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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multicenter Phase II trial investigating two doses of EMD 525797 in subjects with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer (mCRPC)

    Summary
    EudraCT number
    2010-021529-11
    Trial protocol
    BE   DE   NL   ES   SK  
    Global end of trial date
    08 Jul 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    18 Sep 2017
    First version publication date
    26 Jul 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR 62242-006
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01360840
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Str. 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.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
    Interim
    Date of interim/final analysis
    30 Apr 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to evaluate the clinical anti-tumor activity of EMD 525797 administered as 1-hour intravenous infusion every 3 weeks in terms of progression free survival (PFS) time in subjects with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer (mCRPC).
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Apr 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
    South Africa: 3
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United States: 24
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Russian Federation: 42
    Worldwide total number of subjects
    180
    EEA total number of subjects
    89
    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)
    49
    From 65 to 84 years
    125
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    First/Last subject (informed consent): April 2011/December 2012. Study completion date: July 2014. Clinical data cut-off: 30 April 2013. Subjects were recruited in 11 countries (Australia, Belgium, Canada, France, Germany, Netherlands, Poland, Russia, South Africa, Spain, and USA) across the globe in 65 centers.

    Pre-assignment
    Screening details
    Enrolled: 283 screened for eligibility; 103 were excluded (mainly non-fulfillment of inclusion or exclusion criteria). 180 subjects were assigned to the treatment groups., However out of these 180 subject, two subjects did not receive study drug administration.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + SoC
    Arm description
    Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks. Subjects also received SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists).

    Arm title
    EMD 525797 750 mg + SoC
    Arm description
    Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
    Arm type
    Experimental

    Investigational medicinal product name
    EMD 525797
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks.

    Arm title
    EMD 525797 1500 mg + SoC
    Arm description
    Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.
    Arm type
    Experimental

    Investigational medicinal product name
    EMD 525797
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks.

    Number of subjects in period 1
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Started
    60
    60
    60
    Completed
    50
    50
    51
    Not completed
    10
    10
    9
         Ongoing at data cut-off
    10
    10
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + SoC
    Reporting group description
    Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.

    Reporting group title
    EMD 525797 750 mg + SoC
    Reporting group description
    Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.

    Reporting group title
    EMD 525797 1500 mg + SoC
    Reporting group description
    Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.

    Reporting group values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC Total
    Number of subjects
    60 60 60 180
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    69.9 ± 8.43 69 ± 7.31 70 ± 8.88 -
    Gender, Male/Female
    Units: Subjects
        Female
    0 0 0 0
        Male
    60 60 60 180

    End points

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    End points reporting groups
    Reporting group title
    Placebo + SoC
    Reporting group description
    Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.

    Reporting group title
    EMD 525797 750 mg + SoC
    Reporting group description
    Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.

    Reporting group title
    EMD 525797 1500 mg + SoC
    Reporting group description
    Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.

    Primary: Progression free survival (PFS) time

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    End point title
    Progression free survival (PFS) time
    End point description
    PFS was defined as time from randomization until the first documented sign of objective radiographic disease progression (ORDP) or death from any cause. Death was considered as an event only if it was reported within 12 weeks after last tumor assessment without progression. ORDP was defined as: Bone lesion progression (2 or more new bone lesions compared to baseline) assessed with bone scintigraphy. Assessment was based on Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0) modified as per Prostate Cancer Working Group 2 (PCWG-2); Soft-tissue lesion progression assessed with CT scans according to RECIST v1.0 modified as per PCWG-2; Presence of skeletal events defined as cord compression/fracture documented via a scheduled or unscheduled radiographic assessment triggered by increased pain or other signs and/or symptoms, based on the investigator’s discretion; Non-radiological events, including emergency bone irradiation and surgery, were not investigated.
    End point type
    Primary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    60
    60
    60
    Units: months
        median (confidence interval 95%)
    3.3 (2.8 to 4.8)
    3.4 (2.8 to 5.6)
    4.3 (2.8 to 6.6)
    Statistical analysis title
    Placebo + SoC versus EMD 525797 750 mg + SoC
    Comparison groups
    Placebo + SoC v EMD 525797 750 mg + SoC
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.57
         upper limit
    1.39
    Statistical analysis title
    Placebo + SoC versus EMD 525797 1500 mg + SoC
    Comparison groups
    Placebo + SoC v EMD 525797 1500 mg + SoC
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    1.26

