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    Clinical Trial Results:
    An open-label phase IIIb study of regorafenib in patients with metastatic colorectal cancer (CRC) who have progressed after standard therapy

    Summary
    EudraCT number
    		 2011-005836-25
    Trial protocol
    		 BE   DE   CZ   ES   GB   IT   AT   NL   IE   FR   PT   FI   SE   GR   HU   PL   DK  
    Global end of trial date
    30 Apr 2019

    Results information
    Results version number
    		 v3(current)
    This version publication date
    22 Jan 2020
    First version publication date
    02 Jul 2016
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    CSR updated after study completion

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY73-4506 / 15967
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01538680
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    30 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study were: - to provide regorafenib to subjects diagnosed with metastatic colorectal cancer who had failed after all approved standard therapies, - to assess the safety of regorafenib, and - to estimate progression-free survival (PFS).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 308
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Switzerland: 39
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 364
    Country: Number of subjects enrolled
    Australia: 87
    Country: Number of subjects enrolled
    Austria: 46
    Country: Number of subjects enrolled
    Belgium: 172
    Country: Number of subjects enrolled
    Canada: 99
    Country: Number of subjects enrolled
    Czech Republic: 39
    Country: Number of subjects enrolled
    Denmark: 24
    Country: Number of subjects enrolled
    Finland: 16
    Country: Number of subjects enrolled
    France: 329
    Country: Number of subjects enrolled
    Germany: 327
    Country: Number of subjects enrolled
    Greece: 28
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Ireland: 11
    Country: Number of subjects enrolled
    Israel: 113
    Country: Number of subjects enrolled
    Italy: 686
    Country: Number of subjects enrolled
    Mexico: 37
    Country: Number of subjects enrolled
    Netherlands: 33
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Portugal: 14
    Country: Number of subjects enrolled
    Russian Federation: 45
    Worldwide total number of subjects
    2872
    EEA total number of subjects
    2088
    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)
    1720
    From 65 to 84 years
    1152
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at centers in Europe, North America (including Mexico), Israel, and Australia. From 02 April 2012 (first subject first visit) to 30 April 2019 (date of last visit).

    Pre-assignment
    Screening details
    		 Overall, 3309 subjects were screened and enrolled. Of these, a total of 2872 subjects were assigned to receive treatment (trt). A total of 2864 subjects started treatment, and all terminated the treatment.

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

    Arms
    Arm title
    		 Regorafenib (BAY73-4506)
    Arm description
    		 Subjects received regorafenib 160 milligram (mg) (4 x 40 mg tablets) per oral once daily for 3 weeks of every 4 week cycle (that is 3 weeks on, 1 week off). Subjects continued in the study until at least one of the following occurred: PD by radiological assessments or clinical progression (only the date of progression and the presence/absence of new/progressive brain and liver metastases were recorded); death; unacceptable toxicity; subject withdrew consent; treating physician determined discontinuation of treatment was in the subject's best interest; substantial non-compliance with the protocol or until other withdrawal criterion was met. If, in the investigator’s opinion, treatment with regorafenib was providing clinical benefit to a subject experiencing disease progression, the subject may have continued treatment at the investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    BAY73-4506
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received regorafenib 160 mg (4 x 40 mg tablets) per oral once daily for 3 weeks of every 4 week cycle (i.e. 3 weeks on, 1 week off).

    Number of subjects in period 1
    		Regorafenib (BAY73-4506)
    Started
    2872
    Started treatment
    2864
    Start safety follow-up
    1597
    Safety follow-up completed
    374
    Completed
    0
    Not completed
    2872
         Adverse event associated with clinical disease
    405
         Physician decision
    11
         Adverse event not associated with clinical dis
    327
         Protocol driven decision point
    5
         Not specified
    4
         Study terminated by sponsor
    1
         Progressive disease - radiological progression
    1640
         Withdrawal by subject
    212
         Therapeutic procedure required
    3
         Progressive disease - clinical progression
    205
         Protocol violation
    5
         Death
    1
         Non-compliance with study drug
    4
         Switching to other therapy
    1
         Never treated
    8
         Lost to follow-up
    40

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Regorafenib (BAY73-4506)
    Reporting group description
    		 Subjects received regorafenib 160 milligram (mg) (4 x 40 mg tablets) per oral once daily for 3 weeks of every 4 week cycle (that is 3 weeks on, 1 week off). Subjects continued in the study until at least one of the following occurred: PD by radiological assessments or clinical progression (only the date of progression and the presence/absence of new/progressive brain and liver metastases were recorded); death; unacceptable toxicity; subject withdrew consent; treating physician determined discontinuation of treatment was in the subject's best interest; substantial non-compliance with the protocol or until other withdrawal criterion was met. If, in the investigator’s opinion, treatment with regorafenib was providing clinical benefit to a subject experiencing disease progression, the subject may have continued treatment at the investigator’s discretion.

    Reporting group values
    		 Regorafenib (BAY73-4506) Total
    Number of subjects
    		 2872
    Age categorical
    Units: Subjects
    Total
    Units: years
        arithmetic mean (standard deviation)
    		 61.1 ( 10.5 ) -
    Gender, Male/Female
    Units: subjects
        Female
    		 1180 1180
        Male
    		 1692 1692
    Eastern Cooperative Oncology Group (ECOG) performance status (PS)
    ECOG PS score was measured in a scale of 0-5, where 0= Fully active, able to carry on all pre-disease performance without restriction, 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 2= Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50 percent (%) waking hours, 3= Capable of only limited self-care, confined to bed or chair, more than 50% waking hours, 4= Completely disabled, cannot carry on any self-care. Totally confined to bed or chair and, 5= Death.
    Units: Subjects
        0 = Fully Active
    		 1357 1357
        1= Restricted Activity
    		 1509 1509
        Missing
    		 6 6
    Histology
    Subjects with relating to disease factors includes Adenocarcinoma, Adenocarcinoma In Situ, Mucinous Carcinoma, Missing were reported.
    Units: Subjects
        Adenocarcinoma
    		 2852 2852
        Adenocarcinoma In Situ
    		 15 15
        Mucinous Carcinoma
    		 3 3
        Missing
    		 2 2
    Primary Site of Disease
    Subjects with primary site of disease (Colon, Rectum, Colon and Rectum) were reported.
    Units: Subjects
        Colon Cancer
    		 1846 1846
        Rectal Cancer
    		 808 808
        Colon and Rectal Cancer
    		 217 217
        Missing
    		 1 1
    Kirsten rat sarcoma viral oncogene homolog, protein (KRAS) Mutation
    KRAS Mutation was defined as historical data from the primary tumor, analyzed in local laboratories.
    Units: Subjects
        No
    		 1284 1284
        Yes
    		 1465 1465
        Unknown
    		 122 122
        Missing
    		 1 1
    Time Since Initial Diagnosis of Colorectal Cancer to Treatment Assignment
    Treatment assignment was the date of first treatment.
    Units: Subjects
        Less than (<) 18 months
    		 315 315
        Greater than equal (≥)18 months
    		 2549 2549
        Missing
    		 8 8
    Time Since First Diagnosis of Metastatic Disease to Treatment Assignment
    Units: weeks
        arithmetic mean (standard deviation)
    		 158.39 ( 99.32 ) -

    End points

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    End points reporting groups
    Reporting group title
    Regorafenib (BAY73-4506)
    Reporting group description
    		 Subjects received regorafenib 160 milligram (mg) (4 x 40 mg tablets) per oral once daily for 3 weeks of every 4 week cycle (that is 3 weeks on, 1 week off). Subjects continued in the study until at least one of the following occurred: PD by radiological assessments or clinical progression (only the date of progression and the presence/absence of new/progressive brain and liver metastases were recorded); death; unacceptable toxicity; subject withdrew consent; treating physician determined discontinuation of treatment was in the subject's best interest; substantial non-compliance with the protocol or until other withdrawal criterion was met. If, in the investigator’s opinion, treatment with regorafenib was providing clinical benefit to a subject experiencing disease progression, the subject may have continued treatment at the investigator’s discretion.

    Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Discontinuation, and Drug Related TEAEs, and Subjects Who Died

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Discontinuation, and Drug Related TEAEs, and Subjects Who Died [1]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly and another med important serious event as judged by the invest. Treatment-emergent was defined as any event arising or worsening after the start of study drug admin until 30 days after the last study medication. Safety analysis set (SAF) included all subjects who received at least one dose of study drug. Number of subjects analysed signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From the start of study treatment up to 30 days after the last dose of study drug, assessed up to 33 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2864
    Units: subjects
    number (not applicable)
        TEAEs
    2847
        TESAEs
    1253
        TEAEs leading to discontinuation of drug
    724
        Drug related TEAEs
    2613
        Subjects who died (Grade 5 TEAEs)
    406
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Treatment-emergent High Laboratory Abnormalities (TELA)

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    End point title
    		 Percentage of Subjects With Treatment-emergent High Laboratory Abnormalities (TELA) [2]
    End point description
    A TELA was any abnormal event arising after the start of study drug administration, which focused on coagulation, general chemistry, hematology, hormone panels and thyroid function test. The denominator (D) represents the number of subjects at baseline with a normal or lower than normal laboratory assessment (LA) who also had at least one valid laboratory value after start of treatment. Subjects with missing or high abnormal values at baseline are not included in the D. The numerator represents the number of subjects with at least one high LA after the start of treatment who had a normal or lower than normal LA at baseline. If there are repeated observations prior to first study drug intake, baseline is defined as the last non-missing pre-treatment measurement, where baseline cannot be set on the same date as the first study drug intake. SAF, number of subjects analyzed signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for the specified category.
    End point type
    Primary
    End point timeframe
    From the start of study treatment up to 14 days after the last dose of study drug
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2864
    Units: percentage of subjects
    number (not applicable)
        Activated Partial Thromboplastin Time (n=1745)
    23.7
        Prothrombin Intl. Normalized Ratio (n=1719)
    20.9
        Prothrombin Time (n=684)
    29.2
        Alanine Aminotransferase (n=2049)
    44.0
        Alkaline Phosphatase (n=993)
    48.6
        Aspartate Aminotransferase (n=1630)
    61.4
        Bilirubin (n=2290)
    58.2
        Calcium (n=2266)
    3.5
        Chloride (n=2225)
    11.2
        Creatinine (n=2240)
    12.9
        Direct Bilirubin (n=1368)
    61.9
        Phosphate (n=2111)
    3.9
        Potassium (n=2312)
    13.4
        Sodium (n=2392)
    5
        Triacylglycerol Lipase (n=2138)
    37.6
        Basophils (n=1878)
    5.6
        Basophils/Leukocytes (n=695)
    8.3
        Eosinophils (n=1773)
    13.8
        Eosinophils/Leukocytes (n=642)
    20.7
        Erythrocytes (n=2374)
    10.4
        Hematocrit (n=2394)
    7.5
        Hemoglobin (n=2417)
    5.3
        Leukocytes (n=2018)
    36.6
        Lymphocytes (n=1941)
    2.6
        Lymphocytes/Leukocytes (n=715)
    2.5
        Monocytes (n=1593)
    31.5
        Monocytes/Leukocytes (n=558)
    35.1
        Neutrophils (n=1607)
    38.2
        Neutrophils/Leukocytes (n=507)
    49.7
        Platelets (n=2215)
    15.5
        Thyrotropin (n=1805)
    36.4
        Thyroxine, Free (n=1611)
    9.9
        Triiodothyronine, Free (n=1382)
    4.1
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Treatment-emergent Low Laboratory Abnormalities (TELA)

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    End point title
    		 Percentage of Subjects With Treatment-emergent Low Laboratory Abnormalities (TELA) [3]
    End point description
    A TELA was any abnormal event arising after the start of study drug administration, which focused on coagulation, general chemistry, hematology, hormone panels and thyroid function test. The D represents the number of subjects at baseline with a normal or higher than normal LA who also had at least one valid laboratory value after start of treatment. Subjects with missing or low abnormal values at baseline are not included in the D. The numerator represents the number of subjects with at least one low LA after the start of treatment who had a normal or higher than normal LA at baseline. If there are repeated observations prior to first study drug intake, baseline is defined as the last non-missing pre-treatment measurement, where baseline cannot be set on the same date as the first study drug intake. SAF, number of subjects analyzed signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for the specified category.
    End point type
    Primary
    End point timeframe
    From the start of study treatment up to 14 days after the last dose of study drug
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2864
    Units: percentage of subjects
    number (not applicable)
        Activated Partial Thromboplastin Time (n=1905)
    7.9
        Prothrombin Intl. Normalized Ratio (n=1884)
    1.8
        Prothrombin Time (n=771)
    4.2
        Alanine Aminotransferase (n=2402)
    4.1
        Alkaline Phosphatase (n=2407)
    0.9
        Aspartate Aminotransferase (n=2449)
    1
        Bilirubin (n=2437)
    1.2
        Calcium (n=2226)
    44.1
        Chloride (n=2070)
    30.0
        Creatinine (n=2149)
    23.8
        Direct Bilirubin (n=1736)
    0.2
        Phosphate (n=2009)
    69.1
        Potassium (n=2312)
    27.8
        Sodium (n=2220)
    36.1
        Triacylglycerol Lipase (n=2150)
    7.1
        Basophils (n=1879)
    2.5
        Basophils/Leukocytes (n=701)
    2
        Eosinophils (n=1849)
    10.4
        Eosinophils/Leukocytes (n=636)
    18.9
        Erythrocytes (n=1351)
    39.6
        Hematocrit (n=1360)
    48.1
        Hemoglobin (n=1262)
    45.2
        Leukocytes (n=2343)
    13.2
        Lymphocytes (n=1388)
    39.3
        Lymphocytes/Leukocytes (n=369)
    56.1
        Monocytes (n=1920)
    3.9
        Monocytes/Leukocytes (n=714)
    7.6
        Neutrophils (n=1968)
    5.9
        Neutrophils/Leukocytes (n=714)
    4.1
        Platelets (n=2169)
    30.1
        Thyrotropin (n=1926)
    4.8
        Thyroxine, Free (n=1644)
    4.9
        Triiodothyronine, Free (n=1285)
    18.8
    No statistical analyses for this end point

    Primary: Change From Baseline in Heart Rate at Specified Time Points

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    End point title
    		 Change From Baseline in Heart Rate at Specified Time Points [4]
    End point description
    SAF, Here “N” (number of subjects analyzed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for the specified category. In the below table 99999 represents as the sample size was not sufficient. Hence, Standard deviation was not calculated.
    End point type
    Primary
    End point timeframe
    Baseline, Day 1 (Cycle 1 to 33), and end of treatment
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2812
    Units: beats per minute
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n = 1067)
    -0.4 ( 10.8 )
        Cycle 2 Day 1 (n = 1915)
    2.4 ( 13 )
        Cycle 3 Day 1 (n = 1376)
    1.8 ( 12.6 )
        Cycle 4 Day 1 (n = 927)
    1.4 ( 13.2 )
        Cycle 5 Day 1 (n = 651)
    1.4 ( 12.8 )
        Cycle 6 Day 1 (n = 503)
    1.1 ( 12.8 )
        Cycle 7 Day 1 (n = 364)
    0.9 ( 13.4 )
        Cycle 8 Day 1 (n = 287)
    0.4 ( 14 )
        Cycle 9 Day 1 (n = 234)
    1 ( 13 )
        Cycle 10 Day 1 (n = 189)
    1.2 ( 12.6 )
        Cycle 11 Day 1 (n = 157)
    0.2 ( 12.9 )
        Cycle 12 Day 1 (n = 136)
    1.1 ( 12.1 )
        Cycle 13 Day 1 (n = 110)
    1.4 ( 13.8 )
        Cycle 14 Day 1 (n = 88)
    1.3 ( 11.7 )
        Cycle 15 Day 1 (n = 73)
    1.3 ( 13.6 )
        Cycle 16 Day 1 (n = 60)
    0.2 ( 13.8 )
        Cycle 17 Day 1 (n = 52)
    1.4 ( 13.6 )
        Cycle 18 Day 1 (n = 43)
    0.4 ( 12.7 )
        Cycle 20 Day 1 (n = 28)
    1.3 ( 13.0 )
        Cycle 21 Day 1 (n = 24)
    3.7 ( 14.3 )
        Cycle 19 Day 1 (n=37)
    1.3 ( 13.0 )
        Cycle 22 Day 1 (n=20)
    2.8 ( 10 )
        Cycle 23 Day 1 (n=16)
    -1.3 ( 13.1 )
        Cycle 24 Day 1 (n=14)
    -1.1 ( 10.6 )
        Cycle 25 Day 1 (n=14)
    1.2 ( 11.2 )
        Cylce 26 Day 1 (n=13)
    0.9 ( 12.8 )
        Cylce 27 Day 1 (n=11)
    -2.5 ( 9.2 )
        Cylce 28 Day 1 (n=11)
    0.9 ( 11.9 )
        Cylce 29 Day 1 (n=10)
    -4.1 ( 9 )
        Cylce 30 Day 1 (n=10)
    -1.1 ( 12.7 )
        Cylce 31 Day 1 (n=7)
    -2.7 ( 8.7 )
        Cylce 32 Day 1 (n=7)
    -0.4 ( 5.4 )
        Cylce 33 Day 1 (n=7)
    -3.7 ( 6.6 )
        End of treatment (n=1477)
    4.4 ( 14.6 )
    No statistical analyses for this end point

    Primary: Change From Baseline in Diastolic Blood Pressure at Specified Time Points

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    End point title
    		 Change From Baseline in Diastolic Blood Pressure at Specified Time Points [5]
    End point description
    SAF, Here “N” (number of subjects analyzed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for the specified category. In the below table 99999 represents as the sample size was not sufficient. Hence, Standard deviation was not calculated.
    End point type
    Primary
    End point timeframe
    Baseline, Cycle 1 Days 1, 8, 15, 22; Cycle 2 Days 1, 8, 15; Cycle 3 to 33 (Day 1), and End of treatment
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2864
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=1096)
    -0.3 ( 7.8 )
        Cycle 1 Day 8 (n=1896)
    4.1 ( 11 )
        Cycle 1 Day 15 (n=2146)
    3.6 ( 11.5 )
        Cycle 1 Day 22 (n=1578)
    2.4 ( 10.5 )
        Cycle 2 Day 1 (n=1976)
    0 ( 10.2 )
        Cycle 2 Day 8 (n=1343)
    3.1 ( 11.2 )
        Cycle 2 Day 15 (n=1724)
    3.3 ( 10.5 )
        Cycle 3 Day 1 (n=1412)
    -1.2 ( 10.2 )
        Cycle 4 Day 1 (n=959)
    -1 ( 10.2 )
        Cycle 5 Day 1 (n=674)
    -1.5 ( 9.6 )
        Cycle 6 Day 1 (n=527)
    -0.9 ( 10.4 )
        Cycle 7 Day 1 (n=374)
    -1 ( 10.4 )
        Cycle 8 Day 1 (n=297)
    -1.7 ( 11.2 )
        Cycle 9 Day 1 (n=248)
    -1.3 ( 10.3 )
        Cycle 10 Day 1 (n=197)
    -0.8 ( 10.3 )
        Cycle 11 Day 1 (n=163)
    -1 ( 10.3 )
        Cycle 12 Day 1 (n=143)
    -1.2 ( 10.6 )
        Cycle 13 Day 1 (n=113)
    -1.9 ( 10.6 )
        Cycle 14 Day 1 (n=92)
    -2.1 ( 9.9 )
        Cycle 15 Day 1 (n=78)
    -1.6 ( 10.5 )
        Cycle 16 Day 1 (n=63)
    -5.5 ( 10.7 )
        Cycle 17 Day 1 (n=54)
    -2.7 ( 11 )
        Cycle 18 Day 1 (n=44)
    -2.4 ( 11.7 )
        Cycle 19 Day 1 (n=37)
    -3.4 ( 12.1 )
        Cycle 20 Day 1 (n=29)
    -1.4 ( 10.5 )
        Cycle 21 Day 1 (n=24)
    -0.7 ( 12.4 )
        Cycle 22 Day 1 (n=20)
    -5.9 ( 12.7 )
        Cycle 23 Day 1 (n=16)
    -4.6 ( 10.2 )
        Cycle 24 Day 1 (n=14)
    -2.9 ( 10.8 )
        Cycle 25 Day 1 (n=14)
    -5.0 ( 11.9 )
        Cycle 26 Day 1 (n=13)
    -5.2 ( 11.0 )
        Cycle 27 Day 1 (n=11)
    -3.8 ( 11.3 )
        Cycle 28 Day 1 (n=11)
    -6 ( 11.2 )
        Cycle 29 Day 1 (n=10)
    -7.6 ( 10.1 )
        Cycle 30 Day 1 (n=10)
    -6.9 ( 8.4 )
        Cycle 31 Day 1 (n=7)
    -10.6 ( 10.4 )
        Cycle 32 Day 1 (n=7)
    -3.7 ( 10.1 )
        Cycle 33 Day 1 (n=7)
    -10 ( 14.1 )
        End of treatment (n=1529)
    -0.9 ( 11.2 )
    No statistical analyses for this end point

    Primary: Change From Baseline in Systolic Blood Pressure at Specified Time Points

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    End point title
    		 Change From Baseline in Systolic Blood Pressure at Specified Time Points [6]
    End point description
    SAF, Here “N” (number of subjects analyzed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for the specified category. In the below table 99999 represents as the sample size was not sufficient. Hence, Standard deviation was not calculated.
    End point type
    Primary
    End point timeframe
    Baseline, Cycle 1 Days 1, 8, 15, 22; Cycle 2 Days 1, 8, 15; Cycle 3 to 33 (Day 1), and End of treatment
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2864
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=1096)
    0.4 ( 10.8 )
        Cycle 1 Day 8 (n=1896)
    6.4 ( 15.9 )
        Cycle 1 Day 15 (n=2149)
    5.7 ( 16.3 )
        Cycle 1 Day 22 (n=1579)
    3.6 ( 15.7 )
        Cycle 2 Day 1 (n=1978)
    0.6 ( 14.6 )
        Cycle 2 Day 8 (n=1343)
    5.4 ( 15.9 )
        Cycle 2 Day 15 (n=1724)
    4.8 ( 16.5 )
        Cycle 3 Day 1 (n=1413)
    -1.1 ( 15.4 )
        Cycle 4 Day 1 (n=959)
    -0.9 ( 14.9 )
        Cycle 5 Day 1 (n=674)
    -1.3 ( 15.2 )
        Cycle 6 Day 1 (n=527)
    -1.1 ( 15.9 )
        Cycle 7 Day 1 (n=374)
    -0.5 ( 16 )
        Cycle 8 Day 1 (n=297)
    -1.6 ( 15.8 )
        Cycle 9 Day 1 (n=248)
    -0.7 ( 14.9 )
        Cycle 10 Day 1 (n=197)
    -0.9 ( 15.6 )
        Cycle 11 Day 1 (n=163)
    -1.2 ( 14.5 )
        Cycle 12 Day 1 (n=143)
    0.2 ( 15.3 )
        Cycle 13 Day 1 (n=113)
    1.1 ( 14.3 )
        Cycle 14 Day 1 (n=92)
    -1.1 ( 18.1 )
        Cycle 15 Day 1 (n=78)
    0.9 ( 14.5 )
        Cycle 16 Day 1 (n=63)
    -2.8 ( 14.2 )
        Cycle 17 Day 1 (n=54)
    1.1 ( 13.8 )
        Cycle 18 Day 1 (n=44)
    -1 ( 14.3 )
        Cycle 19 Day 1 (n=37)
    0.1 ( 19 )
        Cycle 20 Day 1 (n=29)
    4.6 ( 16.6 )
        Cycle 21 Day 1 (n=24)
    2.5 ( 15.8 )
        Cycle 22 Day 1 (n=20)
    2.7 ( 14 )
        Cycle 23 Day 1 (n=16)
    0.8 ( 10.5 )
        Cycle 24 Day 1 (n=14)
    5.9 ( 17.4 )
        Cycle 25 Day 1 (n=14)
    -0.2 ( 13.8 )
        Cycle 26 Day 1 (n=13)
    6.1 ( 21.1 )
        Cycle 27 Day 1 (n=11)
    2.3 ( 15.2 )
        Cycle 28 Day 1 (n=11)
    -2.7 ( 10.9 )
        Cycle 29 Day 1 (n=10)
    2.3 ( 16.6 )
        Cycle 30 Day 1 (n=10)
    4.0 ( 17.7 )
        Cycle 31 Day 1 (n=7)
    4.0 ( 13.2 )
        Cycle 32 Day 1 (n=7)
    9.3 ( 9.9 )
        Cycle 33 Day 1 (n=7)
    9.0 ( 13.7 )
        End of treatment (n=1530)
    -1.8 ( 16.1 )
    No statistical analyses for this end point

