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    Clinical Trial Results:
    A Randomized, Open-label, Phase 3 Study of Carfilzomib vs Best Supportive Care in Subjects with Relapsed and Refractory Multiple Myeloma

    Summary
    EudraCT number
    		 2009-016840-38
    Trial protocol
    		 AT   HU   CZ   ES   IT   GB   SE   SK   GR   DE   BE  
    Global end of trial date
    03 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Sep 2016
    First version publication date
    19 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PX-171-011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01302392
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Amgen Study ID: 20130396
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    10 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for subjects with multiple myeloma who have received all available approved treatment options and may therefore be considered candidates for palliative care.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Essential documents will be retained in accordance with ICH GCP. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Sep 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Austria: 17
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Czech Republic: 35
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Israel: 28
    Country: Number of subjects enrolled
    Italy: 45
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Spain: 42
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 22
    Worldwide total number of subjects
    315
    EEA total number of subjects
    266
    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)
    151
    From 65 to 84 years
    163
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled from 06 September 2010 to 21 October 2012. Results are reported as of the data cut-off date of 10 Jul 2014.

    Pre-assignment
    Screening details
    		 Eligible subjects were randomized in a 1:1 ratio to carfilzomib or best supportive care. Randomization was stratified based on the number of previous therapies (3 versus 4 versus ≥ 5) and geographical region (Europe versus non-Europe).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Best Supportive Care
    Arm description
    		 Subjects received corticosteroids (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid) for a maximum of 84 mg dexamethasone, or equivalent, per 28-day cycle. Additionally, optional cyclophosphamide (50 mg/day; maximum 1400 mg per 28-day cycle) could be given.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Corticosteriod
    Investigational medicinal product code
    Other name
    prednisolone, dexamethasone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Either prednisolone 30 mg every other day, dexamethasone 6 mg every other day, or equivalent corticosteroid regimen

    Arm title
    		 Carfilzomib
    Arm description
    		 Subjects received carfilzomib 20 mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8, 9, 15, and 16 of Cycle 1 and continuing on Days 1, 2, 8, 9, 15, and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond received 27 mg/m² IV on Days 1, 2, 15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Krypolis®
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion 20 mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8, 9, 15, and 16 of Cycle 1 and continuing on Days 1, 2, 8, 9, 15, and 16 of Cycle 2 through Cycle 9. From cycle 10, 27 mg/m² (or at the last dose given in Cycle 9) IV on Days 1, 2, 15, and 16 (omitting Days 8 and 9) unless the Investigator chose to reinstate the dosing frequency to the original regimen (Days 1, 2, 8, 9, 15,16) for individual patients.

    Number of subjects in period 1
    		Best Supportive Care Carfilzomib
    Started
    158
    157
    Treated
    153
    157
    Completed
    151
    156
    Not completed
    7
    1
         Consent withdrawn by subject
    6
    1
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Best Supportive Care
    Reporting group description
    		 Subjects received corticosteroids (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid) for a maximum of 84 mg dexamethasone, or equivalent, per 28-day cycle. Additionally, optional cyclophosphamide (50 mg/day; maximum 1400 mg per 28-day cycle) could be given.

    Reporting group title
    Carfilzomib
    Reporting group description
    		 Subjects received carfilzomib 20 mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8, 9, 15, and 16 of Cycle 1 and continuing on Days 1, 2, 8, 9, 15, and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond received 27 mg/m² IV on Days 1, 2, 15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).

    Reporting group values
    		 Best Supportive Care Carfilzomib Total
    Number of subjects
    		 158 157 315
    Age categorical
    Units: Subjects
        < 65 years
    		 83 68 151
        ≥ 65 years
    		 75 89 164
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.5 ± 8.02 63.3 ± 10.71 -
    Gender, Male/Female
    Units: participants
        Female
    		 62 75 137
        Male
    		 96 82 178
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 4 1 5
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 148 151 299
        Other
    		 5 4 9
    Region
    Units: Subjects
        Europe
    		 138 140 278
        Non-Europe
    		 20 17 37
    Number of Prior Regimens to Treat Multiple Myeloma
    Units: Subjects
        3 regimens
    		 19 17 36
        4 regimens
    		 35 34 69
        ≥ 5 regimens
    		 104 106 210

    End points

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    End points reporting groups
    Reporting group title
    Best Supportive Care
    Reporting group description
    		 Subjects received corticosteroids (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid) for a maximum of 84 mg dexamethasone, or equivalent, per 28-day cycle. Additionally, optional cyclophosphamide (50 mg/day; maximum 1400 mg per 28-day cycle) could be given.

