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    Clinical Trial Results:
    A multi-center phase III randomized, double-blind placebo-controlled study of the cancer vaccine Stimuvax® (L-BLP25 or BLP25 liposome vaccine) in non-small cell lung cancer (NSCLC) subjects with unresectable stage III disease.

    Summary
    EudraCT number
    		 2006-000579-14
    Trial protocol
    		 AT   BE   GB   HU   CZ   SE   DE   ES   DK   FR   GR   IT   NL   SK   IE   PT  
    Global end of trial date
    09 Sep 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR 63325-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00409188
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Serono, a division of Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Merck KGaA Communication Center, Merck Serono, a division of Merck KGaA, service@merckgroup.com
    Scientific contact
    Responsible, Merck Serono, a division of Merck KGaA, 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
    Final
    Date of interim/final analysis
    08 Aug 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Aug 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine whether the cancer vaccine tecemotide (L-BLP25) in addition to best supportive care is effective in prolonging the lives of subjects with unresectable stage III non-small cell lung cancer, compared to best supportive care alone.
    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
    25 Jan 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 66 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 17
    Country: Number of subjects enrolled
    Spain: 78
    Country: Number of subjects enrolled
    Sweden: 64
    Country: Number of subjects enrolled
    Switzerland: 9
    Country: Number of subjects enrolled
    Taiwan: 27
    Country: Number of subjects enrolled
    United Kingdom: 57
    Country: Number of subjects enrolled
    United States: 188
    Country: Number of subjects enrolled
    Argentina: 40
    Country: Number of subjects enrolled
    Australia: 43
    Country: Number of subjects enrolled
    Austria: 28
    Country: Number of subjects enrolled
    Belgium: 59
    Country: Number of subjects enrolled
    Brazil: 42
    Country: Number of subjects enrolled
    Canada: 142
    Country: Number of subjects enrolled
    China: 1
    Country: Number of subjects enrolled
    Czech Republic: 95
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    France: 65
    Country: Number of subjects enrolled
    Germany: 109
    Country: Number of subjects enrolled
    Greece: 20
    Country: Number of subjects enrolled
    Hong Kong: 9
    Country: Number of subjects enrolled
    Hungary: 26
    Country: Number of subjects enrolled
    India: 5
    Country: Number of subjects enrolled
    Ireland: 9
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Netherlands: 25
    Country: Number of subjects enrolled
    Poland: 165
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Romania: 46
    Country: Number of subjects enrolled
    Russian Federation: 45
    Country: Number of subjects enrolled
    Singapore: 7
    Worldwide total number of subjects
    1513
    EEA total number of subjects
    919
    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)
    970
    From 65 to 84 years
    542
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 First/last subject (informed consent): 25 January 2007/31 October 2011. Data cut-off for primary endpoint analysis: 08 August 2012. Subjects randomized at 264 centers in 33 countries worldwide.

    Pre-assignment
    Screening details
    		 A total of 1908 subjects were screened for eligibility and 1513 subjects were enrolled and randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tecemotide (L-BLP25) + Cyclophosphamide
    Arm description
    		 A single intravenous infusion of 300 milligram per square meter (mg/m^2) (to a maximum 600 mg) of cyclophosphamide was given 3 days before first tecemotide (L-BLP25) vaccination. After receiving cyclophosphamide, subjects received 8 consecutive weekly subcutaneous vaccinations with 806 microgram (mcg) of tecemotide (L-BLP25) at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance vaccinations with 806 mcg of tecemotide (L-BLP25) at 6-week intervals, commencing at Week 13, until disease progression was documented.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tecemotide (L-BLP25)
    Investigational medicinal product code
    Other name
    Stimuvax
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    After receiving cyclophosphamide, subjects received 8 consecutive weekly subcutaneous vaccinations with 806 microgram (mcg) of tecemotide (L-BLP25) at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance vaccinations with 806 mcg of tecemotide (L-BLP25) at 6-week intervals, commencing at Week 13, until disease progression is documented.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects administered with a single intravenous infusion of 300 milligram per square meter (mg/m^2) (to a maximum 600 mg) of cyclophosphamide 3 days before first tecemotide (L-BLP25) vaccination.

