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    Clinical Trial Results:
    A Phase 2, Randomize d, Double-blind, Placebo-controlled Study Comparing the Combination of CNTO 328 (Anti-IL-6 Monoclonal Antibody) and VELCADE versus VELCADE Alone in Subjects with Relapsed or Refractory Multiple Myeloma

    Summary
    EudraCT number
    		 2006-001904-36
    Trial protocol
    		 NL   BE   FR   GB   CZ   PT   DE   GR   BG   SK   ES  
    Global end of trial date
    24 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2020
    First version publication date
    04 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CR012784
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00401843
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route, 202 South Raritan, United States,
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Jun 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the safety (Part 1) and to compare the efficacy, in terms of progression-free survival (PFS) (Part 2), of CNTO 328 when administered as an intravenous (IV) infusion in combination with bortezomib in subjects with relapsed or refractory multiple myeloma.
    Protection of trial subjects
    The investigator acknowledges that, within legal and regulatory restrictions and institutional and ethical considerations, Centocor, their designee, or responsible government agencies (as required by law) may, at any time, review or copy source documents (example, laboratory reports, electrocardiograms, X-rays, workbooks and subjects’ medical records) in order to verify eCRF data. Safety evaluations for all subjects will include; physical exam and neurological exam, weight, vitals signs before and after CNTO 328 and bortezomib administrations, and monitoring of routine clinical laboratory assessments (hematology, coagulation, blood chemistry, lipid panel, amylase and lipase, urinalysis).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Nov 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Brazil: 10
    Country: Number of subjects enrolled
    Bulgaria: 26
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Czech Republic: 24
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    307
    EEA total number of subjects
    211
    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)
    169
    From 65 to 84 years
    137
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 144 subjects were randomized to bortezomib plus placebo group; of which, 3 subjects received incorrect treatment (bortezomib plus siltuximab).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 - Bortezomib + Siltuximab
    Arm description
    		 Subjects received siltuximab 6 milligram per kilogram (mg/kg) as intravenous infusion once every 2 weeks along with bortezomib 1.3 milligram per square meter (mg/m^2) during cycle 1 (22-day cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Bortezomib 1.3 mg/m^2 was administered as intravenous bolus once every 2 weeks during cycle 1 (22-day cycle) in Part 1.

    Investigational medicinal product name
    Siltuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Siltuximab 6 mg/kg was administered as intravenous infusion once every 2 weeks during cycle 1 (22-day cycle) in Part 1.

    Arm title
    		 Part 2 - Bortezomib + Placebo
    Arm description
    		 Subjects received bortezomib 1.3 mg/m^2 will be administered as intravenous bolus along with matching placebo administered as intravenous infusion once every 2 weeks during 42-day treatment cycle during treatment phase. Bortezomib 1.3 mg/m^2 was administered as intravenous bolus along with matching placebo once every 2 weeks during 35-day treatment cycle during Maintenance Phase. Dexamethasone tablet was administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Bortezomib 1.3 mg/m^2 was administered as intravenous bolus during 42-day treatment phase and during 35-day Maintenance Phase in Part 2.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Matching placebo was administered as intravenous infusion once every 2 weeks during 42-day treatment phase and 35-day maintenance phase in Part 2.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 40 or 20 milligram per day (mg/day) tablet was administered to the treatment regimen if bortezomib was discontinued.

    Arm title
    		 Part 2 - Bortezomib + Siltuximab
    Arm description
    		 Subjects received bortezomib 1.3 mg/m^2 as intravenous bolus along with Siltuximab 6 mg/kg administered as intravenous infusion once every 2 weeks during 42-day treatment cycle during treatment phase. Bortezomib 1.3 mg/m^2 was administered as intravenous bolus along with Siltuximab 6 mg/kg administered as intravenous infusion once every 2 weeks for 35-day treatment cycle during Maintenance Phase. Dexamethasone tablet was administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Bortezomib 1.3 mg/m^2 was administered as intravenous bolus during 42-day treatment phase and during 35-day Maintenance Phase in Part 2.