    Primary: Percentage of Subject With Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Specified Time Points

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    End point title
    		 Percentage of Subject With Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Specified Time Points [7]
    End point description
    ECOG PS score was measured in a scale of 0-5, where 0= Fully active, able to carry on all pre-disease performance without restriction, 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 2= Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50 percent (%) waking hours, 3= Capable of only limited self-care, confined to bed or chair, more than 50% waking hours, 4= Completely disabled, cannot carry on any self-care. Totally confined to bed or chair and, 5= Death. SAF, Here “N” (number of subjects analyzed) signifies subjects evaluable for this endpoint and "n" signifies subjects evaluable for the specified category.
    End point type
    Primary
    End point timeframe
    Baseline, Day 1 (Cycle 1 to 33), and End of treatment
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2864
    Units: percentage of subjects
    number (not applicable)
        Cycle 1 Day 1 (n=1553): Unchanged
    89.4
        Cycle 1 Day 1 (n=1553): 0 to 1
    6
        Cycle 1 Day 1 (n=1553): 0 to 2
    0
        Cycle 1 Day 1 (n=1553): 0 to 3
    0
        Cycle 1 Day 1 (n=1553): 0 to 4
    0
        Cycle 1 Day 1 (n=1553): 1 to 0
    4.3
        Cycle 1 Day 1 (n=1553): 1 to 2
    0.3
        Cycle 1 Day 1 (n=1553): 1 to 3
    0
        Cycle 1 Day 1 (n=1553): 1 to 4
    0
        Cycle 1 Day 1 (n=1553): Missing
    0.1
        Cycle 2 Day 1 (n=2298): Unchanged
    71
        Cycle 2 Day 1 (n=2298): 0 to 1
    16.6
        Cycle 2 Day 1 (n=2298): 0 to 2
    1.3
        Cycle 2 Day 1 (n=2298): 0 to 3
    0
        Cycle 2 Day 1 (n=2298): 0 to 4
    0
        Cycle 2 Day 1 (n=2298): 1 to 0
    5
        Cycle 2 Day 1 (n=2298): 1 to 2
    5.4
        Cycle 2 Day 1 (n=2298): 1 to 3
    0.4
        Cycle 2 Day 1 (n=2298): 1 to 4
    0
        Cycle 2 Day 1 (n=2298): Missing
    0.2
        Cycle 3 Day 1 (n=1616): Unchanged
    69.8
        Cycle 3 Day 1 (n=1616): 0 to 1
    19.5
        Cycle 3 Day 1 (n=1616): 0 to 2
    0.9
        Cycle 3 Day 1 (n=1616): 0 to 3
    0.2
        Cycle 3 Day 1 (n=1616): 0 to 4
    0
        Cycle 3 Day 1 (n=1616): 1 to 0
    5.3
        Cycle 3 Day 1 (n=1616): 1 to 2
    4.1
        Cycle 3 Day 1 (n=1616): 1 to 3
    0.1
        Cycle 3 Day 1 (n=1616): 1 to 4
    0
        Cycle 3 Day 1 (n=1616): Missing
    0.1
        Cycle 4 Day 1 (n=1098): Unchanged
    69.9
        Cycle 4 Day 1 (n=1098): 0 to 1
    17.8
        Cycle 4 Day 1 (n=1098): 0 to 2
    1.3
        Cycle 4 Day 1 (n=1098): 0 to 3
    0
        Cycle 4 Day 1 (n=1098): 0 to 4
    0
        Cycle 4 Day 1 (n=1098): 1 to 0
    5.9
        Cycle 4 Day 1 (n=1098): 1 to 2
    4.6
        Cycle 4 Day 1 (n=1098): 1 to 3
    0.5
        Cycle 4 Day 1 (n=1098): 1 to 4
    0
        Cycle 4 Day 1 (n=1098): Missing
    0.2
        Cycle 5 Day 1 (n=769): Unchanged
    68.4
        Cycle 5 Day 1 (n=769): 0 to 1
    19.4
        Cycle 5 Day 1 (n=769): 0 to 2
    1.3
        Cycle 5 Day 1 (n=769): 0 to 3
    0
        Cycle 5 Day 1 (n=769): 0 to 4
    0
        Cycle 5 Day 1 (n=769): 1 to 0
    6.5
        Cycle 5 Day 1 (n=769): 1 to 2
    4.3
        Cycle 5 Day 1 (n=769): 1 to 3
    0.1
        Cycle 5 Day 1 (n=769): 1 to 4
    0
        Cycle 6 Day 1 (n=599): Unchanged
    68.8
        Cycle 6 Day 1 (n=599): 0 to 1
    20
        Cycle 6 Day 1 (n=599): 0 to 2
    0.8
        Cycle 6 Day 1 (n=599): 0 to 3
    0
        Cycle 6 Day 1 (n=599): 0 to 4
    0
        Cycle 6 Day 1 (n=599): 1 to 0
    5.3
        Cycle 6 Day 1 (n=599): 1 to 2
    4.7
        Cycle 6 Day 1 (n=599): 1 to 3
    0.2
        Cycle 6 Day 1 (n=599): 1 to 4
    0
        Cycle 6 Day 1 (n=599): Missing
    0.2
        Cycle 7 Day 1 (n=422): Unchanged
    70.1
        Cycle 7 Day 1 (n=422): 0 to 1
    20.1
        Cycle 7 Day 1 (n=422): 0 to 2
    0.5
        Cycle 7 Day 1 (n=422): 0 to 3
    0
        Cycle 7 Day 1 (n=422): 0 to 4
    0
        Cycle 7 Day 1 (n=422): 1 to 0
    5.7
        Cycle 7 Day 1 (n=422): 1 to 2
    3.3
        Cycle 7 Day 1 (n=422): 1 to 3
    0.2
        Cycle 7 Day 1 (n=422): 1 to 4
    0
        Cycle 8 Day 1 (n=332): Unchanged
    69.3
        Cycle 8 Day 1 (n=332): 0 to 1
    21.4
        Cycle 8 Day 1 (n=332): 0 to 2
    0.9
        Cycle 8 Day 1 (n=332): 0 to 3
    0.3
        Cycle 8 Day 1 (n=332): 0 to 4
    0
        Cycle 8 Day 1 (n=332): 1 to 0
    6
        Cycle 8 Day 1 (n=332): 1 to 2
    2.1
        Cycle 8 Day 1 (n=332): 1 to 3
    0
        Cycle 8 Day 1 (n=332): 1 to 4
    0
        Cycle 9 Day 1 (n=278): Unchanged
    67.3
        Cycle 9 Day 1 (n=278): 0 to 1
    22.7
        Cycle 9 Day 1 (n=278): 0 to 2
    0.7
        Cycle 9 Day 1 (n=278): 0 to 3
    0
        Cycle 9 Day 1 (n=278): 0 to 4
    0
        Cycle 9 Day 1 (n=278): 1 to 0
    7.2
        Cycle 9 Day 1 (n=278): 1 to 2
    1.4
        Cycle 9 Day 1 (n=278): 1 to 3
    0.4
        Cycle 9 Day 1 (n=278): 1 to 4
    0
        Cycle 9 Day 1 (n=278): Missing
    0.4
        Cycle 10 Day 1 (n=221): Unchanged
    69.2
        Cycle 10 Day 1 (n=221): 0 to 1
    21.3
        Cycle 10 Day 1 (n=221): 0 to 2
    1.4
        Cycle 10 Day 1 (n=221): 0 to 3
    0
        Cycle 10 Day 1 (n=221): 0 to 4
    0
        Cycle 10 Day 1 (n=221): 1 to 0
    6.3
        Cycle 10 Day 1 (n=221): 1 to 2
    1.4
        Cycle 10 Day 1 (n=221): 1 to 3
    0
        Cycle 10 Day 1 (n=221): 1 to 4
    0
        Cycle 10 Day 1 (n=221): Missing
    0.5
        Cycle 11 Day 1 (n=188): Unchanged
    63.3
        Cycle 11 Day 1 (n=188): 0 to 1
    23.4
        Cycle 11 Day 1 (n=188): 0 to 2
    2.1
        Cycle 11 Day 1 (n=188): 0 to 3
    0
        Cycle 11 Day 1 (n=188): 0 to 4
    0
        Cycle 11 Day 1 (n=188): 1 to 0
    8
        Cycle 11 Day 1 (n=188): 1 to 2
    2.7
        Cycle 11 Day 1 (n=188): 1 to 3
    0.5
        Cycle 11 Day 1 (n=188): 1 to 4
    0
        Cycle 12 Day 1 (n=159): Unchanged
    62.9
        Cycle 12 Day 1 (n=159): 0 to 1
    25.8
        Cycle 12 Day 1 (n=159): 0 to 2
    1.3
        Cycle 12 Day 1 (n=159): 0 to 3
    0
        Cycle 12 Day 1 (n=159): 0 to 4
    0
        Cycle 12 Day 1 (n=159): 1 to 0
    6.3
        Cycle 12 Day 1 (n=159): 1 to 2
    3.1
        Cycle 12 Day 1 (n=159): 1 to 3
    0
        Cycle 12 Day 1 (n=159): 1 to 4
    0
        Cycle 12 Day 1 (n=159): Missing
    0.6
        Cycle 13 Day 1 (n=130): Unchanged
    68.5
        Cycle 13 Day 1 (n=130): 0 to 1
    22.3
        Cycle 13 Day 1 (n=130): 0 to 2
    0.8
        Cycle 13 Day 1 (n=130): 0 to 3
    0.8
        Cycle 13 Day 1 (n=130): 0 to 4
    0
        Cycle 13 Day 1 (n=130): 1 to 0
    5.4
        Cycle 13 Day 1 (n=130): 1 to 2
    1.5
        Cycle 13 Day 1 (n=130): 1 to 3
    0
        Cycle 13 Day 1 (n=130): 1 to 4
    0
        Cycle 13 Day 1 (n=130): Missing
    0.8
        Cycle 14 Day 1 (n=105): Unchanged
    62.9
        Cycle 14 Day 1 (n=105): 0 to 1
    27.6
        Cycle 14 Day 1 (n=105): 0 to 2
    1.9
        Cycle 14 Day 1 (n=105): 0 to 3
    0
        Cycle 14 Day 1 (n=105): 0 to 4
    0
        Cycle 14 Day 1 (n=105): 1 to 0
    5.7
        Cycle 14 Day 1 (n=105): 1 to 2
    1
        Cycle 14 Day 1 (n=105): 1 to 3
    0
        Cycle 14 Day 1 (n=105): 1 to 4
    0
        Cycle 14 Day 1 (n=105): Missing
    1
        Cycle 15 Day 1 (n=87): Unchanged
    63.2
        Cycle 15 Day 1 (n=87): 0 to 1
    26.4
        Cycle 15 Day 1 (n=87): 0 to 2
    2.3
        Cycle 15 Day 1 (n=87): 0 to 3
    0
        Cycle 15 Day 1 (n=87): 0 to 4
    0
        Cycle 15 Day 1 (n=87): 1 to 0
    6.9
        Cycle 15 Day 1 (n=87): 1 to 2
    0
        Cycle 15 Day 1 (n=87): 1 to 3
    0
        Cycle 15 Day 1 (n=87): 1 to 4
    0