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall Survival was defined as the time from the date of randomization to the date of death from any cause. Here, the value "99999.9" indicates that the endpoint was not evaluable.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    60
    60
    60
    Units: months
        median (confidence interval 95%)
    99999.9 (14.8 to 99999.9)
    99999.9 (12.4 to 99999.9)
    99999.9 (14.4 to 99999.9)
    Statistical analysis title
    Placebo + SoC versus EMD 525797 750 mg + SoC
    Comparison groups
    Placebo + SoC v EMD 525797 750 mg + SoC
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    2.31
    Statistical analysis title
    Placebo + SoC versus EMD 525797 1500 mg + SoC
    Comparison groups
    Placebo + SoC v EMD 525797 1500 mg + SoC
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    2.15

    Secondary: Time to tumor progression

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    End point title
    Time to tumor progression
    End point description
    Time to tumor progression was defined as the time from the date of randomization to the date of ORDP. ORDP was defined as: Bone lesion progression (2 or more new bone lesions compared to baseline) assessed with bone scintigraphy, which had to be confirmed by bone scintigraphy 6 weeks later if subjects remained asymptomatic or mildly symptomatic. Assessments were to be based on RECIST v1.0 modified according to PCWG-2; Soft-tissue lesion progression assessed with CT scans according to RECIST v1.0 modified as per PCWG-2; Presence of skeletal events defined as cord compression or fracture documented via a scheduled or unscheduled radiographic assessment triggered by increased pain or other signs and/or symptoms, based on the investigator’s discretion; Non-radiological events, including emergency bone irradiation and surgery, were not investigated.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    60
    60
    60
    Units: months
        median (confidence interval 95%)
    3.3 (2.8 to 5.4)
    3.4 (2.8 to 5.6)
    4.6 (2.8 to 6.9)
    Statistical analysis title
    Placebo + SoC versus EMD 525797 750 mg + SoC
    Comparison groups
    Placebo + SoC v EMD 525797 750 mg + SoC
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    1.44
    Statistical analysis title
    Placebo + SoC versus EMD 525797 1500 mg + SoC
    Comparison groups
    Placebo + SoC v EMD 525797 1500 mg + SoC
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    1.27

    Secondary: Number of subjects with presence of tumor response and disease control (DC) in soft tissue lesions

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    End point title
    Number of subjects with presence of tumor response and disease control (DC) in soft tissue lesions
    End point description
    Presence of tumor response in soft tissue lesions was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) in soft tissue lesions, documented by computed tomography (CT) scans. Presence of DC in soft tissue lesions was defined as the presence of at least 1 confirmed CR or confirmed PR or stable disease (SD) lasting at least 12 weeks after randomization. Tumor response assessments were based on RECIST v1.0 modified according to the PCWG-2. The response was evaluated for subjects with measurable disease at baseline. According to RECIST v1.0, CR=disappearance of all target and non-target lesions; PR=at least 30% decrease in the sum of the longest diameter of target lesions and non-complete response/non-progressive disease in non-target lesions. This endpoint was assessed in ITT analysis set subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    28
    22
    24
    Units: Subjects
        Tumor response
    1
    0
    1
        Disease control
    2
    3
    4
    No statistical analyses for this end point

    Secondary: Number of subjects with new bone lesions compared to baseline

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    End point title
    Number of subjects with new bone lesions compared to baseline
    End point description
    New bone lesions were evaluated by bone scintigraphy for subjects with bone lesions at baseline. This endpoint was assessed in ITT analysis set subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    57
    57
    57
    Units: Subjects
    40
    34
    34
    No statistical analyses for this end point

