymphoma treatment (mITT)
    Statistical analysis description
    Cumulative incidence of next lymphoma treatment was calculated using cumulative incidence function and compared by Gray’s test, treating death without next lymphoma treatment as competing event. Hazard ratio was calculated from proportional subdistribution hazard regression model.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Gray's test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1.25

    Secondary: Time to next lymphoma treatment (PP)

    		 Close Top of page
    End point title
    		 Time to next lymphoma treatment (PP)
    End point description
    Time to next lymphoma treatment: time from treatment start to the start of next lymphoma treatment outside the protocol. Patients in which no further treatment has been started are censored at the day of the last follow-up staging.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation, follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    59
    59
    Units: events
    19
    12
    Attachments
    		 Next lymphoma treatment (PP)
    Statistical analysis title
    		 Next lymphoma treatment (PP)
    Statistical analysis description
    Cumulative incidence of next lymphoma treatment was calculated using cumulative incidence function and compared by Gray’s test, treating death without next lymphoma treatment as competing event. Hazard ratio was calculated from proportional subdistribution hazard regression model.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14
    Method
    		 Gray's test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.2

    Secondary: Overall survival (mITT)

    		 Close Top of page
    End point title
    		 Overall survival (mITT)
    End point description
    Overall survival (OS): time from randomization to death. Patients who were alive at the day of the last contact are censored at that time. Since upper confidence intervall could not be valid calculated and database does not provide entries like "not reached", the value 100 was entered.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation, follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    64
    63
    Units: Months
        median (confidence interval 95%)
    35.0 (21.0 to 71.0)
    30.7 (21.5 to 100)
    Attachments
    		 OS (mITT)
    Statistical analysis title
    		 OS (mITT)
    Statistical analysis description
    Kaplan-Meier estimates at 12, 24, and 36 months were calculated with 95% confidence intervals. OS was compared between two treatment arms by log-rank test. Hazard ratios with 95% confidence intervals and the corresponding P values were calculated from multivariate Cox proportional hazards models adjusted for the MIPI prognostic score at baseline and time from first diagnosis.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.58

    Secondary: Overall survival (PP)

    		 Close Top of page
    End point title
    		 Overall survival (PP)
    End point description
    Overall survival (OS): time from randomization to death. Patients who were alive at the day of the last contact are censored at that time. Since upper confidence intervall could not be valid calculated and database does not provide entries like "not reached", the value 999999 was entered.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation, follow-up evaluations
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    59
    59
    Units: Months
        median (confidence interval 95%)
    35.0 (21.0 to 999999)
    47.3 (25.8 to 999999)
    Attachments
    		 OS (PP)
    Statistical analysis title
    		 OS (PP)
    Statistical analysis description
    Kaplan-Meier estimates at 12, 24, and 36 months were calculated with 95% confidence intervals. OS was compared between two treatment arms by log-rank test. Hazard ratios with 95% confidence intervals and the corresponding P values were calculated from multivariate Cox proportional hazards models adjusted for the MIPI prognostic score at baseline and time from first diagnosis.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.48

    Secondary: Overall response rate (mITT)

    		 Close Top of page
    End point title
    		 Overall response rate (mITT)
    End point description
    Overall response (OR) rate: the rate of complete, complete unconfirmed, and partial remissions (CR, CRu, PR) after induction therapy.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    64
    60 [17]
    Units: patients
    29
    38
    Notes
    [17] - 3 patients from mITT set were excluded from the analysis because of missing staging results.
    Statistical analysis title
    		 Overall response
    Statistical analysis description
    OR-rates for each treatment arm were calculated with the corresponding 95% confidence intervals, and compared by two-sided Fisher’s exact test.
    Comparison groups
    R-HAD (Arm A) v R-HAD+Bortezomib (Arm B)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Overall response rate (PP)