    Arm title
    		 Saline + Placebo
    Arm description
    		 A single intravenous infusion of 0.9 percent (%) saline solution in the same calculated dose as cyclophosphamide was given 3 days before first placebo vaccination. After receiving saline, subjects received 8 consecutive weekly subcutaneous vaccinations with placebo at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance placebo vaccinations at 6-week intervals, commencing at Week 13, until disease progression was documented.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received eight consecutive weekly subcutaneous vaccinations with placebo at weeks 0; 1; 2; 3; 4; 5; 6 and 7 followed by maintenance placebo vaccinations at 6-week intervals, commencing at week 13, until disease progression is documented.

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects administered with a single infusion (IV) of 0.9% Saline solution instead of cyclophosphamide but in the same calculated dose given three days before first placebo vaccination.

    Number of subjects in period 1
    		Tecemotide (L-BLP25) + Cyclophosphamide Saline + Placebo
    Started
    1006
    507
    Completed
    623
    332
    Not completed
    383
    175
         Ongoing at data cut-off
    383
    175

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tecemotide (L-BLP25) + Cyclophosphamide
    Reporting group description
    		 A single intravenous infusion of 300 milligram per square meter (mg/m^2) (to a maximum 600 mg) of cyclophosphamide was given 3 days before first tecemotide (L-BLP25) vaccination. After receiving cyclophosphamide, subjects received 8 consecutive weekly subcutaneous vaccinations with 806 microgram (mcg) of tecemotide (L-BLP25) at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance vaccinations with 806 mcg of tecemotide (L-BLP25) at 6-week intervals, commencing at Week 13, until disease progression was documented.

    Reporting group title
    Saline + Placebo
    Reporting group description
    		 A single intravenous infusion of 0.9 percent (%) saline solution in the same calculated dose as cyclophosphamide was given 3 days before first placebo vaccination. After receiving saline, subjects received 8 consecutive weekly subcutaneous vaccinations with placebo at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance placebo vaccinations at 6-week intervals, commencing at Week 13, until disease progression was documented.

    Reporting group values
    		 Tecemotide (L-BLP25) + Cyclophosphamide Saline + Placebo Total
    Number of subjects
    		 1006 507 1513
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 657 313 970
        From 65 to 84 years
    		 348 194 542
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.7 ( 9.1 ) 60.9 ( 9 ) -
    Gender, Male/Female
    Units: subjects
        Female
    		 315 162 477
        Male
    		 691 345 1036

    End points

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    End points reporting groups
    Reporting group title
    Tecemotide (L-BLP25) + Cyclophosphamide
    Reporting group description
    		 A single intravenous infusion of 300 milligram per square meter (mg/m^2) (to a maximum 600 mg) of cyclophosphamide was given 3 days before first tecemotide (L-BLP25) vaccination. After receiving cyclophosphamide, subjects received 8 consecutive weekly subcutaneous vaccinations with 806 microgram (mcg) of tecemotide (L-BLP25) at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance vaccinations with 806 mcg of tecemotide (L-BLP25) at 6-week intervals, commencing at Week 13, until disease progression was documented.

    Reporting group title
    Saline + Placebo
    Reporting group description
    		 A single intravenous infusion of 0.9 percent (%) saline solution in the same calculated dose as cyclophosphamide was given 3 days before first placebo vaccination. After receiving saline, subjects received 8 consecutive weekly subcutaneous vaccinations with placebo at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance placebo vaccinations at 6-week intervals, commencing at Week 13, until disease progression was documented.

    Subject analysis set title
    Tecemotide (L-BLP25) + Cyclophosphamide
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    A single intravenous infusion of 300 milligram per square meter (mg/m^2) (to a maximum 600 mg) of cyclophosphamide was given 3 days before first tecemotide (L-BLP25) vaccination. After receiving cyclophosphamide, subjects received 8 consecutive weekly subcutaneous vaccinations with 806 microgram (mcg) of tecemotide (L-BLP25) at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance vaccinations with 806 mcg of tecemotide (L-BLP25) at 6-week intervals, commencing at Week 13, until disease progression was documented. Safety analysis set included all subjects who received at least 1 dose of trial treatment (cyclophosphamide, tecemotide, saline, or placebo). Subjects were reported based on the actual treatment received (as-treated).

    Subject analysis set title
    Saline + Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    A single intravenous infusion of 0.9 percent (%) saline solution in the same calculated dose as cyclophosphamide was given 3 days before first placebo vaccination. After receiving saline, subjects received 8 consecutive weekly subcutaneous vaccinations with placebo at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance placebo vaccinations at 6-week intervals, commencing at Week 13, until disease progression was documented. Safety analysis set included all subjects who received at least 1 dose of trial treatment (cyclophosphamide, tecemotide, saline, or placebo). subjects were reported based on the actual treatment received (as-treated).

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival time was defined as the time from randomization to death. Subjects without events were censored at the last date they were known to be alive or the clinical cut-off date, whatever was earlier. Primary analysis set (modified intention-to-treat [ITT] population) was based on the ITT population but prospectively excluded all subjects (274 subjects) that were randomized during the 6 months (22 Sep 2009 to 22 Mar 2010) prior to the effective date of clinical hold.
    End point type
    Primary
    End point timeframe
    Up to 66 months
    End point values
    		 Tecemotide (L-BLP25) + Cyclophosphamide Saline + Placebo
    Number of subjects analysed
    829
    410
    Units: months
        median (confidence interval 95%)
    25.6 (22.5 to 29.2)
    22.3 (19.6 to 25.5)
    Statistical analysis title
    		 Overall Survival Statistical Analysis
    Comparison groups
    Tecemotide (L-BLP25) + Cyclophosphamide v Saline + Placebo
    Number of subjects included in analysis
    1239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1566
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.893
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.763
         upper limit
    		 1.044

    Secondary: Time To Symptom Progression (TTSP) as Measured by the Lung Cancer Symptom Scale (LCSS)

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    End point title
    		 Time To Symptom Progression (TTSP) as Measured by the Lung Cancer Symptom Scale (LCSS)
    End point description
    Time to symptom progression (TTSP) was measured by LCSS. Symptomatic progression was defined as an increase (worsening) of the Average Symptomatic Burden Index (ASBI that is, the mean of the six major lung cancer specific symptom scores of the LCSS patient scale – ranging from 0 to 100 where higher score indicates worst outcome). Worsening was defined as a 10% increase in the scale breadth from the baseline score. TTSP is defined as the time from randomization to worsening in ASBI. Subjects without event are censored at the date of the last LCSS assessment. Primary analysis set (modified ITT population) was based on the ITT population but prospectively excluded all subjects (274 subjects) that were randomized during the 6 months (22-Sep-2009 to 22-Mar-2010) prior to the effective date of clinical hold. Number of subjects analysed were the subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to 66 months
    End point values
    		 Tecemotide (L-BLP25) + Cyclophosphamide Saline + Placebo
    Number of subjects analysed
    829
    409
    Units: months
        median (confidence interval 95%)
    14.2 (12.9 to 15.7)
    11.4 (9.3 to 13.1)
    Statistical analysis title
    		 TTSP Statistical Analysis
    Comparison groups
    Tecemotide (L-BLP25) + Cyclophosphamide v Saline + Placebo
    Number of subjects included in analysis
    1238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0226
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.845
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.732
         upper limit
    		 0.977

    Secondary: Time To Progression (TTP)

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    End point title
    		 Time To Progression (TTP)
    End point description
    Time from randomization to disease progression. Disease progression was defined based on Response Evaluation Criteria in Solid Tumors Version 1.0 [RECIST v1.0]) as at least a 20% increase in the sum of the longest diameter of target lesions from nadir, or the appearance of one or more new lesions. Primary analysis set (modified ITT population) was based on the ITT population but prospectively excluded all subjects (274 subjects) that were randomized during the 6 months (22 Sep 2009 to 22 Mar 2010) prior to the effective date of clinical hold.
    End point type
    Secondary
    End point timeframe
    Up to 66 months
    End point values
    		 Tecemotide (L-BLP25) + Cyclophosphamide Saline + Placebo
    Number of subjects analysed
    829
    410
    Units: months
        median (confidence interval 95%)
    10 (9.1 to 11.5)
    8.4 (7.2 to 10.8)
    Statistical analysis title
    		 TTP Statistical Analysis
    Comparison groups
    Tecemotide (L-BLP25) + Cyclophosphamide v Saline + Placebo
    Number of subjects included in analysis
    1239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0528
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.868
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.752
         upper limit
    		 1.002

