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    Clinical Trial Results:
    A Randomized, Open-label, Multicenter, Phase 3 Study to Compare the Efficacy and Safety of Eribulin with Dacarbazine in Subjects with Soft Tissue Sarcoma

    Summary
    EudraCT number
    		 2010-024483-17
    Trial protocol
    		 BE   DE   CZ   GB   AT   DK   ES   IT  
    Global end of trial date
    10 Aug 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Jul 2020
    First version publication date
    27 Feb 2020
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updates in adverse event section

    Trial information

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    Trial identification
    Sponsor protocol code
    E7389-G000-309
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01327885
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Medical Research Inc.
    Sponsor organisation address
    155 Tice Boulevard, Woodcliff Lake, United States, 07677
    Public contact
    Eisai Medical Information, Eisai Inc., +1 1-888-274-2378, esi_oncmedinfo@eisai.com
    Scientific contact
    Eisai Medical Information, Eisai Inc., +1 1-888-274-2378, esi_oncmedinfo@eisai.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 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare overall survival (OS) in subjects with advanced soft tissue sarcoma (STS) (one of two subtypes: adipocytic sarcoma [ADI] or leiomyosarcoma [LMS]) when treated with eribulin (Arm A) or dacarbazine (Arm B).
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Mar 2011
    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
    Spain: 23
    Country: Number of subjects enrolled
    Thailand: 5
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 157
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 65
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Italy: 38
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Singapore: 4
    Worldwide total number of subjects
    452
    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)
    356
    From 65 to 84 years
    96
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There were 594 subjects screened for entry into the study. Of these subjects, 452 were randomized into the study and 142 were identified as screen failures.

    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
    		 Arm A: Eribulin mesylate
    Arm description
    		 Eribulin mesylate at a dose of 1.4 milligram per square meter (mg/m^2) was administered intravenously (IV) as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin mesylate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Eribulin mesylate at a dose of 1.4 mg/m^2 was administered IV as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.

    Arm title
    		 Arm B: Dacarbazine
    Arm description
    		 Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the principal investigator [PI] or designee prior to randomization according to the subject's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the PI or designee prior to randomization according to the subject's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.

    Number of subjects in period 1
    		Arm A: Eribulin mesylate Arm B: Dacarbazine
    Started
    228
    224
    Completed
    0
    0
    Not completed
    228
    224
         Clinical progression
    24
    27
         Participant choice
    5
    10
         Adverse event, non-fatal
    14
    10
         Disease progression-according to RECIST
    173
    165
         Not specified
    8
    6
         Study terminated by sponsor
    -
    1
         Withdrawal of consent from study
    3
    4
         Not treated
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Eribulin mesylate
    Reporting group description
    		 Eribulin mesylate at a dose of 1.4 milligram per square meter (mg/m^2) was administered intravenously (IV) as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.

    Reporting group title
    Arm B: Dacarbazine
    Reporting group description
    		 Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the principal investigator [PI] or designee prior to randomization according to the subject's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.

    Reporting group values
    		 Arm A: Eribulin mesylate Arm B: Dacarbazine Total
    Number of subjects
    		 228 224 452
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.6 ± 11.01 55.7 ± 10.35 -
    Gender categorical
    Units: Subjects
        Female
    		 161 142 303
        Male
    		 67 82 149

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Eribulin mesylate
    Reporting group description
    		 Eribulin mesylate at a dose of 1.4 milligram per square meter (mg/m^2) was administered intravenously (IV) as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.