    		 Close Top of page
    End point title
    		 Overall response rate (PP)
    End point description
    Overall response (OR) rate: the rate of complete, complete unconfirmed, and partial remissions (CR, CRu, PR) after induction therapy.
    End point type
    Secondary
    End point timeframe
    Midterm staging, end of treatment evaluation
    End point values
    		 R-HAD (Arm A) R-HAD+Bortezomib (Arm B)
    Number of subjects analysed
    58 [18]
    58 [19]
    Units: patients
    26
    37
    Notes
    [18] - 1 patient from PP set was excluded from the analysis because of missing staging result.
    [19] - 1 patient from PP set was excluded from the analysis because of missing staging result.
    Statistical analysis title
    		 Overall response
    Statistical analysis description
    OR-rates for each treatment arm were calculated with the corresponding 95% confidence intervals, and compared by two-sided Fisher’s exact test.
    Comparison groups
    R-HAD+Bortezomib (Arm B) v R-HAD (Arm A)
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.062
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    After each treatment cycle
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    R-HAD
    Reporting group description
    		 Rituximab, high-dose Ara-C and dexamethasone

    Reporting group title
    R-HAD+Bortezomib
    Reporting group description
    		 Rituximab, high-dose Ara-C and dexamethasone in combination with Bortezomib