    Secondary: One, two- and three-year survival rate

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    End point title
    		 One, two- and three-year survival rate
    End point description
    The percentages of subjects who were alive at 1, 2, and 3 years were calculated as a cumulative percentage by Kaplan-Meier survival analysis approach. Primary analysis set (modified ITT population) was based on the ITT population but prospectively excluded all subjects (274 subjects) that were randomized during the 6 months (22 Sep 2009 to 22 Mar 2010) prior to the effective date of clinical hold.
    End point type
    Secondary
    End point timeframe
    Years 1, 2, and 3
    End point values
    		 Tecemotide (L-BLP25) + Cyclophosphamide Saline + Placebo
    Number of subjects analysed
    829
    410
    Units: percentage of subjects
    number (not applicable)
        Year 1
    77
    74.7
        Year 2
    50.8
    45.9
        Year 3
    40.2
    37
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Adverse Events and Injection Site Reactions

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events and Injection Site Reactions
    End point description
    Treatment -emergent adverse events were defined as those with onset or worsening occurring at or after the first dosing day of study medication and up to 42 days after the last administration of any study drug or the clinical cut-off date. Injection site reactions were reported as assessed by the Investigator. Safety analysis set included all subjects who received at least 1 dose of trial treatment (cyclophosphamide, tecemotide, saline, or placebo). subjects were reported based on the actual treatment received (as-treated).
    End point type
    Secondary
    End point timeframe
    From first dose up to 42 days after the last dose of the trial treatment
    End point values
    		 Tecemotide (L-BLP25) + Cyclophosphamide Saline + Placebo
    Number of subjects analysed
    1024
    477
    Units: subjects
        Treatment Emergent Adverse events
    938
    432
        Injection site reaction
    176
    56
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 66 months
    Adverse event reporting additional description
    Safety analysis set included all subjects who received at least 1 dose of trial treatment (cyclophosphamide, tecemotide, saline, or placebo). Subjects were reported based on the actual treatment received (as-treated).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Tecemotide (L-BLP25) + Cyclophosphamide
    Reporting group description
    		 A single intravenous infusion of 300 milligram per square meter (mg/m^2) (to a maximum 600 mg) of cyclophosphamide was given 3 days before first tecemotide (L-BLP25) vaccination. After receiving cyclophosphamide, subjects received 8 consecutive weekly subcutaneous vaccinations with 806 microgram (mcg) of tecemotide (L-BLP25) at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance vaccinations with 806 mcg of tecemotide (L-BLP25) at 6-week intervals, commencing at Week 13, until disease progression was documented.

    Reporting group title
    Saline + Placebo
    Reporting group description
    		 A single intravenous infusion of 0.9 percent (%) saline solution in the same calculated dose as cyclophosphamide was given 3 days before first placebo vaccination. After receiving saline, subjects received 8 consecutive weekly subcutaneous vaccinations with placebo at Weeks 0, 1, 2, 3, 4, 5, 6, and 7 followed by maintenance placebo vaccinations at 6-week intervals, commencing at Week 13, until disease progression was documented.