    Reporting group title
    Arm B: Dacarbazine
    Reporting group description
    		 Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the principal investigator [PI] or designee prior to randomization according to the subject's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time in months from the date of treatment start until death, regardless of cause. In the absence of confirmation of death, participants were censored either at the date that participant was last known to be alive or the date of study cut-off, whichever was earlier. Participants who died on the date of randomization had a survival time of 0.5 day. Allocation of randomization numbers were performed based upon the following stratification factors: (a) Histology (adipocytic [ADI] or leiomyosarcoma [LMS]), (b) Region (Region 1: USA and Canada; or Region 2: Western Europe, Australia, Israel; or Region 3: Eastern Europe, Latin America, and Asia), and (c) Number of prior regimens for advanced soft tissue sarcoma (STS) (2 or greater than [>] 2 prior regimens).Full analysis set (FAS) (Intent-to-Treat [ITT] analysis set) included all subjects who were randomized.
    End point type
    Primary
    End point timeframe
    From date of treatment start until date of death from any cause, up to 5 years 5 months
    End point values
    		 Arm A: Eribulin mesylate Arm B: Dacarbazine
    Number of subjects analysed
    228
    224
    Units: Months
        median (confidence interval 95%)
    13.5 (10.9 to 15.6)
    11.5 (9.6 to 13.0)
    Statistical analysis title
    		 OS
    Statistical analysis description
    Statistical analysis was designed to detect superiority of Arm A (eribulin) over Arm B (dacarbazine). OS was compared between the two treatment arms using a two-sided stratified log-rank test at a nominal significance level of 0.0455 (adjusted for the interim analysis). This was the primary analysis that was performed when the target number of events (~353 deaths) was observed.
    Comparison groups
    Arm B: Dacarbazine v Arm A: Eribulin mesylate
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0169 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.768
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.618
         upper limit
    		 0.954
    Notes
    [1] - The P-value was calculated by 2-sided log-rank test as stratified by histology, geographic region, and number of prior regimens for advanced STS.

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS was defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death (whichever occurred first). The date of disease progression was defined as the date of radiologic disease progression as assessed by the investigator or designee based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Subjects who did not have an event (that is subjects who were lost to follow-up or who did not progress or die at the date of data cut-off), were censored. Subjects who discontinued study treatment without disease progression were censored on the date of their last radiological assessment (scan date). FAS (ITT analysis set) included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    Randomization (day 1) to the date of first documentation of disease progression, or date of death (whichever occurred first), approximately up to 5 years 5 months.
    End point values
    		 Arm A: Eribulin mesylate Arm B: Dacarbazine
    Number of subjects analysed
    228
    224
    Units: Months
        median (confidence interval 95%)
    2.6 (1.9 to 2.8)
    2.6 (1.8 to 2.7)
    Statistical analysis title
    		 Progression-free Survival (PFS)
    Statistical analysis description
    The PFS and PFS rate at 3, 6, and 12 months (95% confidence interval[CI]) was calculated using Kaplan-Meier (K-M) product-limit method and Greenwood Formula. PFS was compared between the treatment arms using two-sided stratified log-rank test, stratified by histology, geographic region, and number of prior regimens for advanced STS.
    Comparison groups
    Arm B: Dacarbazine v Arm A: Eribulin mesylate
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2287 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.877
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.085
    Notes
    [2] - P-value was calculated by 2-sided log-rank test, as stratified by histology, geographic region, and number of prior regimens for advanced STS.

    Secondary: Progression-free Rate at 12 Weeks (PFR12wks)

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    End point title
    		 Progression-free Rate at 12 Weeks (PFR12wks)
    End point description
    The PFR12wks was defined as the percentage of subjects who were still alive without disease progression at 12 weeks from the date of randomization. Tumor assessment by the investigator or designee was based on RECIST 1.1. FAS (ITT analysis set) included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    From date of randomization start until Week 12
    End point values
    		 Arm A: Eribulin mesylate Arm B: Dacarbazine
    Number of subjects analysed
    228
    224
    Units: Percentage of participants
        number (confidence interval 95%)
    33.3 (27.2 to 39.9)
    28.6 (22.8 to 35.0)
    Statistical analysis title
    		 Progression-Free Rate at 12 Weeks (PFR12wks)
    Statistical analysis description
    The PFR12wks was compared between the treatment arms using stratified Cochran-Mantel-Haenszel (CMH) chi-square test stratified by histology, geographic region, and number of prior regimens for advanced STS. The odds ratio between eribulin and dacarbazine was calculated by stratified CMH method. The stratified factors were as described above. The 2-sided 95% CI of the odds ratio is based on asymptotic normal approximation.
    Comparison groups
    Arm A: Eribulin mesylate v Arm B: Dacarbazine
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.253 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.9
    Notes
    [3] - The P-value was calculated using the stratified CMH method, the stratified factors included histology, geographic region, and number of prior regimens for advanced STS.