    Secondary: Number of subjects with Presence of DC in bone lesions

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    End point title
    Number of subjects with Presence of DC in bone lesions
    End point description
    Presence of DC in bone lesions was defined as the appearance of less than 2 new bone lesions, documented by bone scintigraphy. This endpoint was assessed in ITT analysis set.
    End point type
    Secondary
    End point timeframe
    At Weeks 13, 19 and 25
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    60
    60
    60
    Units: Subjects
        Week 13
    4
    7
    7
        Week 19
    2
    7
    6
        Week 25
    2
    4
    3
    No statistical analyses for this end point

    Secondary: Bone and soft tissue lesions Composite Tumor Response

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    End point title
    Bone and soft tissue lesions Composite Tumor Response
    End point description
    Bone and soft tissue lesions composite tumor response was defined as the presence of both a confirmed CR or PR, documented by CT scans, and a DC in bone lesions, documented by bone scintigraphy. CR was defined as disappearance of all target and non-target lesions and PR was defined as at least 30% decrease in the sum of the longest diameter of target lesions and non-complete response/non-progressive disease in non-target lesions. Presence of DC in bone lesions was defined as the appearance of less than 2 new bone lesions.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    60
    60
    60
    Units: Subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with presence of skeletal related events

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    End point title
    Number of subjects with presence of skeletal related events
    End point description
    Presence of skeletal related events was defined as cord compression or fracture documented via a scheduled or unscheduled radiographic assessment triggered by increased pain or other signs and/or symptoms at the investigator discretion. Non-radiological events, including emergency bone irradiation and surgery, were not investigated. This endpoint was assessed in ITT analysis set.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    60
    60
    60
    Units: Subjects
        number (not applicable)
    2
    8
    3
    No statistical analyses for this end point

    Secondary: Number of subjects with Presence of prostate specific antigen (PSA) response

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    End point title
    Number of subjects with Presence of prostate specific antigen (PSA) response
    End point description
    PSA response was defined as a decrease greater than 50 percent (%) in PSA value from baseline for 2 consecutive evaluations greater than or equal to (>=) 3 Weeks apart. This endpoint was assessed in ITT analysis set subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    60
    58
    60
    Units: Subjects
    3
    6
    5
    No statistical analyses for this end point

    Secondary: Minimum Percentage change from baseline in PSA serum concentration

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    End point title
    Minimum Percentage change from baseline in PSA serum concentration
    End point description
    This endpoint was assessed in ITT analysis set subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    58
    57
    60
    Units: Percent change
        arithmetic mean (standard deviation)
    24 ± 86.156
    35.65 ± 127.677
    14.7 ± 50.841
    No statistical analyses for this end point

    Secondary: Minimum Percentage change from baseline in the number of circulating tumor cells (CTCs)

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    End point title
    Minimum Percentage change from baseline in the number of circulating tumor cells (CTCs)
    End point description
    This endpoint was assessed in ITT analysis set subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    29
    27
    22
    Units: Percent change
        arithmetic mean (standard deviation)
    49.02 ± 127.643
    354.74 ± 1038.195
    280.58 ± 482.653
    No statistical analyses for this end point

    Secondary: Minimum Percentage change from previous time point in CTC

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    End point title
    Minimum Percentage change from previous time point in CTC
    End point description
    This endpoint was assessed in ITT analysis set subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    36
    34
    30
    Units: Percent change
        arithmetic mean (standard deviation)
    9.54 ± 103.225
    223.97 ± 868.941
    179.11 ± 446.428
    No statistical analyses for this end point

    Secondary: Number of Subjects With Any treatment emergent adverse events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation

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    End point title
    Number of Subjects With Any treatment emergent adverse events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation
    End point description
    An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as those AEs that started between first dose of study drug and up to 50 days after last dose. This endpoint was assessed in the safety analysis set which included all the randomized subjects who received at least 1 dose of planned trial treatment and had at least one safety assessment following the trial treatment.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off date (30 April 2013)
    End point values
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    60
    58
    60
    Units: Subjects
        TEAEs
    55
    49
    53
        Serious TEAEs
    16
    13
    14
        TEAEs leading to death
    2
    2
    3
        TEAEs Leading to Permanent Discontinuation
    5
    11
    8
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter: Clearance of intravenously administered EMD 525797 after first dose (CL) and clearance in steady state of EMD52597 after fifth dose (CLss)

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    End point title
    Pharmacokinetic Parameter: Clearance of intravenously administered EMD 525797 after first dose (CL) and clearance in steady state of EMD52597 after fifth dose (CLss) [1]
    End point description
    The apparent total body clearance of drug following intravenous administration (CL); The apparent total body clearance of drug at steady state following intravenous administration (CLss). This endpoint was assessed in pharmacokinetic analysis set (PKA) which included all the randomized subjects who received at least the first dose of the trial drug and provided sufficient data for a concentration time profile for EMD 525797. "n" signifies the number of subjects evaluable for each category in the evaluated group, respectively.
    End point type
    Secondary
    End point timeframe
    Week1 until pre-dose of Week 4: First dose; Week 13 until pre-dose Week 16: Fifth dose
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reported in only EMD 52597 750 mg+SoC and EMD 525 1500 mg+SoC as per planned analysis.
    End point values
    EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    4
    6
    Units: Liter per hour
    arithmetic mean (standard deviation)
        First dose: CL (n=4, 6)
    0.017 ± 0.007
    0.013 ± 0.003
        Fifth dose: CLss (n=2, 4)
    0.017 ± 0.002
    0.01 ± 0.001
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter: Volume of distribution of EMD 525797 after the first dose (V) and in steady state after the fifth dose (Vss) of intravenous infusion

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    End point title
    Pharmacokinetic Parameter: Volume of distribution of EMD 525797 after the first dose (V) and in steady state after the fifth dose (Vss) of intravenous infusion [2]
    End point description
    The apparent volume of distribution during the terminal phase following intravenous administration (V). The estimate of the apparent volume of distribution at steady state following intravenous administration (Vss). This endpoint was assessed in PKA. "n" signifies the number of subjects evaluable for each category in the evaluated group, respectively. The value "99999.9" here indicates the standard deviation for this parameter which was not evaluable.
    End point type
    Secondary
    End point timeframe
    Week1 until pre-dose of Week 4: First dose; Week 13 until pre-dose Week 16: Fifth dose
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reported in only EMD 52597 750 mg+SoC and EMD 525 1500 mg+SoC as per planned analysis.
    End point values
    EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    4
    6
    Units: liter
    arithmetic mean (standard deviation)
        First dose (n=4, 6)
    4.55 ± 1.02
    4.6 ± 0.74
        Fifth dose (n=2, 4)
    4.81 ± 99999.9
    5.18 ± 0.56
    No statistical analyses for this end point

    Other pre-specified: To explore the relationship between number and/or changes of numbers of biomarker and the clinical outcome

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    End point title
    To explore the relationship between number and/or changes of numbers of biomarker and the clinical outcome [3]
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Up to data cut-off date (30 April 2013)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reported in only EMD 52597 750 mg+SoC and EMD 525 1500 mg+SoC as per planned analysis.
    End point values
    EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Number of biomarkers
    Notes
    [4] - Data for this outcome measure was presented graphically as per planned analysis.
    [5] - Data for this outcome measure was presented graphically as per planned analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the initiation of the trial treatment until 30 days after last administration of trial treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo + SoC
    Reporting group description
    Subjects were administered with placebo 0.9% sodium chloride as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.

    Reporting group title
    EMD 525797 750 mg + SoC
    Reporting group description
    Subjects were administered with EMD 525797 at a dose of 750 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.

    Reporting group title
    EMD 525797 1500 mg + SoC
    Reporting group description
    Subjects were administered with EMD 525797 at a dose of 1500 mg (diluted with 0.9% sodium chloride) as a 1-hour intravenous infusion every 3 Weeks until disease progression or unacceptable toxicity, whichever comes first, unless the subject stopped the trial treatment for other reasons. All the subjects followed the SoC consisting of the continued treatment with luteinizing-hormone releasing hormone agonists (or antagonists). In order to avoid any confounding effects, bisphosphonate treatment was initiated 2 days before start of treatment with EMD 525797.