        Cycle 15 Day 1 (n=87): Missing
    1.1
        Cycle 16 Day 1 (n=69): Unchanged
    68.1
        Cycle 16 Day 1 (n=69): 0 to 1
    21.7
        Cycle 16 Day 1 (n=69): 0 to 2
    1.4
        Cycle 16 Day 1 (n=69): 0 to 3
    0
        Cycle 16 Day 1 (n=69): 0 to 4
    0
        Cycle 16 Day 1 (n=69): 1 to 0
    5.8
        Cycle 16 Day 1 (n=69): 1 to 2
    1.4
        Cycle 16 Day 1 (n=69): 1 to 3
    0
        Cycle 16 Day 1 (n=69): 1 to 4
    0
        Cycle 16 Day 1 (n=69): Missing
    1.4
        Cycle 17 Day 1 (n=59): Unchanged
    69.5
        Cycle 17 Day 1 (n=59): 0 to 1
    20.3
        Cycle 17 Day 1 (n=59): 0 to 2
    3.4
        Cycle 17 Day 1 (n=59): 0 to 3
    0
        Cycle 17 Day 1 (n=59): 0 to 4
    0
        Cycle 17 Day 1 (n=59): 1 to 0
    5.1
        Cycle 17 Day 1 (n=59): 1 to 2
    1.7
        Cycle 17 Day 1 (n=59): 1 to 3
    0
        Cycle 17 Day 1 (n=59): 1 to 4
    0
        Cycle 18 Day 1 (n=47): Unchanged
    70.2
        Cycle 18 Day 1 (n=47): 0 to 1
    17
        Cycle 18 Day 1 (n=47): 0 to 2
    2.1
        Cycle 18 Day 1 (n=47): 0 to 3
    0
        Cycle 18 Day 1 (n=47): 0 to 4
    0
        Cycle 18 Day 1 (n=47): 1 to 0
    8.5
        Cycle 18 Day 1 (n=47): 1 to 2
    2.1
        Cycle 18 Day 1 (n=47): 1 to 3
    0
        Cycle 18 Day 1 (n=47): 1 to 4
    0
        Cycle 19 Day 1 (n=40): Unchanged
    77.5
        Cycle 19 Day 1 (n=40): 0 to 1
    15
        Cycle 19 Day 1 (n=40): 0 to 2
    2.5
        Cycle 19 Day 1 (n=40): 0 to 3
    0
        Cycle 19 Day 1 (n=40): 0 to 4
    0
        Cycle 19 Day 1 (n=40): 1 to 0
    5
        Cycle 19 Day 1 (n=40): 1 to 2
    0
        Cycle 19 Day 1 (n=40): 1 to 3
    0
        Cycle 19 Day 1 (n=40): 1 to 4
    0
        Cycle 20 Day 1 (n=31): Unchanged
    77.4
        Cycle 20 Day 1 (n=31): 0 to 1
    16.1
        Cycle 20 Day 1 (n=31): 0 to 2
    0
        Cycle 20 Day 1 (n=31): 0 to 3
    0
        Cycle 20 Day 1 (n=31): 0 to 4
    0
        Cycle 20 Day 1 (n=31): 1 to 0
    6.5
        Cycle 20 Day 1 (n=31): 1 to 2
    0
        Cycle 20 Day 1 (n=31): 1 to 3
    0
        Cycle 20 Day 1 (n=31): 1 to 4
    0
        Cycle 21 Day 1 (n=28): Unchanged
    75
        Cycle 21 Day 1 (n=28): 0 to 1
    17.9
        Cycle 21 Day 1 (n=28): 0 to 2
    3.6
        Cycle 21 Day 1 (n=28): 0 to 3
    0
        Cycle 21 Day 1 (n=28): 0 to 4
    0
        Cycle 21 Day 1 (n=28): 1 to 0
    3.6
        Cycle 21 Day 1 (n=28): 1 to 2
    0
        Cycle 21 Day 1 (n=28): 1 to 3
    0
        Cycle 21 Day 1 (n=28): 1 to 4
    0
        Cycle 22 Day 1 (n=22): Unchanged
    72.7
        Cycle 22 Day 1 (n=22): 0 to 1
    18.2
        Cycle 22 Day 1 (n=22): 0 to 2
    0
        Cycle 22 Day 1 (n=22): 0 to 3
    0
        Cycle 22 Day 1 (n=22): 0 to 4
    0
        Cycle 22 Day 1 (n=22): 1 to 0
    4.5
        Cycle 22 Day 1 (n=22): 1 to 2
    4.5
        Cycle 22 Day 1 (n=22): 1 to 3
    0
        Cycle 22 Day 1 (n=22): 1 to 4
    0
        Cycle 23 Day 1 (n=17): Unchanged
    70.6
        Cycle 23 Day 1 (n=17): 0 to 1
    23.5
        Cycle 23 Day 1 (n=17): 0 to 2
    0
        Cycle 23 Day 1 (n=17): 0 to 3
    0
        Cycle 23 Day 1 (n=17): 0 to 4
    0
        Cycle 23 Day 1 (n=17): 1 to 0
    5.9
        Cycle 23 Day 1 (n=17): 1 to 2
    0
        Cycle 23 Day 1 (n=17): 1 to 3
    0
        Cycle 23 Day 1 (n=17): 1 to 4
    0
        Cycle 24 Day 1 (n=15): Unchanged
    73.3
        Cycle 24 Day 1 (n=15): 0 to 1
    26.7
        Cycle 24 Day 1 (n=15): 0 to 2
    0
        Cycle 24 Day 1 (n=15): 0 to 3
    0
        Cycle 24 Day 1 (n=15): 0 to 4
    0
        Cycle 24 Day 1 (n=15): 1 to 0
    0
        Cycle 24 Day 1 (n=15): 1 to 2
    0
        Cycle 24 Day 1 (n=15): 1 to 3
    0
        Cycle 24 Day 1 (n=15): 1 to 4
    0
        Cycle 25 Day 1 (n=14): Unchanged
    71.4
        Cycle 25 Day 1 (n=14): 0 to 1
    21.4
        Cycle 25 Day 1 (n=14): 0 to 2
    0
        Cycle 25 Day 1 (n=14): 0 to 3
    0
        Cycle 25 Day 1 (n=14): 0 to 4
    0
        Cycle 25 Day 1 (n=14): 1 to 0
    7.1
        Cycle 25 Day 1 (n=14): 1 to 2
    0
        Cycle 25 Day 1 (n=14): 1 to 3
    0
        Cycle 25 Day 1 (n=14): 1 to 4
    0
        Cycle 26 Day 1 (n=14): Unchanged
    64.3
        Cycle 26 Day 1 (n=14): 0 to 1
    28.6
        Cycle 26 Day 1 (n=14): 0 to 2
    0
        Cycle 26 Day 1 (n=14): 0 to 3
    0
        Cycle 26 Day 1 (n=14): 0 to 4
    0
        Cycle 26 Day 1 (n=14): 1 to 0
    0
        Cycle 26 Day 1 (n=14): 1 to 2
    0
        Cycle 26 Day 1 (n=14): 1 to 3
    7.1
        Cycle 26 Day 1 (n=14): 1 to 4
    0
        Cycle 27 Day 1 (n=12): Unchanged
    66.7
        Cycle 27 Day 1 (n=12): 0 to 1
    33.3
        Cycle 27 Day 1 (n=12): 0 to 2
    0
        Cycle 27 Day 1 (n=12): 0 to 3
    0
        Cycle 27 Day 1 (n=12): 0 to 4
    0
        Cycle 27 Day 1 (n=12): 1 to 0
    0
        Cycle 27 Day 1 (n=12): 1 to 2
    0
        Cycle 27 Day 1 (n=12): 1 to 3
    0
        Cycle 27 Day 1 (n=12): 1 to 4
    0
        Cycle 28 Day 1 (n=12): Unchanged
    58.3
        Cycle 28 Day 1 (n=12): 0 to 1
    41.7
        Cycle 28 Day 1 (n=12): 0 to 2
    0
        Cycle 28 Day 1 (n=12): 0 to 3
    0
        Cycle 28 Day 1 (n=12): 0 to 4
    0
        Cycle 28 Day 1 (n=12): 1 to 0
    0
        Cycle 28 Day 1 (n=12): 1 to 2
    0
        Cycle 28 Day 1 (n=12): 1 to 3
    0
        Cycle 28 Day 1 (n=12): 1 to 4
    0
        Cycle 29 Day 1 (n=10): Unchanged
    50
        Cycle 29 Day 1 (n=10): 0 to 1
    50
        Cycle 29 Day 1 (n=10): 0 to 2
    0
        Cycle 29 Day 1 (n=10): 0 to 3
    0
        Cycle 29 Day 1 (n=10): 0 to 4
    0
        Cycle 29 Day 1 (n=10): 1 to 0
    0
        Cycle 29 Day 1 (n=10): 1 to 2
    0
        Cycle 29 Day 1 (n=10): 1 to 3
    0
        Cycle 29 Day 1 (n=10): 1 to 4
    0
        Cycle 30 Day 1 (n=10): Unchanged
    50
        Cycle 30 Day 1 (n=10): 0 to 1
    50
        Cycle 30 Day 1 (n=10): 0 to 2
    0
        Cycle 30 Day 1 (n=10): 0 to 3
    0
        Cycle 30 Day 1 (n=10): 0 to 4
    0
        Cycle 30 Day 1 (n=10): 1 to 0
    0
        Cycle 30 Day 1 (n=10): 1 to 2
    0
        Cycle 30 Day 1 (n=10): 1 to 3
    0
        Cycle 30 Day 1 (n=10): 1 to 4
    0
        Cycle 31 Day 1 (n=7): Unchanged
    57.1
        Cycle 31 Day 1 (n=7): 0 to 1
    42.9
        Cycle 31 Day 1 (n=7): 0 to 2
    0
        Cycle 31 Day 1 (n=7): 0 to 3
    0
        Cycle 31 Day 1 (n=7): 0 to 4
    0
        Cycle 31 Day 1 (n=7): 1 to 0
    0
        Cycle 31 Day 1 (n=7): 1 to 2
    0
        Cycle 31 Day 1 (n=7): 1 to 3
    0
        Cycle 31 Day 1 (n=7): 1 to 4
    0
        Cycle 32 Day 1 (n=7): Unchanged
    42.9
        Cycle 32 Day 1 (n=7): 0 to 1
    57.1
        Cycle 32 Day 1 (n=7): 0 to 2
    0
        Cycle 32 Day 1 (n=7): 0 to 3
    0
        Cycle 32 Day 1 (n=7): 0 to 4
    0
        Cycle 32 Day 1 (n=7): 1 to 0
    0
        Cycle 32 Day 1 (n=7): 1 to 2
    0
        Cycle 32 Day 1 (n=7): 1 to 3
    0
        Cycle 32 Day 1 (n=7): 1 to 4
    0
        Cycle 33 Day 1 (n=6): Unchanged
    33.3
        Cycle 33 Day 1 (n=6): 0 to 1
    66.7
        Cycle 33 Day 1 (n=6): 0 to 2
    0
        Cycle 33 Day 1 (n=6): 0 to 3
    0
        Cycle 33 Day 1 (n=6): 0 to 4
    0
        Cycle 33 Day 1 (n=6): 1 to 0
    0
        Cycle 33 Day 1 (n=6): 1 to 2
    0
        Cycle 33 Day 1 (n=6): 1 to 3
    0
        Cycle 33 Day 1 (n=6): 1 to 4
    0
        End of treatment (n=1855): Unchanged
    43.5
        End of treatment (n=1855): 0 to 1
    21.7
        End of treatment (n=1855): 0 to 2
    7
        End of treatment (n=1855): 0 to 3
    2.4
        End of treatment (n=1855): 0 to 4
    0.2
        End of treatment (n=1855): 1 to 0
    2.2
        End of treatment (n=1855): 1 to 2
    13.5
        End of treatment (n=1855): 1 to 3
    8.6
        End of treatment (n=1855): 1 to 4
    0.8
        End of treatment (n=1855): Missing
    0.2
    No statistical analyses for this end point