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    CBR was defined as the percentage of subjects who have best overall response (BOR) of complete response (CR), or partial response (PR), or duration of stable disease (dSD) greater than or equal to 11 weeks, between Arm A and Arm B. CBR was estimated by treatment arm based on the tumor response evaluation performed by the PI or designee according to RECIST 1.1. CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. FAS (ITT analysis set) included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    From date of treatment start (Day 1) until disease progression, development of unacceptable toxicity, withdrawal of consent, subject's choice to stop study treatment, up to approximately 5 years 5 months
    End point values
    		 Arm A: Eribulin mesylate Arm B: Dacarbazine
    Number of subjects analysed
    228
    224
    Units: Percentage of participants
        number (confidence interval 95%)
    46.1 (39.5 to 52.8)
    47.8 (41.1 to 54.5)
    Statistical analysis title
    		 Clinical Benefit Rate (CBR)
    Statistical analysis description
    The CBR was compared between the treatment arms using stratified CMH chi-square test stratified by histology, geographic region, and number of prior regimens for advanced STS. The odds ratio between eribulin and dacarbazine was calculated by stratified CMH method. The stratified factors were as described above. The 2-sided 95% CI of odds ratio is based on asymptotic normal approximation.
    Comparison groups
    Arm A: Eribulin mesylate v Arm B: Dacarbazine
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.741 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.4
    Notes
    [4] - The P-value was calculated using the CMH method. The stratified factors were histology, geographic region, and number of prior regimens for advanced STS.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of signing of informed consent up to 30 days after the last dose of study treatment, up to 5 years 5 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Arm A: Eribulin mesylate
    Reporting group description
    		 Eribulin mesylate at a dose of 1.4 mg/m^2 was administered IV as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.

    Reporting group title
    Arm B: Dacarbazine
    Reporting group description
    		 Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the PI or designee prior to randomization according to the subject's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.