    Investigational medicinal product name
    Siltuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Siltuximab 6 mg/kg was administered as intravenous infusion once every 2 weeks during 42-day Treatment Phase and 35-day Maintenance Phase in Part 2.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet
    Routes of administration
    Intravenous bolus use , Oral use
    Dosage and administration details
    Dexamethasone 40 or 20 mg/day tablet was administered to the treatment regimen if bortezomib was discontinued.

    Number of subjects in period 1
    		Part 1 - Bortezomib + Siltuximab Part 2 - Bortezomib + Placebo Part 2 - Bortezomib + Siltuximab
    Started
    21
    144
    142
    Completed
    0
    0
    0
    Not completed
    21
    144
    142
         Adverse event, serious fatal
    2
    9
    12
         Physician decision
    -
    16
    10
         Disease progression
    10
    60
    49
         End of study
    1
    1
    2
         Consent withdrawn by subject
    1
    5
    5
         Adverse event, non-fatal
    5
    25
    25
         Randomized but not treated
    -
    2
    3
         Other
    -
    5
    5
         Withdrawal of consent to study agent tx
    1
    15
    17
         Achieved complete response
    1
    5
    11
         Unspecified
    -
    1
    -
         Lost to follow-up
    -
    -
    2
         Protocol deviation
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 - Bortezomib + Siltuximab
    Reporting group description
    		 Subjects received siltuximab 6 milligram per kilogram (mg/kg) as intravenous infusion once every 2 weeks along with bortezomib 1.3 milligram per square meter (mg/m^2) during cycle 1 (22-day cycle).

    Reporting group title
    Part 2 - Bortezomib + Placebo
    Reporting group description
    		 Subjects received bortezomib 1.3 mg/m^2 will be administered as intravenous bolus along with matching placebo administered as intravenous infusion once every 2 weeks during 42-day treatment cycle during treatment phase. Bortezomib 1.3 mg/m^2 was administered as intravenous bolus along with matching placebo once every 2 weeks during 35-day treatment cycle during Maintenance Phase. Dexamethasone tablet was administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity.

    Reporting group title
    Part 2 - Bortezomib + Siltuximab
    Reporting group description
    		 Subjects received bortezomib 1.3 mg/m^2 as intravenous bolus along with Siltuximab 6 mg/kg administered as intravenous infusion once every 2 weeks during 42-day treatment cycle during treatment phase. Bortezomib 1.3 mg/m^2 was administered as intravenous bolus along with Siltuximab 6 mg/kg administered as intravenous infusion once every 2 weeks for 35-day treatment cycle during Maintenance Phase. Dexamethasone tablet was administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity.

    Reporting group values
    		 Part 1 - Bortezomib + Siltuximab Part 2 - Bortezomib + Placebo Part 2 - Bortezomib + Siltuximab Total
    Number of subjects
    		 21 144 142 307
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 9 86 74 169
        From 65 to 84 years
    		 11 58 68 137
        85 years and over
    		 1 0 0 1
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 66 ( 10.76 ) 62.3 ( 9.65 ) 63.5 ( 9.32 ) -
    Title for Gender
    Units: subjects
        Female
    		 13 59 70 142
        Male
    		 8 85 72 165

    End points

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    End points reporting groups
    Reporting group title
    Part 1 - Bortezomib + Siltuximab
    Reporting group description
    		 Subjects received siltuximab 6 milligram per kilogram (mg/kg) as intravenous infusion once every 2 weeks along with bortezomib 1.3 milligram per square meter (mg/m^2) during cycle 1 (22-day cycle).

    Reporting group title
    Part 2 - Bortezomib + Placebo
    Reporting group description
    		 Subjects received bortezomib 1.3 mg/m^2 will be administered as intravenous bolus along with matching placebo administered as intravenous infusion once every 2 weeks during 42-day treatment cycle during treatment phase. Bortezomib 1.3 mg/m^2 was administered as intravenous bolus along with matching placebo once every 2 weeks during 35-day treatment cycle during Maintenance Phase. Dexamethasone tablet was administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity.

    Reporting group title
    Part 2 - Bortezomib + Siltuximab
    Reporting group description
    		 Subjects received bortezomib 1.3 mg/m^2 as intravenous bolus along with Siltuximab 6 mg/kg administered as intravenous infusion once every 2 weeks during 42-day treatment cycle during treatment phase. Bortezomib 1.3 mg/m^2 was administered as intravenous bolus along with Siltuximab 6 mg/kg administered as intravenous infusion once every 2 weeks for 35-day treatment cycle during Maintenance Phase. Dexamethasone tablet was administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity.

    Primary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS) [1]
    End point description
    PFS was defined as time interval between randomization and first documented sign of disease progression (including relapse from CR) by the European Bone Marrow Transplant (EBMT) criteria or death, whichever occurred first. Relapse from CR requires at least 1 of the following: Reappearance of serum or urinary M-protein on immunofixation or routine electrophoresis, confirmed by at least 1 further investigation and excluding oligoclonal immune reconstitution; >=5 percent (%) plasma cells either in a bone marrow aspirate or on trephine bone biopsy; Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in the size of residual bone lesions (development of a compression fracture does not exclude continued response and may not indicate progression); Development of hypercalcemia not attributable to any other cause. Intent-to-treat (ITT) population included all subjects randomized in Part 2. Subjects were analyzed as per initial randomization.
    End point type
    Primary
    End point timeframe
    Randomization until disease progression or death, which ever occurred first (maximum up to 4.5 years)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis was planned only for the reported arms of Part 2 of baseline period.
    End point values
    		 Part 2 - Bortezomib + Placebo Part 2 - Bortezomib + Siltuximab
    Number of subjects analysed
    144
    142
    Units: days
        median (confidence interval 95%)
    232 (191 to 302)
    245 (217 to 300)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 2 - Bortezomib + Placebo v Part 2 - Bortezomib + Siltuximab
    Number of subjects included in analysis
    286
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.345
    Method
    		 Logrank
    Parameter type
    		 Log hazard ratio
    Point estimate
    0.869
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.162

    Secondary: Percentage of Subjects With Confirmed Complete Response (CR Rate)

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    End point title
    		 Percentage of Subjects With Confirmed Complete Response (CR Rate) [2]
    End point description
    CR rate was defined as the percentage of subjects who achieved a confirmed CR before dexamethasone was added. CR: Absence of original M-protein in serum/urine by immunofixation,maintained for minimum of 6 weeks. The presence of oligoclonal bands consistent with oligoclonal immune reconstitution does not exclude CR; Less than 5 percent (%) plasma cells in bone marrow aspirate and also on trephine bone biopsy if biopsy is performed; No increase in size/number of lytic bone lesions; Disappearance of soft tissue plasmacytomas. Response-evaluable population:all participants in Part 2 with confirmed diagnosis of multiple myeloma and measurable,secretory disease:either serum M-protein 1 greater than or equal to (>=) gram per deciliter(g/dL)/urine M-protein >200 mg per 24 hours,at study entry;had at least 1 study agent administration;at least 1 post-baseline disease assessment before dexamethasone.
    End point type
    Secondary
    End point timeframe
    Randomization until disease progression (maximum up to 4.5 years)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis was planned only for the reported arms of Part 2 of baseline period.
    End point values
    		 Part 2 - Bortezomib + Placebo Part 2 - Bortezomib + Siltuximab
    Number of subjects analysed
    137
    131
    Units: percentage of subjects
        number (not applicable)
    7.3
    10.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Best Confirmed Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR])

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    End point title
    		 Percentage of Subjects With Best Confirmed Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) [3]
    End point description
    ORR was defined as best response for subject recorded from first administration of study agent/randomization (Part 2) until disease progression/recurrence and before dexamethasone. CR: Absence of Mprotein in serum/urine by immunofixation, maintained for minimum of 6 weeks. Presence of oligoclonal bands consistent with oligoclonal immune reconstitution does not exclude CR; >5% plasma cells in bone marrow aspirate and on trephine bone biopsy if performed; No increase in size/number of lytic bone lesions; Disappearance of soft tissue plasmacytomas. PR:>=50% reduction in level of serum M-protein, maintained for minimum of 6 weeks. Reduction in 24hour urinary light chain excretion either by >=90% or to <200mg, maintained for minimum of 6 weeks; >=50% reduction in size of soft tissue plasmacytomas; No increase in size/number of lytic bone lesions. Response-evaluable population was the subject population.
    End point type
    Secondary
    End point timeframe
    Randomization until disease progression (maximum up to 4.5 years)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis was planned only for the reported arms of Part 2 of baseline period.
    End point values
    		 Part 2 - Bortezomib + Placebo Part 2 - Bortezomib + Siltuximab
    Number of subjects analysed
    137
    131
    Units: percentage of subjects
        number (not applicable)
    46.7
    55.0
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival [4]
    End point description
    Overall survival was defined as the interval between the first administration of study agent or randomization (Part 2) and the participant’s death from any cause. For participants with unknown survival status as of the data cut-off date, overall survival was censored at the last date known to be alive. Here '99999' signifies that upper limit of 95% CI which was not estimable due to high censorship rate and lesser number of events. ITT population included all subjects randomized in Part 2. Subjects were analyzed as per initial randomization.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 years
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis was planned only for the reported arms of Part 2 of baseline period.
    End point values
    		 Part 2 - Bortezomib + Placebo Part 2 - Bortezomib + Siltuximab
    Number of subjects analysed
    144
    142
    Units: days
        median (confidence interval 95%)
    1121 (1038.0 to 99999)
    937 (713 to 1127)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs) or Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Adverse Events (AEs) or Serious Adverse Events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The safety population included all subjects who received at least 1 dose of study treatment in Part 1 or Part 2. Subjects were analyzed as per actual treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 years
    End point values
    		 Part 1 - Bortezomib + Siltuximab Part 2 - Bortezomib + Placebo Part 2 - Bortezomib + Siltuximab
    Number of subjects analysed
    21
    139
    142
    Units: subjects
        Adverse Events (AEs)
    21
    138
    140
        Serious Adverse Events (SAEs)
    10
    44
    47
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 4.5 years
    Adverse event reporting additional description
    The safety population included all subjects who received at least 1 dose of study treatment in Part 1 or Part 2. Subjects were analyzed as per actual treatment received.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Part 1 - Bortezomib + Siltuximab
    Reporting group description
    		 Siltuximab 6 milligram per kilogram (mg/kg) will be administered as intravenous infusion once every 2 weeks along with bortezomib 1.3 milligram per square meter (mg/m^2) during cycle 1.

    Reporting group title
    Part 2 - Bortezomib + CNTO328
    Reporting group description
    		 Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 4, 8, 11, followed by a 10- day rest period; and on Days 22, 25, 29, and 32 followed by a 10-day rest period along with Siltuximab administered as intravenous infusion once every 2 weeks during 42-day treatment phase. Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 8, 15, 22 followed by a 13-day rest period (cycle Days 23 to 35) along with Siltuximab administered as intravenous infusion once every 2 weeks for 35-day Maintenance Phase. Dexamethasone tablet will be administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity. Dexamethasone 40 mg/day was administered on days 1-4, 9-12, and 17-20 for four 28-day cycles then 40 mg/day for Days 1-4 for all subsequent cycles.

    Reporting group title
    Part 2 - Bortezomib + Placebo
    Reporting group description
    		 Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 4, 8, 11, followed by a 10- day rest period; and on Days 22, 25, 29, and 32 followed by a 10-day rest period along with matching placebo administered as intravenous infusion once every 2 weeks during 42-day treatment phase. Bortezomib 1.3 mg/m^2 will be administered as intravenous bolus on Days 1, 8, 15, 22 followed by a 13- day rest period (cycle Days 23 to 35) along with matching placebo once every 2 weeks during 35-day Maintenance Phase. Dexamethasone tablet will be administered at first occurrence of documented disease progression or if bortezomib was discontinued due to intolerable toxicity. Dexamethasone 40 milligram per day (mg/day) was administered on days 1-4, 9-12, and 17-20 for four 28-day cycles then 40 mg/day for Days 1-4 for all subsequent cycles.

    Serious adverse events
    		 Part 1 - Bortezomib + Siltuximab Part 2 - Bortezomib + CNTO328 Part 2 - Bortezomib + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 21 (47.62%)
    47 / 142 (33.10%)
    44 / 139 (31.65%)
         number of deaths (all causes)
    1
    13
    10
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 142 (1.41%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Transitional Cell Carcinoma
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon Adenoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pancreatic Carcinoma Metastatic
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Plasma Cell Leukaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Plasma Cell Myeloma
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Plasmacytoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 142 (1.41%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic Shock
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jugular Vein Thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Fatigue Syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face Oedema
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mass
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance Status Decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden Cardiac Death
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Atelectasis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 142 (1.41%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mediastinal Shift
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 142 (1.41%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Respiratory Arrest
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna Fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Disorder
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular Fibrillation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive Disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Stroke
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Mononeuritis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 142 (1.41%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viith Nerve Paralysis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal Cord Paresis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye Swelling
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth Ulceration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal Haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug Eruption
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive Uropathy
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 142 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 142 (1.41%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 142 (2.11%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone Lesion
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle Haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute Hepatitis B
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 142 (1.41%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
    Endocarditis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterobacter Bacteraemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney Infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis Bacterial
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis Pneumococcal
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 21 (4.76%)
    5 / 142 (3.52%)
    6 / 139 (4.32%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Streptococcal
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 142 (2.82%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Streptococcal Bacteraemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 142 (1.41%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour Lysis Syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1 - Bortezomib + Siltuximab Part 2 - Bortezomib + CNTO328 Part 2 - Bortezomib + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    140 / 142 (98.59%)
    135 / 139 (97.12%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 142 (1.41%)
    1 / 139 (0.72%)
         occurrences all number
    2
    2
    2
    Hypertension
         subjects affected / exposed
    4 / 21 (19.05%)
    18 / 142 (12.68%)
    9 / 139 (6.47%)
         occurrences all number
    5
    27
    19
    Hypotension
         subjects affected / exposed
    4 / 21 (19.05%)
    11 / 142 (7.75%)
    12 / 139 (8.63%)
         occurrences all number
    4
    22
    18
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 21 (23.81%)
    24 / 142 (16.90%)
    27 / 139 (19.42%)
         occurrences all number
    10
    35
    51
    Chills
         subjects affected / exposed