    Serious adverse events
    		 R-HAD R-HAD+Bortezomib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 64 (43.75%)
    23 / 64 (35.94%)
         number of deaths (all causes)
    62
    33
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Small cell lung cancer
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 64 (6.25%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 R-HAD R-HAD+Bortezomib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 64 (96.88%)
    63 / 64 (98.44%)
    Vascular disorders
    Vena cava thrombosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Thrombosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Lymphoedema
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 64 (1.56%)
    5 / 64 (7.81%)
         occurrences all number
    1
    8
    Haemorrhage
         subjects affected / exposed
    5 / 64 (7.81%)
    2 / 64 (3.13%)
         occurrences all number
    6
    3
    Deep vein thrombosis
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 64 (3.13%)
         occurrences all number
    1
    5
    Angiopathy
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Catheter site inflammation
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Chills
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    23 / 64 (35.94%)
    29 / 64 (45.31%)
         occurrences all number
    41
    52
    Malaise
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Mucosal inflammation
         subjects affected / exposed
    3 / 64 (4.69%)
    2 / 64 (3.13%)
         occurrences all number
    4
    2
    Oedema
         subjects affected / exposed
    7 / 64 (10.94%)
    3 / 64 (4.69%)
         occurrences all number
    11
    6
    Oedema peripheral
         subjects affected / exposed
    6 / 64 (9.38%)
    9 / 64 (14.06%)
         occurrences all number
    7
    14
    Pain
         subjects affected / exposed
    2 / 64 (3.13%)
    2 / 64 (3.13%)
         occurrences all number
    2
    3
    Pyrexia
         subjects affected / exposed
    18 / 64 (28.13%)
    19 / 64 (29.69%)
         occurrences all number
    27
    23
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 64 (4.69%)
    2 / 64 (3.13%)
         occurrences all number
    3
    5
    Anaphylactic reaction
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Pneumothorax
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Lung disorder
         subjects affected / exposed
    10 / 64 (15.63%)
    10 / 64 (15.63%)
         occurrences all number
    12
    12
    Hiccups
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    5 / 64 (7.81%)
    2 / 64 (3.13%)
         occurrences all number
    10
    2
    Dysphonia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    4 / 64 (6.25%)
    4 / 64 (6.25%)
         occurrences all number
    5
    6
    Anxiety
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    Confusional state
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    3
    Insomnia
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Mental disorder
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Obsessive-compulsive disorder
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Schizophrenia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Weight increased
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 64 (1.56%)
         occurrences all number
    5
    2
    Weight decreased
         subjects affected / exposed
    11 / 64 (17.19%)
    16 / 64 (25.00%)
         occurrences all number
    15
    19
    Transaminases
         subjects affected / exposed
    18 / 64 (28.13%)
    20 / 64 (31.25%)
         occurrences all number
    31
    32
    Platelet count increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    leukocyte count increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Glomerular filtration rate
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    3
    General physical condition
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 64 (1.56%)
    3 / 64 (4.69%)
         occurrences all number
    1
    3
    Blood urine present
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Blood urea increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    Blood glucose abnormal
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Blood creatine
         subjects affected / exposed
    18 / 64 (28.13%)
    23 / 64 (35.94%)
         occurrences all number
    42
    50
    Blood bilirubin abnormal
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    3
    Blood bilirubin
         subjects affected / exposed
    9 / 64 (14.06%)
    9 / 64 (14.06%)
         occurrences all number
    15
    16
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Spinal fracture
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Ligament sprain
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    4 / 64 (6.25%)
    4 / 64 (6.25%)
         occurrences all number
    7
    4
    Cardiac dysfunction
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 64 (1.56%)
         occurrences all number
    8
    1
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    3
    Tachycardia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    11 / 64 (17.19%)
    16 / 64 (25.00%)
         occurrences all number
    22
    28
    Migraine with aura
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    3 / 64 (4.69%)
    3 / 64 (4.69%)
         occurrences all number
    4
    3
    Dizziness
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 64 (3.13%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    59 / 64 (92.19%)
    59 / 64 (92.19%)
         occurrences all number
    157
    178
    Febrile neutropenia
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Leukopenia
         subjects affected / exposed
    44 / 64 (68.75%)
    46 / 64 (71.88%)
         occurrences all number
    97
    120
    Lymphopenia
         subjects affected / exposed
    44 / 64 (68.75%)
    50 / 64 (78.13%)
         occurrences all number
    102
    131
    Neutropenia
         subjects affected / exposed
    41 / 64 (64.06%)
    48 / 64 (75.00%)
         occurrences all number
    83
    113
    Thrombocytopenia
         subjects affected / exposed
    56 / 64 (87.50%)
    54 / 64 (84.38%)
         occurrences all number
    145
    150
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    9 / 64 (14.06%)
    21 / 64 (32.81%)
         occurrences all number
    12
    30
    Diarrhoea
         subjects affected / exposed
    6 / 64 (9.38%)
    13 / 64 (20.31%)
         occurrences all number
    8
    15
    Dyspepsia
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Faecaloma
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Large intestine perforation
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    8 / 64 (12.50%)
    17 / 64 (26.56%)
         occurrences all number
    10
    23
    Pancreatitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 64 (1.56%)
    6 / 64 (9.38%)
         occurrences all number
    1
    8
    Skin and subcutaneous tissue disorders
    Skin disorder
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    Rash
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    3
    Pruritus
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    Petechiae
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Night sweats
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Ecchymosis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    3
    Dry skin
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Strangury
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    Nocturia
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 64 (3.13%)
         occurrences all number
    4
    4
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    7 / 64 (10.94%)
    6 / 64 (9.38%)
         occurrences all number
    9
    9
    Musculoskeletal pain
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Bone pain
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    back pain
         subjects affected / exposed
    2 / 64 (3.13%)
    2 / 64 (3.13%)
         occurrences all number
    3
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    Device related infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 64 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    3
    Infection
         subjects affected / exposed
    22 / 64 (34.38%)
    26 / 64 (40.63%)
         occurrences all number
    28
    33
    Localised infection
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Neutropenic infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Otitis media acute
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    Pneumonia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Schizophrenia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Sepsis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Steroid diabetes
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    3 / 64 (4.69%)
    6 / 64 (9.38%)
         occurrences all number
    6
    9
    Gout
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    fluid overload
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Diabetes mellitus
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Dehydration
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2
    Decreased appetite
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2010
    Deletion of Rituximab as an IMP (only IMP left: Bortezomib), Amendment was implemented before enrollment of first patient
    10 Apr 2012
    The Inclusion criterion of prior anthracyclin-containing regimen was deleted
    13 Jan 2015
    Switch from Vecalde iv to sc administration Clarification of the Inclusion criterion concerning enrollment of patients who become progressive under Rituximab maintenance Deletion of the Exclusion criterion concerning previous treatment with Bortezomib

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

    European Medicines Agency © 1995-Fri May 03 05:22:24 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA