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    Clinical Trial Results:
    A randomized, double blind, placebo-controlled, multicenter phase III study of regorafenib in patients with hepatocellular carcinoma (HCC) after sorafenib

    Summary
    EudraCT number
    2012-003649-14
    Trial protocol
    DE   BE   GB   AT   ES   CZ   FR   HU   NL   IT  
    Global end of trial date
    05 Jul 2019

    Results information
    Results version number
    v3(current)
    This version publication date
    28 Aug 2020
    First version publication date
    25 Feb 2017
    Other versions
    v1 , v2
    Version creation reason
    • Correction of full data set
    Subject dispostion and Age categorical updated.

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY73-4506/15982
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01774344
    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
    05 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate efficacy and safety of regorafenib in subjects with hepatocellular carcinoma (HCC) who had progressed after sorafenib.
    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
    Best Supportive Care includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic
    Evidence for comparator
    -
    Actual start date of recruitment
    14 May 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    42 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    China: 137
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    France: 118
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Japan: 40
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Taiwan: 19
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 2
    Worldwide total number of subjects
    573
    EEA total number of subjects
    297
    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)
    315
    From 65 to 84 years
    258
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted between 14 May 2013 (first subject first visit) , 29 February 2016 (primary completion date)and 05-July-2019 (Last Patient Last Visit =End of study).

    Pre-assignment
    Screening details
    Overall, 843 subjects were screened, of them 270 subjects were screening failures. 573 subjects were randomized and assigned to treatment; of them 6 subjects never received treatment.436 Entered survival Follow-up and 4 End of survival follow-up data not available.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best BSC.

    Arm title
    Regorafenib 160 mg (BAY73-4506)
    Arm description
    Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.
    Arm type
    Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    BAY73-4506
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received regorafenib 160 mg coated tablets orally every day for 3 weeks followed by 1 week off treatment plus BSC.

    Number of subjects in period 1
    Placebo Regorafenib 160 mg (BAY73-4506)
    Started
    194
    379
    Treated
    193
    374
    Entered survival FU
    145
    291
    Completed
    132
    258
    Not completed
    62
    121
         Consent withdrawn by subject
    3
    10
         Did not enter Survival Follow up
    49
    83
         End of survival follow-up not available
    2
    2
         Unspecified
    -
    1
         Lost to follow-up
    4
    10
         Data collection finished
    4
    14
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.

    Reporting group title
    Regorafenib 160 mg (BAY73-4506)
    Reporting group description
    Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.

    Reporting group values
    Placebo Regorafenib 160 mg (BAY73-4506) Total
    Number of subjects
    194 379
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.1 ( 11.6 ) 61.8 ( 12.4 ) -
    Gender categorical
    Units: Subjects
        Female
    23 46 69
        Male
    171 333 504
    Eastern cooperative oncology group (ECOG) Performance Status (PS) (data collection system-RAVE)
    ECOG PS was measured in a scale from 0 (best) to grade 4 (worst), where 0= Fully active, able to carry on all pre-diseases 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 (h), 3= Capable of only limited self-care, confined to bed/chair, more than 50% waking hours, and 4= Completely disabled, cannot carry on any self-care, totally confined to bed/chair.
    Units: Subjects
        ECOG PS 0
    130 247 377
        ECOG PS 1
    64 132 196
    ECOG PS: Interactive voice response system (IVRS)
    ECOG PS was measured in a scale from 0 (best) to grade 4 (worst), where 0= Fully active, able to carry on all pre-diseases 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 % waking h, 3= Capable of only limited self-care, confined to bed/chair, more than 50% waking hours, and 4= Completely disabled, cannot carry on any self-care, totally confined to bed/chair.
    Units: Subjects
        ECOG PS 0
    129 251 380
        ECOG PS 1
    65 128 193
    Alpha-fetoprotein (AFP) (RAVE)
    Alpha-Fetoprotein blood test was performed and baseline data were reported.
    Units: Subjects
        less than (<) 400 nanogram per milliliter (ng/mL)
    107 217 324
        greater than or equal to (>=) 400 ng/mL
    87 162 249
    Alpha-fetoprotein (AFP) (IVRS)
    AFP blood test was performed and baseline data were reported.
    Units: Subjects
        < 400 ng/mL
    105 212 317
        >= 400 ng/mL
    89 167 256
    Macrovascular invasion (RAVE)
    Macrovascular invasion was defined as presence or absence of invasion of portal or hepatic vasculature by tumor.
    Units: Subjects
        Absence
    140 269 409
        Presence
    54 110 164
    Macrovascular invasion (IVRS)
    Macrovascular invasion was defined as presence or absence of invasion of portal or hepatic vasculature by tumor.
    Units: Subjects
        Absence
    135 262 397
        Presence
    59 117 176
    The Barcelona-Clinic Liver Cancer (BCLC) stage at study entry
    BCLC classification divides HCC subjects in 5 stages (0=very early stage, A=early stage, B=intermediate stage, C=advanced stage and D=terminal stage) according to pre-established prognostic variables, and allocates therapies according to treatment-related status. Thus, it provides information on both prognostic prediction and treatment allocation.
    Units: Subjects
        Early stage
    0 1 1
        Intermediate stage
    22 53 75
        Advanced stage
    172 325 497
    Extrahepatic disease (RAVE)
    Extrahepatic disease defined as presence or absence of tumor outside the liver.
    Units: Subjects
        Absence
    47 114 161
        Presence
    147 265 412
    Extrahepatic disease (IVRS)
    Extrahepatic disease defined as presence or absence of tumor outside the liver.
    Units: Subjects
        Absence
    62 129 191
        Presence
    132 250 382
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FAS (N=573) included all randomized subjects.

    Subject analysis sets values
    Full Analysis Set (FAS)
    Number of subjects
    573
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.6 ( 12.1 )
    Gender categorical
    Units: Subjects
        Female
    69
        Male
    504
    Eastern cooperative oncology group (ECOG) Performance Status (PS) (data collection system-RAVE)
    ECOG PS was measured in a scale from 0 (best) to grade 4 (worst), where 0= Fully active, able to carry on all pre-diseases 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 (h), 3= Capable of only limited self-care, confined to bed/chair, more than 50% waking hours, and 4= Completely disabled, cannot carry on any self-care, totally confined to bed/chair.
    Units: Subjects
        ECOG PS 0
    377
        ECOG PS 1
    196
    ECOG PS: Interactive voice response system (IVRS)
    ECOG PS was measured in a scale from 0 (best) to grade 4 (worst), where 0= Fully active, able to carry on all pre-diseases 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 % waking h, 3= Capable of only limited self-care, confined to bed/chair, more than 50% waking hours, and 4= Completely disabled, cannot carry on any self-care, totally confined to bed/chair.
    Units: Subjects
        ECOG PS 0
    380
        ECOG PS 1
    193
    Alpha-fetoprotein (AFP) (RAVE)
    Alpha-Fetoprotein blood test was performed and baseline data were reported.
    Units: Subjects
        less than (<) 400 nanogram per milliliter (ng/mL)
    324
        greater than or equal to (>=) 400 ng/mL
    249
    Alpha-fetoprotein (AFP) (IVRS)
    AFP blood test was performed and baseline data were reported.
    Units: Subjects
        < 400 ng/mL
    317
        >= 400 ng/mL
    256
    Macrovascular invasion (RAVE)
    Macrovascular invasion was defined as presence or absence of invasion of portal or hepatic vasculature by tumor.
    Units: Subjects
        Absence
    409
        Presence
    164
    Macrovascular invasion (IVRS)
    Macrovascular invasion was defined as presence or absence of invasion of portal or hepatic vasculature by tumor.
    Units: Subjects
        Absence
    262
        Presence
    117
    The Barcelona-Clinic Liver Cancer (BCLC) stage at study entry
    BCLC classification divides HCC subjects in 5 stages (0=very early stage, A=early stage, B=intermediate stage, C=advanced stage and D=terminal stage) according to pre-established prognostic variables, and allocates therapies according to treatment-related status. Thus, it provides information on both prognostic prediction and treatment allocation.
    Units: Subjects
        Early stage
    1
        Intermediate stage
    75
        Advanced stage
    497
    Extrahepatic disease (RAVE)
    Extrahepatic disease defined as presence or absence of tumor outside the liver.
    Units: Subjects
        Absence
    161
        Presence
    412
    Extrahepatic disease (IVRS)
    Extrahepatic disease defined as presence or absence of tumor outside the liver.
    Units: Subjects
        Absence
    191
        Presence
    382

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.

    Reporting group title
    Regorafenib 160 mg (BAY73-4506)
    Reporting group description
    Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FAS (N=573) included all randomized subjects.

    Primary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.
    End point type
    Primary
    End point timeframe
    From randomization (Day 1) of the first subject until 419 days later
    End point values
    Placebo Regorafenib 160 mg (BAY73-4506)
    Number of subjects analysed
    194
    379
    Units: days
        median (confidence interval 95%)
    237 (192 to 269)
    323 (276 to 369)
    Statistical analysis title
    Regorafenib v Placebo: Stratified (IVRS)
    Statistical analysis description
    Hazard ratio for OS and 95% confidence interval was calculated for stratified IVRS by using Cox model, stratified by the geographic region: Asia or Rest of the World (ROW), ECOG-PS: 0 versus 1, AFP level, presence versus absence of extrahepatic disease and presence versus absence of macrovascular invasion. Kaplan-Meier (KM) estimated for OS and KM survival curves were presented for each treatment arm.
    Comparison groups
    Regorafenib 160 mg (BAY73-4506) v Placebo
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.000017
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.624
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.498
         upper limit
    0.782
    Statistical analysis title
    Regorafenib v Placebo: Stratified (RAVE)
    Statistical analysis description
    Hazard ratio for OS and 95% confidence interval was calculated for stratified RAVE (Sensitivity) by using Cox model, stratified by the geographic region: Asia or Rest of the World (ROW), ECOG-PS: 0 versus 1, AFP level, presence versus absence of extrahepatic disease and presence versus absence of macrovascular invasion. Kaplan-Meier (KM) estimated for OS and KM survival curves were presented for each treatment arm.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.000149
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.527
         upper limit
    0.828
    Statistical analysis title
    Regorafenib v Placebo: Unstratified (Sensitivity)
    Statistical analysis description
    Hazard ratio for OS and 95% confidence interval was calculated for unstratified (sensitivity) by using Cox model, stratified by the geographic region: Asia or Rest of the World (ROW), ECOG-PS: 0 versus 1, AFP level, presence versus absence of extrahepatic disease and presence versus absence of macrovascular invasion. Kaplan-Meier (KM) estimated for OS and KM survival curves were presented for each treatment arm.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.000107
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.674
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.546
         upper limit
    0.831