    3 / 21 (14.29%)
    6 / 142 (4.23%)
    6 / 139 (4.32%)
         occurrences all number
    3
    7
    13
    Fatigue
         subjects affected / exposed
    8 / 21 (38.10%)
    39 / 142 (27.46%)
    40 / 139 (28.78%)
         occurrences all number
    13
    68
    73
    Gait Disturbance
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences all number
    2
    1
    1
    Influenza Like Illness
         subjects affected / exposed
    3 / 21 (14.29%)
    4 / 142 (2.82%)
    5 / 139 (3.60%)
         occurrences all number
    5
    6
    6
    Oedema Peripheral
         subjects affected / exposed
    4 / 21 (19.05%)
    16 / 142 (11.27%)
    16 / 139 (11.51%)
         occurrences all number
    6
    22
    22
    Pyrexia
         subjects affected / exposed
    3 / 21 (14.29%)
    8 / 142 (5.63%)
    27 / 139 (19.42%)
         occurrences all number
    5
    8
    56
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 21 (28.57%)
    12 / 142 (8.45%)
    18 / 139 (12.95%)
         occurrences all number
    8
    16
    29
    Dyspnoea
         subjects affected / exposed
    6 / 21 (28.57%)
    20 / 142 (14.08%)
    14 / 139 (10.07%)
         occurrences all number
    6
    24
    19
    Epistaxis
         subjects affected / exposed
    1 / 21 (4.76%)
    8 / 142 (5.63%)
    7 / 139 (5.04%)
         occurrences all number
    1
    9
    9
    Nasal Congestion
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 142 (0.70%)
    1 / 139 (0.72%)
         occurrences all number
    2
    2
    1
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 21 (9.52%)
    7 / 142 (4.93%)
    9 / 139 (6.47%)
         occurrences all number
    2
    11
    13
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 21 (19.05%)
    8 / 142 (5.63%)
    6 / 139 (4.32%)
         occurrences all number
    4
    8
    16
    Insomnia
         subjects affected / exposed
    5 / 21 (23.81%)
    15 / 142 (10.56%)
    15 / 139 (10.79%)
         occurrences all number
    6
    18
    18
    Investigations
    Weight Decreased
         subjects affected / exposed
    7 / 21 (33.33%)
    20 / 142 (14.08%)
    20 / 139 (14.39%)
         occurrences all number
    10
    35
    30
    Weight Increased
         subjects affected / exposed
    3 / 21 (14.29%)
    5 / 142 (3.52%)
    3 / 139 (2.16%)
         occurrences all number
    4
    5
    3
    Nervous system disorders
    Balance Disorder
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    3
    0
    1
    Dizziness
         subjects affected / exposed
    4 / 21 (19.05%)
    14 / 142 (9.86%)
    10 / 139 (7.19%)
         occurrences all number
    5
    14
    16
    Dysgeusia
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 142 (2.82%)
    2 / 139 (1.44%)
         occurrences all number
    2
    5
    13
    Headache
         subjects affected / exposed
    8 / 21 (38.10%)
    18 / 142 (12.68%)
    14 / 139 (10.07%)
         occurrences all number
    16
    27
    33
    Hypoaesthesia
         subjects affected / exposed
    0 / 21 (0.00%)
    5 / 142 (3.52%)
    7 / 139 (5.04%)
         occurrences all number
    0
    5
    9
    Lethargy
         subjects affected / exposed
    0 / 21 (0.00%)
    7 / 142 (4.93%)
    7 / 139 (5.04%)
         occurrences all number
    0
    21
    19
    Neuralgia
         subjects affected / exposed
    1 / 21 (4.76%)
    31 / 142 (21.83%)
    33 / 139 (23.74%)
         occurrences all number
    1
    72
    59
    Paraesthesia
         subjects affected / exposed
    3 / 21 (14.29%)
    14 / 142 (9.86%)
    16 / 139 (11.51%)
         occurrences all number
    3
    30
    34
    Peripheral Motor Neuropathy
         subjects affected / exposed
    1 / 21 (4.76%)
    8 / 142 (5.63%)
    8 / 139 (5.76%)
         occurrences all number
    1
    12
    13
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    9 / 21 (42.86%)
    73 / 142 (51.41%)
    73 / 139 (52.52%)
         occurrences all number
    19
    157
    160
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 21 (42.86%)
    45 / 142 (31.69%)
    46 / 139 (33.09%)
         occurrences all number
    13
    138
    129
    Leukopenia
         subjects affected / exposed
    8 / 21 (38.10%)
    38 / 142 (26.76%)
    16 / 139 (11.51%)
         occurrences all number
    68
    104
    56
    Lymphopenia
         subjects affected / exposed
    8 / 21 (38.10%)
    13 / 142 (9.15%)
    5 / 139 (3.60%)
         occurrences all number
    57
    52
    39
    Neutropenia
         subjects affected / exposed
    17 / 21 (80.95%)
    86 / 142 (60.56%)
    53 / 139 (38.13%)
         occurrences all number