    Serious adverse events
    		 Arm A: Eribulin mesylate Arm B: Dacarbazine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    76 / 228 (33.33%)
    71 / 224 (31.70%)
         number of deaths (all causes)
    198
    206
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 228 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to neck
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myxoid liposarcoma
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         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
    0 / 228 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 228 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 228 (4.39%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    4 / 13
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 228 (1.32%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 228 (1.75%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    4 / 228 (1.75%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 228 (0.88%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 228 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 228 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 228 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 228 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    7 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 228 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (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
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (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
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    11 / 228 (4.82%)
    10 / 224 (4.46%)
         occurrences causally related to treatment / all
    18 / 18
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    5 / 228 (2.19%)
    9 / 224 (4.02%)
         occurrences causally related to treatment / all
    4 / 5
    9 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 228 (1.32%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    4 / 4
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 228 (0.88%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 228 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 228 (0.00%)
    13 / 224 (5.80%)
         occurrences causally related to treatment / all
    0 / 0
    19 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 228 (1.75%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    4 / 228 (1.75%)
    5 / 224 (2.23%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 228 (0.88%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 228 (0.88%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal fistula
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 228 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 228 (1.75%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 228 (1.32%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 228 (0.44%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Serratia bacteraemia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    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
    		 Arm A: Eribulin mesylate Arm B: Dacarbazine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    224 / 228 (98.25%)
    218 / 224 (97.32%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    13 / 228 (5.70%)
    4 / 224 (1.79%)
         occurrences all number
    13
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    98 / 228 (42.98%)
    86 / 224 (38.39%)
         occurrences all number
    191
    127
    Pyrexia
         subjects affected / exposed
    58 / 228 (25.44%)
    28 / 224 (12.50%)
         occurrences all number
    85
    35
    Asthenia
         subjects affected / exposed
    46 / 228 (20.18%)
    51 / 224 (22.77%)
         occurrences all number
    82
    80
    Oedema peripheral
         subjects affected / exposed
    27 / 228 (11.84%)
    17 / 224 (7.59%)
         occurrences all number
    30
    21
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    39 / 228 (17.11%)
    28 / 224 (12.50%)
         occurrences all number
    50
    33
    Dyspnoea
         subjects affected / exposed
    34 / 228 (14.91%)
    33 / 224 (14.73%)
         occurrences all number
    40
    37
    Oropharyngeal pain
         subjects affected / exposed
    12 / 228 (5.26%)
    5 / 224 (2.23%)
         occurrences all number
    15
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    22 / 228 (9.65%)
    10 / 224 (4.46%)
         occurrences all number
    24
    10
    Anxiety
         subjects affected / exposed
    12 / 228 (5.26%)
    14 / 224 (6.25%)
         occurrences all number
    13
    16
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    21 / 228 (9.21%)
    5 / 224 (2.23%)
         occurrences all number
    53
    6
    Neutrophil count decreased
         subjects affected / exposed
    19 / 228 (8.33%)
    12 / 224 (5.36%)
         occurrences all number
    90
    34
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 228 (7.89%)
    8 / 224 (3.57%)
         occurrences all number
    57
    10
    White blood cell count decreased
         subjects affected / exposed
    16 / 228 (7.02%)
    15 / 224 (6.70%)
         occurrences all number
    71
    56
    Electrocardiogram QT prolonged
         subjects affected / exposed
    14 / 228 (6.14%)
    11 / 224 (4.91%)
         occurrences all number
    23
    13
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    12 / 228 (5.26%)
    7 / 224 (3.13%)
         occurrences all number
    20
    8
    Platelet count decreased
         subjects affected / exposed
    2 / 228 (0.88%)
    17 / 224 (7.59%)
         occurrences all number
    8
    45
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    46 / 228 (20.18%)
    8 / 224 (3.57%)
         occurrences all number
    81
    8
    Headache
         subjects affected / exposed
    41 / 228 (17.98%)
    21 / 224 (9.38%)
         occurrences all number
    55
    25
    Dizziness
         subjects affected / exposed
    21 / 228 (9.21%)
    16 / 224 (7.14%)
         occurrences all number
    21
    16
    Paraesthesia
         subjects affected / exposed
    20 / 228 (8.77%)
    7 / 224 (3.13%)
         occurrences all number
    28
    11
    Dysgeusia
         subjects affected / exposed
    18 / 228 (7.89%)
    5 / 224 (2.23%)
         occurrences all number
    34
    6
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    95 / 228 (41.67%)
    51 / 224 (22.77%)
         occurrences all number
    234
    139
    Anaemia
         subjects affected / exposed