    Serious adverse events
    		 Tecemotide (L-BLP25) + Cyclophosphamide Saline + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    303 / 1024 (29.59%)
    151 / 477 (31.66%)
         number of deaths (all causes)
    46
    35
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bile duct cancer
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 1024 (0.20%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 1024 (0.10%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    32 / 1024 (3.13%)
    9 / 477 (1.89%)
         occurrences causally related to treatment / all
    0 / 32
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to large intestine
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to kidney
         subjects affected / exposed
    2 / 1024 (0.20%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to salivary gland
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to pancreas
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oncologic complication
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to small intestine
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour invasion
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    5 / 1024 (0.49%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral arterial stenosis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Pericardial drainage
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 1024 (0.20%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Death
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    9 / 1024 (0.88%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    6 / 1024 (0.59%)
    11 / 477 (2.31%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 1024 (0.29%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 1024 (0.20%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non−cardiac chest pain
         subjects affected / exposed
    4 / 1024 (0.39%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    8 / 1024 (0.78%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spermatocele
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 1024 (0.29%)
    7 / 477 (1.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphonia
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    3 / 1024 (0.29%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    29 / 1024 (2.83%)
    13 / 477 (2.73%)
         occurrences causally related to treatment / all
    0 / 29
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    11 / 1024 (1.07%)
    5 / 477 (1.05%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cyst
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 1024 (0.10%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    13 / 1024 (1.27%)
    12 / 477 (2.52%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 1024 (0.20%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    6 / 1024 (0.59%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    10 / 1024 (0.98%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    8 / 1024 (0.78%)
    4 / 477 (0.84%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 1024 (0.00%)
    4 / 477 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 1024 (0.29%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation associated pain
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation myelopathy
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    7 / 1024 (0.68%)
    5 / 477 (1.05%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic lung injury
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound evisceration
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 1024 (0.10%)
    4 / 477 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    3 / 1024 (0.29%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 1024 (0.29%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    8 / 1024 (0.78%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    2 / 1024 (0.20%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio−respiratory arrest
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 1024 (0.29%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 1024 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    3 / 1024 (0.29%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery dissection
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 1024 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataplexy
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    4 / 1024 (0.39%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 1024 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 1024 (0.20%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    4 / 1024 (0.39%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain−Barre syndrome
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 1024 (0.29%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    4 / 1024 (0.39%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 1024 (0.39%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 1024 (0.29%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocoagulable state
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 1024 (0.29%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 1024 (0.29%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal vascular thrombosis
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 1024 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphagia
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    4 / 1024 (0.39%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 1024 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 1024 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal dilatation
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1024 (0.10%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatitis alcoholic
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 1024 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 1024 (0.10%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle atrophy
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 1024 (0.20%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 1024 (0.39%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    9 / 1024 (0.88%)
    4 / 477 (0.84%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 1024 (0.39%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia primary atypical
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    30 / 1024 (2.93%)
    14 / 477 (2.94%)
         occurrences causally related to treatment / all
    0 / 30
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella sepsis
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    7 / 1024 (0.68%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 1024 (0.10%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 1024 (0.20%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 1024 (0.10%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 1024 (0.39%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 1024 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 1024 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tecemotide (L-BLP25) + Cyclophosphamide Saline + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    918 / 1024 (89.65%)
    417 / 477 (87.42%)
    Injury, poisoning and procedural complications
    Radiation pneumonitis
         subjects affected / exposed
    77 / 1024 (7.52%)
    30 / 477 (6.29%)
         occurrences all number
    77
    30
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    87 / 1024 (8.50%)
    37 / 477 (7.76%)
         occurrences all number
    87
    37
    Headache
         subjects affected / exposed
    123 / 1024 (12.01%)
    54 / 477 (11.32%)
         occurrences all number
    123
    54
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    195 / 1024 (19.04%)
    102 / 477 (21.38%)
         occurrences all number
    195
    102
    Asthenia
         subjects affected / exposed
    71 / 1024 (6.93%)
    29 / 477 (6.08%)
         occurrences all number
    71
    29
    Chest pain
         subjects affected / exposed
    130 / 1024 (12.70%)
    43 / 477 (9.01%)
         occurrences all number
    130
    43
    Influenza like illness
         subjects affected / exposed
    45 / 1024 (4.39%)
    27 / 477 (5.66%)
         occurrences all number
    45
    27
    Pyrexia
         subjects affected / exposed
    80 / 1024 (7.81%)
    41 / 477 (8.60%)
         occurrences all number
    80
    41
    Non−cardiac chest pain
         subjects affected / exposed
    57 / 1024 (5.57%)
    24 / 477 (5.03%)
         occurrences all number
    57
    24
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    75 / 1024 (7.32%)
    26 / 477 (5.45%)
         occurrences all number
    75
    26
    Diarrhoea
         subjects affected / exposed
    85 / 1024 (8.30%)
    46 / 477 (9.64%)
         occurrences all number
    85
    46
    Nausea
         subjects affected / exposed
    140 / 1024 (13.67%)
    39 / 477 (8.18%)
         occurrences all number
    140
    39
    Vomiting
         subjects affected / exposed
    65 / 1024 (6.35%)
    26 / 477 (5.45%)
         occurrences all number
    65
    26
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    336 / 1024 (32.81%)
    133 / 477 (27.88%)
         occurrences all number
    336
    133
    Haemoptysis
         subjects affected / exposed
    60 / 1024 (5.86%)
    32 / 477 (6.71%)
         occurrences all number
    60
    32
    Dyspnoea
         subjects affected / exposed
    225 / 1024 (21.97%)
    103 / 477 (21.59%)
         occurrences all number
    225
    103
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    53 / 1024 (5.18%)
    27 / 477 (5.66%)
         occurrences all number
    53
    27
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    64 / 1024 (6.25%)
    25 / 477 (5.24%)
         occurrences all number
    64
    25
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    108 / 1024 (10.55%)
    33 / 477 (6.92%)
         occurrences all number
    108
    33
    Back pain
         subjects affected / exposed
    146 / 1024 (14.26%)
    52 / 477 (10.90%)
         occurrences all number
    146
    52
    Musculoskeletal pain
         subjects affected / exposed
    92 / 1024 (8.98%)
    33 / 477 (6.92%)
         occurrences all number
    93
    33
    Musculoskeletal chest pain
         subjects affected / exposed
    54 / 1024 (5.27%)
    22 / 477 (4.61%)
         occurrences all number
    54
    22
    Myalgia
         subjects affected / exposed
    73 / 1024 (7.13%)
    18 / 477 (3.77%)
         occurrences all number
    73
    18
    Pain in extremity
         subjects affected / exposed
    69 / 1024 (6.74%)
    29 / 477 (6.08%)
         occurrences all number
    69
    29
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    128 / 1024 (12.50%)
    44 / 477 (9.22%)
         occurrences all number
    128
    44
    Bronchitis
         subjects affected / exposed
    83 / 1024 (8.11%)
    38 / 477 (7.97%)
         occurrences all number
    83
    38
    Upper respiratory tract infection
         subjects affected / exposed
    96 / 1024 (9.38%)
    37 / 477 (7.76%)
         occurrences all number
    96
    37
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    109 / 1024 (10.64%)
    44 / 477 (9.22%)
         occurrences all number
    109
    44