    Primary: Extent of Exposure - Number of Cycles Completed

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    End point title
    		 Extent of Exposure - Number of Cycles Completed [8]
    End point description
    SAF, number of subjects analysed signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From start of study treatment until 33 months
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2862
    Units: cycles
        arithmetic mean (standard deviation)
    4.1 ( 4.3 )
    No statistical analyses for this end point

    Primary: Extent of Exposure - Treatment Duration in Weeks

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    End point title
    		 Extent of Exposure - Treatment Duration in Weeks [9]
    End point description
    Overall treatment duration in weeks including interruptions/delays and drug holidays was calculated as (Day of last dose minus day of first dose + 1) / 7. SAF, number of subjects analysed signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From start of study treatment until 33 months
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2864
    Units: weeks
        arithmetic mean (standard deviation)
    15.6 ( 18.1 )
    No statistical analyses for this end point

    Primary: Extent of Exposure - Treatment Duration for Actual Weeks Study Drug Received

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    End point title
    		 Extent of Exposure - Treatment Duration for Actual Weeks Study Drug Received [10]
    End point description
    Actual treatment duration in weeks excluding interruptions/delays and drug holidays was calculated as (Day of last dose minus day of first dose + 1) minus days of interruption and drug holidays / 7. SAF, number of subjects analysed signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From start of study treatment until 33 months
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2864
    Units: weeks
        arithmetic mean (standard deviation)
    11.2 ( 12.6 )
    No statistical analyses for this end point

    Primary: Extent of Exposure - Actual Daily Dose of Regorafenib

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    End point title
    		 Extent of Exposure - Actual Daily Dose of Regorafenib [11]
    End point description
    SAF, number of subjects analysed signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From start of study treatment until 33 months
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2862
    Units: milligram (mg)
        arithmetic mean (standard deviation)
    145.8 ( 19.1 )
    No statistical analyses for this end point

    Primary: Extent of Exposure - Percent of Planned Dose Received

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    End point title
    		 Extent of Exposure - Percent of Planned Dose Received [12]
    End point description
    Planned dose describes the intended initial dose of the study drug. SAF, number of subjects analysed signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From start of study treatment until 33 months
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2862
    Units: percent of planned dose
        arithmetic mean (standard deviation)
    75.1 ( 19.8 )
    No statistical analyses for this end point

    Primary: Extent of Exposure - Percentage of Subjects With Total Amount of Dose Including Categories

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    End point title
    		 Extent of Exposure - Percentage of Subjects With Total Amount of Dose Including Categories [13]
    End point description
    SAF, number of subjects analysed signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From start of study treatment until 33 months
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2862
    Units: percentage of subjects
    number (not applicable)
        =<2000 mg
    7.9
        >2000 to 5000 mg
    21.6
        >5000 to 8000 mg
    23.2
        >8000 to 11000 mg
    16.2
        >11000 to 14000 mg
    8.9
        >14000 mg
    22.2
        Missing
    0.1
    No statistical analyses for this end point

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS) [14]
    End point description
    Progression-free survival was defined as the time from date of treatment assignment (i.e. date of first treatment) to date of first observed disease progression or death due to any cause, if death occurred while the subject was in the study (that is, by the last visit including during the safety follow-up visit date) and before progression was observed. Tumor measurements were made at intervals and with methods that complied with the institution’s best standard of care. Full analysis set (FAS) included all subjects who were assigned to treatment.
    End point type
    Primary
    End point timeframe
    From start of study treatment until 33 months
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Regorafenib (BAY73-4506)
    Number of subjects analysed
    2872
    Units: days
        median (confidence interval 95%)
    82 (79 to 83)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment up to 30 days after the last dose of study drug
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Regorafenib (BAY73-4506)
    Reporting group description
    		 Subjects received regorafenib 160 mg (4 x 40 mg tablets) per oral once daily for 3 weeks of every 4 week cycle (that is 3 weeks on, 1 week off).

    Serious adverse events
    		 Regorafenib (BAY73-4506)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1253 / 2864 (43.75%)
         number of deaths (all causes)
    547
         number of deaths resulting from adverse events
    407
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Colon cancer
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    Malignant ascites
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Malignant pleural effusion
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Sarcoma
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour pain
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metastases to meninges
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Tumour associated fever
         subjects affected / exposed
    6 / 2864 (0.21%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Colorectal cancer metastatic
         subjects affected / exposed
    11 / 2864 (0.38%)
         occurrences causally related to treatment / all
    0 / 15
         deaths causally related to treatment / all
    0 / 10
    Infected neoplasm
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cancer pain
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 5
    Tumour perforation
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Tumour fistulisation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Bleeding varicose vein
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    6 / 2864 (0.21%)
         occurrences causally related to treatment / all
    16 / 18
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Lymphoedema
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    24 / 2864 (0.84%)
         occurrences causally related to treatment / all
    15 / 35
         deaths causally related to treatment / all
    1 / 4
    Chest pain
         subjects affected / exposed
    9 / 2864 (0.31%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Chronic fatigue syndrome
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    8 / 2864 (0.28%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    1 / 8
    Fatigue
         subjects affected / exposed
    20 / 2864 (0.70%)
         occurrences causally related to treatment / all
    14 / 21
         deaths causally related to treatment / all
    0 / 0
    Gait disturbance
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    66 / 2864 (2.30%)
         occurrences causally related to treatment / all
    17 / 76
         deaths causally related to treatment / all
    0 / 1
    Sudden death
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Performance status decreased
         subjects affected / exposed
    7 / 2864 (0.24%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    General physical health deterioration
         subjects affected / exposed
    288 / 2864 (10.06%)
         occurrences causally related to treatment / all
    15 / 433
         deaths causally related to treatment / all
    2 / 213
    Inflammation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 5
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic pain
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Prostatic obstruction
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Female genital tract fistula
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Adnexal torsion
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    Aspiration
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Atelectasis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Bronchial obstruction
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catarrh
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    35 / 2864 (1.22%)
         occurrences causally related to treatment / all
    1 / 53
         deaths causally related to treatment / all
    0 / 12
    Dyspnoea exertional
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Epistaxis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 1
    Hiccups
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Lung disorder
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    26 / 2864 (0.91%)
         occurrences causally related to treatment / all
    0 / 33
         deaths causally related to treatment / all
    0 / 3
    Pleuritic pain
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Pneumothorax
         subjects affected / exposed
    9 / 2864 (0.31%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    18 / 2864 (0.63%)
         occurrences causally related to treatment / all
    7 / 21
         deaths causally related to treatment / all
    1 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    14 / 2864 (0.49%)
         occurrences causally related to treatment / all
    0 / 22
         deaths causally related to treatment / all
    0 / 12
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    11 / 2864 (0.38%)
         occurrences causally related to treatment / all
    1 / 12
         deaths causally related to treatment / all
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hallucination
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Mental status changes
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    Psychotic disorder
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device leakage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    21 / 2864 (0.73%)
         occurrences causally related to treatment / all
    4 / 31
         deaths causally related to treatment / all
    0 / 1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood urine present
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coagulation test abnormal
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Incisional hernia, obstructive
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suture rupture
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural pain
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Angina pectoris
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    9 / 2864 (0.31%)
         occurrences causally related to treatment / all
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    7 / 2864 (0.24%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    1 / 7
    Myocardial infarction
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Apraxia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ataxia
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    1 / 2
    Cerebral ischaemia
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cervical cord compression
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coma hepatic
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Dizziness
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysaesthesia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    Horner's syndrome
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Neuralgia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    6 / 2864 (0.21%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    Somnolence
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain oedema
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Vocal cord paresis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial paresis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial mass
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 2864 (0.52%)
         occurrences causally related to treatment / all
    8 / 23
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    7 / 2864 (0.24%)
         occurrences causally related to treatment / all
    16 / 17
         deaths causally related to treatment / all
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperprothrombinaemia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Retinal vascular occlusion
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Retinal vein thrombosis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    57 / 2864 (1.99%)
         occurrences causally related to treatment / all
    2 / 68
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    7 / 2864 (0.24%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Anal fistula
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    24 / 2864 (0.84%)
         occurrences causally related to treatment / all
    0 / 31
         deaths causally related to treatment / all
    0 / 4
    Colitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colonic fistula
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    Constipation
         subjects affected / exposed
    13 / 2864 (0.45%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    28 / 2864 (0.98%)
         occurrences causally related to treatment / all
    26 / 33
         deaths causally related to treatment / all
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Gastric perforation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis alcoholic
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 1
    Haematemesis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    7 / 2864 (0.24%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    Ileus paralytic
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal fistula
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    33 / 2864 (1.15%)
         occurrences causally related to treatment / all
    1 / 43
         deaths causally related to treatment / all
    0 / 6
    Intestinal perforation
         subjects affected / exposed
    7 / 2864 (0.24%)
         occurrences causally related to treatment / all
    3 / 9
         deaths causally related to treatment / all
    1 / 2
    Jejunal perforation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    Mallory-Weiss syndrome
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    9 / 2864 (0.31%)
         occurrences causally related to treatment / all
    3 / 10
         deaths causally related to treatment / all
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    10 / 2864 (0.35%)
         occurrences causally related to treatment / all
    2 / 12
         deaths causally related to treatment / all
    0 / 1
    Rectal perforation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    28 / 2864 (0.98%)
         occurrences causally related to treatment / all
    1 / 35
         deaths causally related to treatment / all
    0 / 2
    Small intestinal perforation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    19 / 2864 (0.66%)
         occurrences causally related to treatment / all
    10 / 21
         deaths causally related to treatment / all
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    11 / 2864 (0.38%)
         occurrences causally related to treatment / all
    1 / 13
         deaths causally related to treatment / all
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric stenosis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    12 / 2864 (0.42%)
         occurrences causally related to treatment / all
    0 / 16
         deaths causally related to treatment / all
    0 / 4
    Enterovesical fistula
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Rectal obstruction
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fistula of small intestine
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal hernia perforation
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    12 / 2864 (0.42%)
         occurrences causally related to treatment / all
    1 / 12
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    Cholecystitis acute
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholestasis
         subjects affected / exposed
    6 / 2864 (0.21%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 2
    Hepatic failure
         subjects affected / exposed
    29 / 2864 (1.01%)
         occurrences causally related to treatment / all
    0 / 48
         deaths causally related to treatment / all
    0 / 19
    Hepatic function abnormal
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic pain
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    8 / 2864 (0.28%)
         occurrences causally related to treatment / all
    7 / 14
         deaths causally related to treatment / all
    0 / 0
    Jaundice
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    Perforation bile duct
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    12 / 2864 (0.42%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    14 / 2864 (0.49%)
         occurrences causally related to treatment / all
    4 / 18
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermal cyst
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity vasculitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    10 / 2864 (0.35%)
         occurrences causally related to treatment / all
    12 / 13
         deaths causally related to treatment / all
    0 / 0
    Rash macular
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    12 / 2864 (0.42%)
         occurrences causally related to treatment / all
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    Rash vesicular
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urticaria
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin ulcer haemorrhage
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin toxicity
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    7 / 2864 (0.24%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    7 / 2864 (0.24%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 3
    Ureteric obstruction
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Ureteric stenosis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    8 / 2864 (0.28%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Urinary tract obstruction
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    20 / 2864 (0.70%)
         occurrences causally related to treatment / all
    4 / 24
         deaths causally related to treatment / all
    0 / 3
    Prerenal failure
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroid disorder
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 2864 (0.21%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    26 / 2864 (0.91%)
         occurrences causally related to treatment / all
    0 / 32
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fistula
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    6 / 2864 (0.21%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Spinal pain
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fournier's gangrene
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Herpes simplex otitis externa
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    9 / 2864 (0.31%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Necrotising fasciitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Orchitis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Pneumonia
         subjects affected / exposed
    36 / 2864 (1.26%)
         occurrences causally related to treatment / all
    3 / 48
         deaths causally related to treatment / all
    0 / 8
    Pneumonia chlamydial
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retroperitoneal abscess
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    21 / 2864 (0.73%)
         occurrences causally related to treatment / all
    4 / 28
         deaths causally related to treatment / all
    1 / 8
    Septic shock
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    17 / 2864 (0.59%)
         occurrences causally related to treatment / all
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle abscess
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fungal oesophagitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal fistula infection
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    Febrile infection
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Clostridium difficile infection
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    5 / 2864 (0.17%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Psoas abscess
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic infection
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Bacterial pyelonephritis
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    9 / 2864 (0.31%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 2
    Anorectal infection
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Scrotal infection
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Biliary abscess
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    6 / 2864 (0.21%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sphingomonas paucimobilis infection
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infected fistula
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Escherichia pyelonephritis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular device infection
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    24 / 2864 (0.84%)
         occurrences causally related to treatment / all
    8 / 27
         deaths causally related to treatment / all
    0 / 1
    Failure to thrive
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    4 / 2864 (0.14%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    6 / 2864 (0.21%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    3 / 2864 (0.10%)
         occurrences causally related to treatment / all
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malnutrition
         subjects affected / exposed
    2 / 2864 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Decreased appetite
         subjects affected / exposed
    7 / 2864 (0.24%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Steroid diabetes
         subjects affected / exposed
    1 / 2864 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Regorafenib (BAY73-4506)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2767 / 2864 (96.61%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    982 / 2864 (34.29%)
         occurrences all number
    2517
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    610 / 2864 (21.30%)
         occurrences all number
    1159
    Fatigue
         subjects affected / exposed
    1181 / 2864 (41.24%)
         occurrences all number
    2126
    Mucosal inflammation
         subjects affected / exposed
    409 / 2864 (14.28%)
         occurrences all number
    628
    Pyrexia
         subjects affected / exposed
    545 / 2864 (19.03%)
         occurrences all number
    733
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    228 / 2864 (7.96%)
         occurrences all number
    269
    Dysphonia
         subjects affected / exposed
    764 / 2864 (26.68%)
         occurrences all number
    959
    Dyspnoea
         subjects affected / exposed
    350 / 2864 (12.22%)
         occurrences all number
    452
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    262 / 2864 (9.15%)
         occurrences all number
    486
    Aspartate aminotransferase increased
         subjects affected / exposed
    335 / 2864 (11.70%)
         occurrences all number
    572
    Blood bilirubin increased
         subjects affected / exposed
    452 / 2864 (15.78%)
         occurrences all number
    958
    Lipase increased
         subjects affected / exposed
    237 / 2864 (8.28%)
         occurrences all number
    514
    Weight decreased
         subjects affected / exposed
    875 / 2864 (30.55%)
         occurrences all number
    1140
    Blood alkaline phosphatase increased
         subjects affected / exposed
    191 / 2864 (6.67%)
         occurrences all number
    257
    Nervous system disorders
    Headache
         subjects affected / exposed
    294 / 2864 (10.27%)
         occurrences all number
    380
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    295 / 2864 (10.30%)
         occurrences all number
    570
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    509 / 2864 (17.77%)
         occurrences all number
    712
    Abdominal pain upper
         subjects affected / exposed
    169 / 2864 (5.90%)
         occurrences all number
    220
    Constipation
         subjects affected / exposed
    496 / 2864 (17.32%)
         occurrences all number
    602
    Diarrhoea
         subjects affected / exposed
    907 / 2864 (31.67%)
         occurrences all number
    1857
    Dry mouth
         subjects affected / exposed
    147 / 2864 (5.13%)
         occurrences all number
    166
    Nausea
         subjects affected / exposed
    480 / 2864 (16.76%)
         occurrences all number
    632
    Stomatitis
         subjects affected / exposed
    360 / 2864 (12.57%)
         occurrences all number
    505
    Vomiting
         subjects affected / exposed
    376 / 2864 (13.13%)
         occurrences all number
    517
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    149 / 2864 (5.20%)
         occurrences all number
    185
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1230 / 2864 (42.95%)
         occurrences all number
    3218
    Rash
         subjects affected / exposed
    353 / 2864 (12.33%)
         occurrences all number
    488
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    262 / 2864 (9.15%)
         occurrences all number
    435
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    147 / 2864 (5.13%)
         occurrences all number
    173
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    198 / 2864 (6.91%)
         occurrences all number
    248
    Back pain
         subjects affected / exposed
    320 / 2864 (11.17%)
         occurrences all number
    433
    Myalgia
         subjects affected / exposed
    195 / 2864 (6.81%)
         occurrences all number
    236
    Pain in extremity
         subjects affected / exposed
    152 / 2864 (5.31%)
         occurrences all number
    225
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    186 / 2864 (6.49%)
         occurrences all number
    227
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    190 / 2864 (6.63%)
         occurrences all number
    282
    Hypophosphataemia
         subjects affected / exposed
    320 / 2864 (11.17%)
         occurrences all number
    768
    Decreased appetite
         subjects affected / exposed
    1000 / 2864 (34.92%)
         occurrences all number
    1411

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2012
    1. Inclusion criteria concerning previous therapy for KRAS unknown subjects and acceptable limits for total bilirubin in subjects with documented Gilbert’s Syndrome were made consistent with the preceding CORRECT trial to avoid uncertainty among the investigators. 2. Introduction of a more flexible and individualized schedule of liver function monitoring during treatment, where alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin must be monitored closely, at least every two weeks during the first 2 cycles of treatment. 3. Addition of a time window for coagulation measurements on Day 1 of Cycle 1. 4. Determination of a timeframe for blood and urine sample collection prior to dosing, during treatment phase. 5. Changes to make the text consistent with the eCRF concerning demographic and baseline characteristics, and with other study documents (Study Drug Reconciliation and Destruction Log, interactive voice response system (IVRS)/interactive web response system (IWRS) site manual).
    17 Sep 2012
    1. Modification in the wording of the inclusion criterion concerning KRAS negative or unknown subjects, allowing the inclusion of subjects who have not received prior therapy with bevacizumab and cetuximab / panitumumab. 2. Clarification about the planning of subgroup analyses for Mexican and Russian populations.

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

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