    122
    481
    191
    Thrombocytopenia
         subjects affected / exposed
    13 / 21 (61.90%)
    83 / 142 (58.45%)
    65 / 139 (46.76%)
         occurrences all number
    69
    454
    334
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 21 (9.52%)
    6 / 142 (4.23%)
    6 / 139 (4.32%)
         occurrences all number
    3
    8
    6
    Eye disorders
    Chalazion
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    2
    0
    2
    Conjunctivitis
         subjects affected / exposed
    2 / 21 (9.52%)
    7 / 142 (4.93%)
    5 / 139 (3.60%)
         occurrences all number
    2
    8
    5
    Lacrimation Increased
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 142 (2.11%)
    0 / 139 (0.00%)
         occurrences all number
    2
    4
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    3 / 21 (14.29%)
    10 / 142 (7.04%)
    10 / 139 (7.19%)
         occurrences all number
    6
    17
    22
    Abdominal Pain Upper
         subjects affected / exposed
    4 / 21 (19.05%)
    7 / 142 (4.93%)
    8 / 139 (5.76%)
         occurrences all number
    5
    10
    9
    Aphthous Stomatitis
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 142 (2.11%)
    0 / 139 (0.00%)
         occurrences all number
    2
    7
    0
    Constipation
         subjects affected / exposed
    12 / 21 (57.14%)
    31 / 142 (21.83%)
    22 / 139 (15.83%)
         occurrences all number
    18
    47
    38
    Diarrhoea
         subjects affected / exposed
    13 / 21 (61.90%)
    53 / 142 (37.32%)
    50 / 139 (35.97%)
         occurrences all number
    44
    131
    136
    Dyspepsia
         subjects affected / exposed
    3 / 21 (14.29%)
    13 / 142 (9.15%)
    9 / 139 (6.47%)
         occurrences all number
    3
    16
    9
    Haemorrhoids
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences all number
    2
    1
    0
    Nausea
         subjects affected / exposed
    12 / 21 (57.14%)
    40 / 142 (28.17%)
    42 / 139 (30.22%)
         occurrences all number
    28
    70
    80
    Stomatitis
         subjects affected / exposed
    3 / 21 (14.29%)
    6 / 142 (4.23%)
    4 / 139 (2.88%)
         occurrences all number
    3
    9
    6
    Vomiting
         subjects affected / exposed
    4 / 21 (19.05%)
    28 / 142 (19.72%)
    28 / 139 (20.14%)
         occurrences all number
    4
    42
    40
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    1 / 21 (4.76%)
    9 / 142 (6.34%)
    14 / 139 (10.07%)
         occurrences all number
    2
    28
    22
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    5 / 142 (3.52%)
    1 / 139 (0.72%)
         occurrences all number
    27
    10
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 142 (0.00%)
    1 / 139 (0.72%)
         occurrences all number
    4
    0
    2
    Rash
         subjects affected / exposed
    6 / 21 (28.57%)
    15 / 142 (10.56%)
    14 / 139 (10.07%)
         occurrences all number
    9
    21
    27
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences all number
    2
    1
    0
    Renal Impairment
         subjects affected / exposed
    2 / 21 (9.52%)
    14 / 142 (9.86%)
    4 / 139 (2.88%)
         occurrences all number
    6
    34
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 21 (19.05%)
    23 / 142 (16.20%)
    17 / 139 (12.23%)
         occurrences all number
    7
    31
    29
    Back Pain
         subjects affected / exposed
    3 / 21 (14.29%)
    21 / 142 (14.79%)
    29 / 139 (20.86%)
         occurrences all number
    4
    35
    40
    Bone Pain
         subjects affected / exposed
    4 / 21 (19.05%)
    17 / 142 (11.97%)
    15 / 139 (10.79%)
         occurrences all number
    5
    27
    35
    Muscle Spasms
         subjects affected / exposed
    4 / 21 (19.05%)
    11 / 142 (7.75%)
    5 / 139 (3.60%)
         occurrences all number
    4
    13
    10
    Musculoskeletal Chest Pain
         subjects affected / exposed
    5 / 21 (23.81%)
    3 / 142 (2.11%)
    6 / 139 (4.32%)
         occurrences all number
    5
    4
    10
    Musculoskeletal Pain
         subjects affected / exposed
    2 / 21 (9.52%)
    8 / 142 (5.63%)
    10 / 139 (7.19%)
         occurrences all number
    2
    11
    15
    Myalgia
         subjects affected / exposed
    3 / 21 (14.29%)
    12 / 142 (8.45%)
    7 / 139 (5.04%)
         occurrences all number
    3
    15
    20
    Pain in Extremity
         subjects affected / exposed
    4 / 21 (19.05%)
    25 / 142 (17.61%)
    15 / 139 (10.79%)
         occurrences all number
    6
    63
    35
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 21 (14.29%)