    Serious adverse events
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 60 (26.67%)
    13 / 58 (22.41%)
    14 / 60 (23.33%)
         number of deaths (all causes)
    2
    2
    2
         number of deaths resulting from adverse events
    1
    0
    0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    3 / 60 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epiduritis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysaesthesia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 58 (3.45%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pemphigoid
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis orbital
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic shock syndrome
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo + SoC EMD 525797 750 mg + SoC EMD 525797 1500 mg + SoC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 60 (88.33%)
    47 / 58 (81.03%)
    53 / 60 (88.33%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 58 (3.45%)
    1 / 60 (1.67%)
         occurrences all number
    2
    2
    1
    Hypertension
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 58 (1.72%)
    2 / 60 (3.33%)
         occurrences all number
    4
    3
    2
    Hot flush
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 58 (3.45%)
    2 / 60 (3.33%)
         occurrences all number
    3
    2
    2
    Orthostatic hypotension
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Orthostatic hypertension
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone neoplasm malignant
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    2
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Tumour invasion
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Tumour pain
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Asthenia
         subjects affected / exposed
    9 / 60 (15.00%)
    3 / 58 (5.17%)
    6 / 60 (10.00%)
         occurrences all number
    15
    3
    11
    Chest pain
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    1 / 60 (1.67%)
         occurrences all number
    0
    2
    1
    Hypothermia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    12 / 60 (20.00%)
    10 / 58 (17.24%)
    9 / 60 (15.00%)
         occurrences all number
    14
    18
    9
    Feeling hot
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    1
    2
    0
    Gait disturbance
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Crying
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    4 / 60 (6.67%)
    8 / 58 (13.79%)
    3 / 60 (5.00%)
         occurrences all number
    6
    8
    5
    Malaise
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    3
    1
    0
    Non-Cardiac chest pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    0
    2
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 60 (1.67%)
    7 / 58 (12.07%)
    1 / 60 (1.67%)
         occurrences all number
    1
    8
    2
    Pain
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 58 (3.45%)
    3 / 60 (5.00%)
         occurrences all number
    1
    2
    3
    Pyrexia
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 58 (6.90%)
    4 / 60 (6.67%)
         occurrences all number
    2
    5
    9
    Spinal pain
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 58 (3.45%)
    1 / 60 (1.67%)
         occurrences all number
    1
    2
    1
    Temperature intolerance
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    1
    1
    1
    Initial insomnia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 58 (3.45%)
    3 / 60 (5.00%)
         occurrences all number
    3
    2
    3
    Mood altered
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Stress
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Balanitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Testicular pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Perineal pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Penile pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Pelvic pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    1
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    2
    1
    1
    Hand fracture
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Ligament sprain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Skin wound
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Infusion related reaction
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Tooth fracture
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    1
    2
    1
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 58 (3.45%)
    1 / 60 (1.67%)
         occurrences all number
    1
    3
    1
    Blood creatine increased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 58 (3.45%)
    3 / 60 (5.00%)
         occurrences all number
    1
    2
    4
    Blood potassium increased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    0
    0
    2
    Blood cholesterol increased
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    1
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 58 (1.72%)
    4 / 60 (6.67%)
         occurrences all number
    4
    1
    5
    Blood urine present
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Blood urea increased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    1
    C-Reactive protein increased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    3 / 60 (5.00%)
         occurrences all number
    0
    1
    3
    Calcium ionised decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Cardiac murmur
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram st-t segment abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    3
    Fibrin d dimer increased
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 58 (3.45%)
    3 / 60 (5.00%)
         occurrences all number
    5
    3
    5
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    3
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    International normalised ratio decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    1
    0
    3
    Weight decreased
         subjects affected / exposed
    6 / 60 (10.00%)
    1 / 58 (1.72%)
    5 / 60 (8.33%)
         occurrences all number
    6
    1
    5
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Bradycardia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 60 (1.67%)
    5 / 58 (8.62%)
    5 / 60 (8.33%)
         occurrences all number
    1
    6
    5
    Epistaxis
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    3 / 60 (5.00%)
         occurrences all number
    1
    2
    3
    Dyspnoea exertional