    Reporting group title
    Carfilzomib
    Reporting group description
    		 Subjects received carfilzomib 20 mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8, 9, 15, and 16 of Cycle 1 and continuing on Days 1, 2, 8, 9, 15, and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond received 27 mg/m² IV on Days 1, 2, 15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Time elapsed between the randomization date and the date of death. Participants who were still alive were censored at the date when the subject was last known alive or the data cutoff date, whichever occurred earlier.
    End point type
    Primary
    End point timeframe
    From randomization through the final analysis data cutoff with longest follow-up time of approximately 45 months. Median follow up times were 27.8 months and 29.8 months for Carfilzomib and Best Supportive Care groups, respectively.
    End point values
    		 Best Supportive Care Carfilzomib
    Number of subjects analysed
    158
    157
    Units: months
        median (confidence interval 95%)
    10 (7.7 to 12)
    10.2 (8.4 to 14.4)
    Statistical analysis title
    		 Analysis of Overall Survival
    Comparison groups
    Best Supportive Care v Carfilzomib
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4172 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.975
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.249
    Notes
    [1] - P value was from stratified log-rank test with number of previous therapies (3 versus 4 versus ≥ 5) and geographical region (Europe versus non-Europe) as stratification factors.

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Kaplan-Meier estimate of median time from randomization to progressive disease (PD) or all-cause death. PD was assessed using International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). 1 or more conditions were required to meet PD: 2 consecutive rising serum or urine M-protein from central lab; documented new bone lesion(s) or soft tissue plasmacytoma(s) or increased size of existing bone lesion(s) or plasmacytoma(s); or confirmed hypercalcemia due solely to plasma cell proliferative disorder (local lab greater than 11.5 mg/dL on 2 separate occasions). Censoring conditions (censoring dates) were: no post-baseline disease assessment (DA) (randomization date); started non-protocol systemic anticancer treatment before PD or death (last DA date before such treatment); died or had PD after more than 1 missed DA (last DA date without PD before the first missed visit); or were alive and without documentation of PD, including lost to follow-up without PD (last DA date).
    End point type
    Secondary
    End point timeframe
    From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.
    End point values
    		 Best Supportive Care Carfilzomib
    Number of subjects analysed
    158
    157
    Units: months
        median (confidence interval 95%)
    3.3 (2.2 to 5.2)
    3.7 (2.8 to 4.2)
    No statistical analyses for this end point

    Secondary: Overall Response

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    End point title
    		 Overall Response
    End point description
    Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as their best response. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).
    End point type
    Secondary
    End point timeframe
    From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.
    End point values
    		 Best Supportive Care Carfilzomib
    Number of subjects analysed
    158
    157
    Units: participants
        number (not applicable)
    18
    30
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response (DOR) was calculated for subjects who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). Duration of response was defined as the time in months from the initial start of response (PR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for progression-free survival. "99999" indicates not calculable due to a low number of participants reaching PD or all-cause death.
    End point type
    Secondary
    End point timeframe
    From the time achieving response through the final analysis data cutoff with longest follow-up time of approximately 29 months.
    End point values
    		 Best Supportive Care Carfilzomib
    Number of subjects analysed
    18
    30
    Units: months
        median (confidence interval 95%)
    9.5 (3.7 to 99999)
    7.2 (4.6 to 12)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Response

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    End point title
    		 Clinical Benefit Response
    End point description
    Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) as their best response. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC). (MR was determined using European Group for Blood and Marrow Transplantation criteria)
    End point type
    Secondary
    End point timeframe
    From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.
    End point values
    		 Best Supportive Care Carfilzomib
    Number of subjects analysed
    158
    157
    Units: participants
        number (not applicable)
    33
    49
    No statistical analyses for this end point