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Nov 2007
    The purpose of this protocol amendment was: To insert new safety information on the adjuvant component of L-BLP25, as requested by the US Food and Drug Administration (FDA). To explain that elective hospitalization should not be reported as AE or SAE.
    23 Apr 2010
    The purpose of this amendment was: To reflect new safety information on L-BLP25. To adjust the eligibility criteria in order to address the new safety information. To implement new subject discontinuation criteria in order to address the new safety information. To specify new special precautions in order to address the new safety information. To implement new assessments in order to address the new safety information. To instruct investigators on how to proceed with subjects who had received the cyclophosphamide/saline infusion but had not yet received the vaccination due to the clinical hold on the L-BLP25 IND by the FDA in March 2010.
    05 Oct 2010
    The purpose of this amendment was: considering the new safety information by specifying imaging requirements upon suspicion of encephalitis or neuro inflammatory disorders. clarifying on safety monitoring measures for thrombocytopenia and L-BLP25 content recalculation (930 μg instead of 1000 μg). Implementing changes to sample size considerations and the definition of the Primary Analysis Set in order to minimize a potential impact on the trial results caused by the clinical hold. Introducing the assessment of MUC1-specific immune response in peripheral blood of a subset of subjects, which was carried out within an ancillary clinical trial protocol in several EU countries.
    16 Dec 2011
    The purpose of this amendment was: Correct the description of the nominal dose of L-BLP25 (806 μg instead of 930 μg). Clarify changes to the visit and assessment schedule, including safety follow-up for subjects receiving placebo in case of unblinding of the trial or in case of discontinuation of the trial.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Mar 2010
    Due to reporting of a suspected unexpected serious adverse reaction (SUSAR) of encephalitis in a phase II trial of L-BLP25 in multiple myeloma patients (EMR 63325-008), a clinical hold of the trial was implemented from 19 March 2010 to 14 June 2010.
    14 Jun 2010

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

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