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    1
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 58 (5.17%)
    3 / 60 (5.00%)
         occurrences all number
    2
    3
    3
    Dysphonia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    1
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    1
    1
    1
    Haemoptysis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Pleural effusion
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Sinus congestion
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    1
    1
    1
    Sputum retention
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 60 (16.67%)
    6 / 58 (10.34%)
    13 / 60 (21.67%)
         occurrences all number
    16
    7
    25
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Anaemia of chronic disease
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Anaemia macrocytic
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    6
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Hypochromic anaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Leukocytosis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    1
    0
    2
    Lymphopenia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    5
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 58 (5.17%)
    0 / 60 (0.00%)
         occurrences all number
    0
    4
    0
    Paratracheal lymphadenopathy
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Disturbance in attention
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 58 (1.72%)
    3 / 60 (5.00%)
         occurrences all number
    2
    1
    3
    Burning sensation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Cervical root pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    5 / 60 (8.33%)
    1 / 58 (1.72%)
    2 / 60 (3.33%)
         occurrences all number
    6
    1
    2
    Head discomfort
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Epiduritis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    3 / 60 (5.00%)
         occurrences all number
    1
    1
    3
    Memory impairment
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    0
    0
    4
    Hypoaesthesia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    2 / 60 (3.33%)
         occurrences all number
    0
    1
    2
    Paraplegia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Paresis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Sciatica
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    1
    0
    2
    Spinal cord compression
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular encephalopathy
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Asthenopia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    0
    0
    2
    Ocular hyperaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Eye pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    1
    Visual acuity reduced
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    1
    1
    1
    Vision blurred
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    2
    Scleral haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    2 / 60 (3.33%)
         occurrences all number
    0
    2
    2
    Hypoacusis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    2
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    2 / 60 (3.33%)
         occurrences all number
    0
    1
    3
    Cheilitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Aphthous stomatitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 58 (5.17%)
    0 / 60 (0.00%)
         occurrences all number
    2
    3
    0
    Colitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    5 / 60 (8.33%)
    9 / 58 (15.52%)
    3 / 60 (5.00%)
         occurrences all number
    5
    9
    3
    Dental caries
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    7 / 60 (11.67%)
    6 / 58 (10.34%)
    3 / 60 (5.00%)
         occurrences all number
    9
    7
    6
    Eructation
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Gingivitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Pancreatitis acute
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Oral pain
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    Nausea
         subjects affected / exposed
    2 / 60 (3.33%)
    6 / 58 (10.34%)
    6 / 60 (10.00%)
         occurrences all number
    3
    8
    7
    Odynophagia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Parotid gland enlargement
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Periodontitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    0
    0
    3
    Peptic ulcer
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    1
    Stomatitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Retching
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Proctalgia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Proctitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 58 (6.90%)
    3 / 60 (5.00%)
         occurrences all number
    2
    5
    5
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 58 (6.90%)
    3 / 60 (5.00%)
         occurrences all number
    3
    4
    4
    Dysuria
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    1
    1
    1
    Azotaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    3
    0
    2
    Calculus urinary
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    1
    Hydronephrosis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Renal failure
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    2
    0
    2
    Proteinuria
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    2 / 60 (3.33%)
         occurrences all number
    1
    2
    2
    Nocturia
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Leukocyturia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Ureteric obstruction
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Stress urinary incontinence
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Renal pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Renal failure acute
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    1 / 60 (1.67%)
         occurrences all number
    0
    2
    1
    Urinary tract obstruction
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Hepatomegaly
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Cholelithiasis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Actinic keratosis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Eczema
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    2 / 60 (3.33%)
         occurrences all number
    0
    1
    2
    Dermatitis bullous