    Secondary: Duration of Clinical Benefit

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    End point title
    		 Duration of Clinical Benefit
    End point description
    Duration of Clinical Benefit was calculated for subjects who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR) or minimal response (MR). Duration of Clinical Benefit was defined as the time in months from the initial start of response (MR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for progression-free survival.
    End point type
    Secondary
    End point timeframe
    From time of achieving clinical benefit through the final analysis data cutoff with longest follow-up time of approximately 30 months.
    End point values
    		 Best Supportive Care Carfilzomib
    Number of subjects analysed
    33
    49
    Units: months
        median (confidence interval 95%)
    8.3 (6.5 to 12.9)
    6.4 (4.9 to 8.3)
    No statistical analyses for this end point

    Secondary: Disease Control

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    End point title
    		 Disease Control
    End point description
    Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), or stable disease (SD) lasting ≥ 8 weeks as their best response. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC). (MR was determined using European Group for Blood and Marrow Transplantation criteria)
    End point type
    Secondary
    End point timeframe
    From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.
    End point values
    		 Best Supportive Care Carfilzomib
    Number of subjects analysed
    158
    157
    Units: participants
        number (not applicable)
    107
    119
    No statistical analyses for this end point

    Secondary: Duration of Disease Control

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    End point title
    		 Duration of Disease Control
    End point description
    Duration of Disease Control was calculated for subjects who achieved disease control. Duration of Disease Control was defined as the time in months from randomization to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for progression-free survival.
    End point type
    Secondary
    End point timeframe
    From time of achieving disease control through the final analysis data cutoff with longest follow-up time of approximately 31 months.
    End point values
    		 Best Supportive Care Carfilzomib
    Number of subjects analysed
    107
    119
    Units: months
        median (confidence interval 95%)
    6.6 (5.4 to 8.8)
    5.5 (3.9 to 6.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization through the final analysis data cutoff with range of follow-up time of 0.4 - 138.3 weeks with median of 10.7 weeks in Best Supportive Care arm, and 0.3 - 138.4 weeks with median of 16.3 weeks in carfilzomib arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Carfilzomib
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8, 9, 15, and 16 of Cycle 1 and continuing on Days 1, 2, 8, 9, 15, and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond received 27 mg/m² IV on Days 1, 2, 15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).

    Reporting group title
    Best Supportive Care
    Reporting group description
    		 Subjects received corticosteroids (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid) for a maximum of 84 mg dexamethasone, or equivalent, per 28-day cycle. Additionally, optional cyclophosphamide (50 mg/day; maximum 1400 mg per 28-day cycle) could be given.

    Serious adverse events
    		 Carfilzomib Best Supportive Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 157 (58.60%)
    78 / 153 (50.98%)
         number of deaths (all causes)
    129
    123
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic neoplasm malignant
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemia plasmacytic
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (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
    Asthenia
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Disease progression
         subjects affected / exposed
    16 / 157 (10.19%)
    19 / 153 (12.42%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 19
         deaths causally related to treatment / all
    0 / 14
    0 / 14
    General physical health deterioration
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pain
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 157 (3.82%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiac failure
         subjects affected / exposed
    4 / 157 (2.55%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 157 (1.27%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 157 (2.55%)
    8 / 153 (5.23%)
         occurrences causally related to treatment / all
    1 / 6
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 157 (1.91%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperviscosity syndrome
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 157 (0.64%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 157 (1.91%)
    5 / 153 (3.27%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ulcerative keratitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 157 (1.91%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    15 / 157 (9.55%)
    6 / 153 (3.92%)
         occurrences causally related to treatment / all
    1 / 15
    2 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    6 / 157 (3.82%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 157 (1.91%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    6 / 157 (3.82%)
    5 / 153 (3.27%)
         occurrences causally related to treatment / all
    1 / 6
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasopharyngitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 157 (6.37%)
    18 / 153 (11.76%)
         occurrences causally related to treatment / all
    3 / 11
    5 / 22
         deaths causally related to treatment / all
    0 / 1
    2 / 7
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 157 (1.91%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 157 (0.64%)
    4 / 153 (2.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (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
    3 / 157 (1.91%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    7 / 157 (4.46%)
    4 / 153 (2.61%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    3 / 157 (1.91%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Carfilzomib Best Supportive Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    141 / 157 (89.81%)
    135 / 153 (88.24%)
    Investigations
    Creatinine renal clearance decreased
         subjects affected / exposed
    9 / 157 (5.73%)
    4 / 153 (2.61%)
         occurrences all number
    23
    6
    Blood creatinine increased
         subjects affected / exposed
    13 / 157 (8.28%)
    10 / 153 (6.54%)
         occurrences all number
    21
    15
    Neutrophil count decreased
         subjects affected / exposed
    13 / 157 (8.28%)
    10 / 153 (6.54%)
         occurrences all number
    21
    19
    Platelet count decreased
         subjects affected / exposed
    12 / 157 (7.64%)
    12 / 153 (7.84%)
         occurrences all number
    33
    20
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 157 (14.65%)
    9 / 153 (5.88%)
         occurrences all number
    31
    11
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 157 (6.37%)
    3 / 153 (1.96%)
         occurrences all number
    21
    4
    Headache
         subjects affected / exposed
    17 / 157 (10.83%)
    6 / 153 (3.92%)
         occurrences all number
    23
    8
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    9 / 157 (5.73%)
    15 / 153 (9.80%)
         occurrences all number
    37
    48
    Neutropenia
         subjects affected / exposed
    22 / 157 (14.01%)
    23 / 153 (15.03%)
         occurrences all number
    73
    45
    Anaemia
         subjects affected / exposed
    88 / 157 (56.05%)
    72 / 153 (47.06%)
         occurrences all number
    275
    212
    Thrombocytopenia
         subjects affected / exposed
    58 / 157 (36.94%)
    43 / 153 (28.10%)
         occurrences all number
    231
    102
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    26 / 157 (16.56%)
    20 / 153 (13.07%)
         occurrences all number
    44
    27
    Chest pain
         subjects affected / exposed
    5 / 157 (3.18%)
    8 / 153 (5.23%)
         occurrences all number
    6
    8
    Chills
         subjects affected / exposed
    8 / 157 (5.10%)
    1 / 153 (0.65%)
         occurrences all number
    11
    1
    Fatigue
         subjects affected / exposed
    29 / 157 (18.47%)
    28 / 153 (18.30%)
         occurrences all number
    55
    46
    Oedema peripheral
         subjects affected / exposed
    17 / 157 (10.83%)
    12 / 153 (7.84%)
         occurrences all number
    22
    14
    Pain
         subjects affected / exposed
    8 / 157 (5.10%)
    1 / 153 (0.65%)
         occurrences all number
    11
    2
    Pyrexia
         subjects affected / exposed
    41 / 157 (26.11%)
    28 / 153 (18.30%)
         occurrences all number
    92
    34
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 157 (6.37%)