    14 / 142 (9.86%)
    11 / 139 (7.91%)
         occurrences all number
    6
    17
    14
    Ear Infection
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 142 (0.70%)
    0 / 139 (0.00%)
         occurrences all number
    2
    1
    0
    Herpes Simplex
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 142 (2.82%)
    2 / 139 (1.44%)
         occurrences all number
    3
    4
    3
    Herpes Zoster
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 142 (2.82%)
    13 / 139 (9.35%)
         occurrences all number
    3
    5
    21
    Hordeolum
         subjects affected / exposed
    3 / 21 (14.29%)
    6 / 142 (4.23%)
    2 / 139 (1.44%)
         occurrences all number
    3
    8
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 21 (14.29%)
    15 / 142 (10.56%)
    13 / 139 (9.35%)
         occurrences all number
    8
    19
    19
    Pneumonia
         subjects affected / exposed
    3 / 21 (14.29%)
    7 / 142 (4.93%)
    4 / 139 (2.88%)
         occurrences all number
    3
    8
    4
    Respiratory Tract Infection
         subjects affected / exposed
    2 / 21 (9.52%)
    14 / 142 (9.86%)
    11 / 139 (7.91%)
         occurrences all number
    2
    16
    20
    Rhinitis
         subjects affected / exposed
    1 / 21 (4.76%)
    5 / 142 (3.52%)
    7 / 139 (5.04%)
         occurrences all number
    2
    6
    11
    Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 21 (23.81%)
    14 / 142 (9.86%)
    12 / 139 (8.63%)
         occurrences all number
    11
    28
    17
    Urinary Tract Infection
         subjects affected / exposed
    3 / 21 (14.29%)
    12 / 142 (8.45%)
    7 / 139 (5.04%)
         occurrences all number
    4
    19
    11
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    6 / 21 (28.57%)
    32 / 142 (22.54%)
    28 / 139 (20.14%)
         occurrences all number
    7
    51
    43
    Dehydration
         subjects affected / exposed
    4 / 21 (19.05%)
    6 / 142 (4.23%)
    2 / 139 (1.44%)
         occurrences all number
    6
    6
    2
    Enzyme Abnormality
         subjects affected / exposed
    1 / 21 (4.76%)
    5 / 142 (3.52%)
    9 / 139 (6.47%)
         occurrences all number
    1
    5
    16
    Hyperamylasaemia
         subjects affected / exposed
    3 / 21 (14.29%)
    4 / 142 (2.82%)
    2 / 139 (1.44%)
         occurrences all number
    15
    6
    2
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 21 (23.81%)
    8 / 142 (5.63%)
    8 / 139 (5.76%)
         occurrences all number
    20
    11
    9
    Hyperglycaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    9 / 142 (6.34%)
    1 / 139 (0.72%)
         occurrences all number
    0
    41
    56
    Hyperlipasaemia
         subjects affected / exposed
    3 / 21 (14.29%)
    4 / 142 (2.82%)
    4 / 139 (2.88%)
         occurrences all number
    11
    5
    4
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 21 (14.29%)
    7 / 142 (4.93%)
    6 / 139 (4.32%)
         occurrences all number
    19
    20
    8
    Hyperuricaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    10 / 142 (7.04%)
    7 / 139 (5.04%)
         occurrences all number
    2
    14
    9
    Hypocalcaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    8 / 142 (5.63%)
    13 / 139 (9.35%)
         occurrences all number
    0
    31
    35
    Hypokalaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    17 / 142 (11.97%)
    9 / 139 (6.47%)
         occurrences all number
    0
    21
    11
    Hypomagnesaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    11 / 142 (7.75%)
    3 / 139 (2.16%)
         occurrences all number
    1
    17
    3
    Hyponatraemia
         subjects affected / exposed
    0 / 21 (0.00%)
    9 / 142 (6.34%)
    4 / 139 (2.88%)
         occurrences all number
    0
    14
    8
    Hypophosphataemia
         subjects affected / exposed
    4 / 21 (19.05%)
    16 / 142 (11.27%)
    19 / 139 (13.67%)
         occurrences all number
    11
    26
    43

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2006
    The first protocol amendment was adopted before any study related procedures were conducted or subjects were enrolled in the study.
    01 May 2007
    Approximately 6 subjects were enrolled in the study prior to the initiation of Amendment 2.
    14 Jul 2008
    Approximately 113 subjects were enrolled in the study prior to the initiation of Amendment 3.
    01 Nov 2010
    All subjects were enrolled in the study prior to the initiation of Amendment 4.

    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.

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