    66 / 228 (28.95%)
    68 / 224 (30.36%)
         occurrences all number
    151
    149
    Thrombocytopenia
         subjects affected / exposed
    13 / 228 (5.70%)
    60 / 224 (26.79%)
         occurrences all number
    27
    191
    Leukopenia
         subjects affected / exposed
    36 / 228 (15.79%)
    22 / 224 (9.82%)
         occurrences all number
    109
    65
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    18 / 228 (7.89%)
    1 / 224 (0.45%)
         occurrences all number
    29
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    91 / 228 (39.91%)
    106 / 224 (47.32%)
         occurrences all number
    138
    153
    Constipation
         subjects affected / exposed
    70 / 228 (30.70%)
    58 / 224 (25.89%)
         occurrences all number
    102
    69
    Abdominal pain
         subjects affected / exposed
    42 / 228 (18.42%)
    32 / 224 (14.29%)
         occurrences all number
    50
    44
    Vomiting
         subjects affected / exposed
    43 / 228 (18.86%)
    50 / 224 (22.32%)
         occurrences all number
    52
    60
    Diarrhoea
         subjects affected / exposed
    38 / 228 (16.67%)
    35 / 224 (15.63%)
         occurrences all number
    46
    42
    Stomatitis
         subjects affected / exposed
    31 / 228 (13.60%)
    11 / 224 (4.91%)
         occurrences all number
    51
    12
    Abdominal pain upper
         subjects affected / exposed
    19 / 228 (8.33%)
    13 / 224 (5.80%)
         occurrences all number
    22
    15
    Dyspepsia
         subjects affected / exposed
    18 / 228 (7.89%)
    7 / 224 (3.13%)
         occurrences all number
    21
    8
    Abdominal distension
         subjects affected / exposed
    16 / 228 (7.02%)
    12 / 224 (5.36%)
         occurrences all number
    19
    16
    Dry mouth
         subjects affected / exposed
    12 / 228 (5.26%)
    4 / 224 (1.79%)
         occurrences all number
    12
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    79 / 228 (34.65%)
    6 / 224 (2.68%)
         occurrences all number
    106
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    33 / 228 (14.47%)
    31 / 224 (13.84%)
         occurrences all number
    37
    37
    Myalgia
         subjects affected / exposed
    23 / 228 (10.09%)
    17 / 224 (7.59%)
         occurrences all number
    29
    19
    Pain in extremity
         subjects affected / exposed
    20 / 228 (8.77%)
    18 / 224 (8.04%)
         occurrences all number
    27
    24
    Arthralgia
         subjects affected / exposed
    19 / 228 (8.33%)
    13 / 224 (5.80%)
         occurrences all number
    23
    14
    Muscle spasms
         subjects affected / exposed
    13 / 228 (5.70%)
    7 / 224 (3.13%)
         occurrences all number
    19
    8
    Musculoskeletal pain
         subjects affected / exposed
    12 / 228 (5.26%)
    11 / 224 (4.91%)
         occurrences all number
    13
    11
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    23 / 228 (10.09%)
    11 / 224 (4.91%)
         occurrences all number
    28
    14
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 228 (8.77%)
    9 / 224 (4.02%)
         occurrences all number
    25
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    43 / 228 (18.86%)
    43 / 224 (19.20%)
         occurrences all number
    56
    52
    Hypokalaemia
         subjects affected / exposed
    23 / 228 (10.09%)
    9 / 224 (4.02%)
         occurrences all number
    35
    11
    Hyperglycaemia
         subjects affected / exposed
    17 / 228 (7.46%)
    6 / 224 (2.68%)
         occurrences all number
    38
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 May 2012
    Amendment 01: The protocol was amended to update that 1. Subjects should have received at least two standard systemic regimens for advanced STS one of which must have included an anthracycline (unless contraindicated) in inclusion criterion #3. 2. Addition of exclusion of temozolomide from prior therapy in exclusion criterion #3. 3. Removal of exclusion criterion #4, 4. Clarified that only serious and potentially life-threating cardiac arrhythmia would require exclusion from the protocol in exclusion criterion #6. 5. Excluding subjects with a high probability for Long QT Syndrome (LQTS) added in exclusion criterion #7. 6. Exclude serious concomitant illness or infectious disease requiring treatment to exclude infectious disease not requiring treatment but with significant risks for myelosuppressive complications associated with chemotherapy added in exclusion criterion #9. 7. Histologically confirmed complete excision of carcinoma in situ exempted from exclusion criterion #10. 8. Study treatment administration on Day 1 of Cycle 1 and each cycle thereafter. 9. Allowed for dacarbazine dilution up to 500 milliliter (mL) and infusion rate up to 60 minutes. 10. Included instructions for temporary discontinuation of treatment, dose reduction, or resumption of treatment in tabulated form. 11. Permanent discontinuation of study treatment required if unable to administer a scheduled dose of study treatment for more than 21 days due to treatment-related toxicity. 12. Criteria for both arms added for eribulin mesilate and dacarbazine and amendment of serious adverse event (SAE) reporting timeframe to require SAEs to be reported to the Sponsor within 24 hours (and not within 1 business day).
    08 Aug 2012
    Amendment 02 Subjects in Arm A (eribulin) who had a Grade 3 or Grade 4 QTc interval prolongation were to have study drug permanently discontinued.
    01 Dec 2015
    Amendment 03: The protocol was amended to update in the Extension Phase of the study, following the database lock for the primary analysis, ongoing subjects on study treatment in the dacarbazine arm are allowed to cross over to the eribulin arm at the discretion of the investigator decision, frequency of tumor assessments will be permitted to change from every 9 weeks to a frequency at the investigator’s discretion. For subjects who have discontinued study treatment without disease progression, tumor assessments will no longer be required, Sponsor may decide to terminate survival follow-up of all subjects during the Extension Phase after the completion of the primary analysis and when the sponsor considers the data from the primary analysis to be sufficiently mature to no longer require further collection of survival data.

    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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