    20 / 153 (13.07%)
         occurrences all number
    14
    22
    Diarrhoea
         subjects affected / exposed
    23 / 157 (14.65%)
    18 / 153 (11.76%)
         occurrences all number
    37
    19
    Dyspepsia
         subjects affected / exposed
    10 / 157 (6.37%)
    4 / 153 (2.61%)
         occurrences all number
    12
    5
    Vomiting
         subjects affected / exposed
    15 / 157 (9.55%)
    5 / 153 (3.27%)
         occurrences all number
    25
    6
    Nausea
         subjects affected / exposed
    31 / 157 (19.75%)
    14 / 153 (9.15%)
         occurrences all number
    50
    15
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    12 / 157 (7.64%)
    10 / 153 (6.54%)
         occurrences all number
    17
    20
    Dyspnoea
         subjects affected / exposed
    21 / 157 (13.38%)
    12 / 153 (7.84%)
         occurrences all number
    36
    12
    Cough
         subjects affected / exposed
    19 / 157 (12.10%)
    10 / 153 (6.54%)
         occurrences all number
    27
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 157 (2.55%)
    18 / 153 (11.76%)
         occurrences all number
    4
    22
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    8 / 157 (5.10%)
    3 / 153 (1.96%)
         occurrences all number
    8
    5
    Renal impairment
         subjects affected / exposed
    11 / 157 (7.01%)
    5 / 153 (3.27%)
         occurrences all number
    33
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 157 (7.01%)
    6 / 153 (3.92%)
         occurrences all number
    14
    8
    Back pain
         subjects affected / exposed
    13 / 157 (8.28%)
    16 / 153 (10.46%)
         occurrences all number
    15
    23
    Bone pain
         subjects affected / exposed
    18 / 157 (11.46%)
    16 / 153 (10.46%)
         occurrences all number
    25
    20
    Pain in extremity
         subjects affected / exposed
    13 / 157 (8.28%)
    7 / 153 (4.58%)
         occurrences all number
    16
    7
    Musculoskeletal pain
         subjects affected / exposed
    5 / 157 (3.18%)
    10 / 153 (6.54%)
         occurrences all number
    6
    12
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    13 / 157 (8.28%)
    13 / 153 (8.50%)
         occurrences all number
    22
    14
    Nasopharyngitis
         subjects affected / exposed
    13 / 157 (8.28%)
    10 / 153 (6.54%)
         occurrences all number
    23
    14
    Respiratory tract infection
         subjects affected / exposed
    10 / 157 (6.37%)
    6 / 153 (3.92%)
         occurrences all number
    14
    7
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 157 (10.19%)
    3 / 153 (1.96%)
         occurrences all number
    26
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 157 (5.73%)
    7 / 153 (4.58%)
         occurrences all number
    10
    9
    Hypercalcaemia
         subjects affected / exposed
    13 / 157 (8.28%)
    9 / 153 (5.88%)
         occurrences all number
    25
    14
    Hyperglycaemia
         subjects affected / exposed
    6 / 157 (3.82%)
    8 / 153 (5.23%)
         occurrences all number
    10
    14
    Hyperkalaemia
         subjects affected / exposed
    8 / 157 (5.10%)
    2 / 153 (1.31%)
         occurrences all number
    14
    2
    Hyperuricaemia
         subjects affected / exposed
    19 / 157 (12.10%)
    10 / 153 (6.54%)
         occurrences all number
    20
    16
    Hypocalcaemia
         subjects affected / exposed
    11 / 157 (7.01%)
    10 / 153 (6.54%)
         occurrences all number
    20
    15
    Hypokalaemia
         subjects affected / exposed
    14 / 157 (8.92%)
    13 / 153 (8.50%)
         occurrences all number
    25
    16
    Hypomagnesaemia
         subjects affected / exposed
    11 / 157 (7.01%)
    11 / 153 (7.19%)
         occurrences all number
    23
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2011
    1) In order to adhere to CHMP guidance to design a study with survival as the primary endpoint, the primary endpoint was changed from PFS to OS. This was accompanied by an increase in sample size from 84 to 302 in order to provide 80% power to detect a 43% increase in OS for carfilzomib over control. A regional stratification variable was added to control for the additional sites and countries that were added for the increased sample size. 2) The window provided in Inclusion Criterion 2 to demonstrate measurable disease by central laboratory analysis of M-proteins was increased from 14 days originally to 21 days in order to account for the challenges in logistics of trans-country sample shipment followed by analysis and review.
    08 Mar 2012
    1) The interim analysis at 50% of the total number of OS events was removed, and the interim analysis of OS at approximately 75% of the total number of OS events was retained to ensure that the data were mature at the time of the interim analysis and to adhere to CHMP guidance. 2) Inclusion Criterion 11, which required prior treatment with anthracycline, was eliminated in order to expand study access to subjects being managed per current standard of care which does not support the routine use of anthracyclines. 3) Exclusion Criterion 21, which excluded subjects with any contraindications to the required concomitant drugs or supportive treatments, was added to ensure subject safety.
    11 Feb 2013
    1) Since OS was the primary endpoint, the study was amended to remove the requirement of response and progression assessments by an Independent Review Committee and instead to specify that the investigator’s assessment of response and progression was to be used.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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