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Ecchymosis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Erythema
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    3 / 60 (5.00%)
         occurrences all number
    0
    1
    5
    Generalised erythema
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences all number
    1
    2
    0
    Hypertrichosis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Eczema asteatotic
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Pemphigus
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Intertrigo
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Lentigo
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Papule
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 58 (6.90%)
    6 / 60 (10.00%)
         occurrences all number
    1
    4
    6
    Rash generalised
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    2 / 60 (3.33%)
         occurrences all number
    0
    2
    3
    Rash
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 58 (5.17%)
    5 / 60 (8.33%)
         occurrences all number
    1
    3
    6
    Subcutaneous nodule
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    1
    1
    1
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 58 (5.17%)
    2 / 60 (3.33%)
         occurrences all number
    0
    5
    3
    Urticaria
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences all number
    0
    6
    0
    Swelling face
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 60 (16.67%)
    9 / 58 (15.52%)
    6 / 60 (10.00%)
         occurrences all number
    12
    10
    10
    Bone pain
         subjects affected / exposed
    7 / 60 (11.67%)
    6 / 58 (10.34%)
    6 / 60 (10.00%)
         occurrences all number
    11
    10
    12
    Bone swelling
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Bunion
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Arthralgia
         subjects affected / exposed
    7 / 60 (11.67%)
    7 / 58 (12.07%)
    7 / 60 (11.67%)
         occurrences all number
    7
    8
    8
    Flank pain
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    2
    1
    3
    Groin pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Mobility decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 58 (1.72%)
    4 / 60 (6.67%)
         occurrences all number
    2
    1
    8
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 58 (5.17%)
    1 / 60 (1.67%)
         occurrences all number
    1
    3
    1
    Musculoskeletal pain
         subjects affected / exposed
    3 / 60 (5.00%)
    6 / 58 (10.34%)
    3 / 60 (5.00%)
         occurrences all number
    3
    7
    3
    Myalgia
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 58 (5.17%)
    4 / 60 (6.67%)
         occurrences all number
    5
    6
    7
    Neck pain
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 58 (5.17%)
    1 / 60 (1.67%)
         occurrences all number
    1
    3
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences all number
    0
    2
    0
    Osteopenia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    4 / 60 (6.67%)
    8 / 58 (13.79%)
    3 / 60 (5.00%)
         occurrences all number
    5
    11
    4
    Pain in jaw
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Trigger finger
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    Decreased appetite
         subjects affected / exposed
    5 / 60 (8.33%)
    8 / 58 (13.79%)
    4 / 60 (6.67%)
         occurrences all number
    5
    10
    4
    Diabetes mellitus
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    1
    2
    1
    Fluid overload
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Gout
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    3 / 60 (5.00%)
         occurrences all number
    0
    2
    4
    Hyperglycaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 58 (1.72%)
    1 / 60 (1.67%)
         occurrences all number
    3
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    1
    0
    4
    Hypermagnesaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 58 (1.72%)
    7 / 60 (11.67%)
         occurrences all number
    3
    1
    8
    Hypokalaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    3
    0
    0
    Vitamin d deficiency
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Anal fungal infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    1
    0
    2
    Fungal oesophagitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Cystitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    4
    2
    0
    Herpes simplex
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 60 (3.33%)
    5 / 58 (8.62%)
    2 / 60 (3.33%)
         occurrences all number
    2
    5
    2
    Oral fungal infection
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    Perineal infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
    2 / 60 (3.33%)
         occurrences all number
    0
    2
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    0
    0
    2
    Skin candida
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    2 / 60 (3.33%)
         occurrences all number
    0
    1
    2
    Tooth infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    2
    Wound sepsis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 60 (3.33%)
    3 / 58 (5.17%)
    1 / 60 (1.67%)
         occurrences all number
    2
    3
    1
    Wound infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jan 2011
    The purpose of this protocol amendment was to add safety assessments for increased subject safety and safety data validity, to add PK assessments, and to add immunogenicity assessment.
    20 Oct 2011
    The purpose of this protocol amendment was to: Change the statistical method of randomization from Bayesian adaptive randomization to randomization with an allocation ratio of 1:1:1, reduce the number of blood samples taken for biomarker analyses, modify inclusion criteria, and modify ECG recording.
    30 Aug 2012
    The purpose of this protocol amendment was to: Decrease the sample size from 216 to 165 randomized subjects and to change the primary analysis cut-off date, and to adapt the wording of the primary objective of the trial.

    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.
    This trial was prematurely terminated as primary endpoint of the trial i.e. Progression Free Survival, was not met with respect to pre-defined proof of concept criteria. A decision was taken to terminate this trial.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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