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    TTP was the time (days) from randomization to radiological or clinical disease progression assessed by independent radiological review. Median and 95% confidence interval were reported for the modified response evaluation criteria in solid tumors (mRECIST) and response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact.
    End point type
    Secondary
    End point timeframe
    From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)
    End point values
    Placebo Regorafenib 160 mg (BAY73-4506)
    Number of subjects analysed
    194
    379
    Units: days
    median (confidence interval 95%)
        mRECIST
    45 (44 to 49)
    97 (87 to 128)
        RECIST 1.1
    45 (44 to 49)
    119 (87 to 128)
    Statistical analysis title
    Regorafenib v Placebo-mRECIST: Stratified (IVRS)
    Statistical analysis description
    Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.439
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.355
         upper limit
    0.542
    Statistical analysis title
    Regorafenib v Placebo-mRECIST: Unstratified
    Statistical analysis description
    Hazard ratio and its 95% CI was based on unstratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.471
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.388
         upper limit
    0.572
    Statistical analysis title
    Regorafenib v Placebo-RECIST 1.1:Stratified (IVRS)
    Statistical analysis description
    Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.412
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.334
         upper limit
    0.509
    Statistical analysis title
    Regorafenib v Placebo-RECIST 1.1: Unstratified
    Statistical analysis description
    Hazard ratio and its 95% CI was based on unstratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.444
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.365
         upper limit
    0.539

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    Progression Free Survival (PFS) was defined as the time (days) from date of randomization to date of disease progression (radiological or clinical) or death due to any cause, if death occurs before progression was documented. Death in the absence of progression was a PFS event only if it occurred within the 12+1 weeks for subjects who discontinued treatment prior to cycle 8 and 24+2 weeks for subjects who discontinued treatment after to cycle 8 of the last evaluable tumor assessment; PFS were censored at the date of the last evaluable tumor assessment, if it occurred later. Median and 95% confidence interval 95% were reported for the mRECIST and RECIST 1.1 analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact.
    End point type
    Secondary
    End point timeframe
    From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks)
    End point values
    Placebo Regorafenib 160 mg (BAY73-4506)
    Number of subjects analysed
    194
    379
    Units: days
    median (confidence interval 95%)
        mRECIST
    45 (44 to 47)
    95 (86 to 127)
        RECIST 1.1
    45 (44 to 49)
    102 (87 to 127)
    Statistical analysis title
    Regorafenib v Placebo-mRECIST: Stratified (IVRS)
    Statistical analysis description
    Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.453
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.369
         upper limit
    0.555
    Statistical analysis title
    Regorafenib v Placebo-mRECIST: Unstratified
    Statistical analysis description
    Hazard ratio and its 95% CI was based on unstratified Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.397
         upper limit
    0.58
    Statistical analysis title
    Regorafenib v Placebo-RECIST 1.1:Stratified (IVRS)
    Statistical analysis description
    Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.425
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.347
         upper limit
    0.522
    Statistical analysis title
    Regorafenib v Placebo-RECIST 1.1: Unstratified
    Statistical analysis description
    Hazard ratio and its 95% CI was based on unstratified Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.454
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.376
         upper limit
    0.548

    Secondary: Objective Tumor Response Rate (ORR)

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    End point title
    Objective Tumor Response Rate (ORR)
    End point description
    Objective tumor response rate (ORR) was defined as the percentage of subjects whose best tumor response CR or Partial Response (PR) observed during trial period assessed according to the mRECIST criteria and RECIST 1.1. CR= Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10 mm. PR= At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions. Subjects prematurely discontinuing without an assessment were to be considered non-responders for the analysis.
    End point type
    Secondary
    End point timeframe
    From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)
    End point values
    Placebo Regorafenib 160 mg (BAY73-4506)
    Number of subjects analysed
    194
    379
    Units: percentage of subjects
    number (not applicable)
        mRECIST
    4.1
    10.8
        RECIST 1.1
    2.6
    6.6
    Statistical analysis title
    Regorafenib v Placebo-mRECIST
    Statistical analysis description
    Comparison of treatments were calculated.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00365
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    -6.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.13
         upper limit
    -2.63
    Statistical analysis title
    Regorafenib v Placebo-RECIST 1.1
    Statistical analysis description
    Comparison of treatments were calculated.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.019991
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    -4.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.55
         upper limit
    -0.75

    Secondary: Disease Control Rate (DCR)

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    End point title
    Disease Control Rate (DCR)
    End point description
    Disease control rate (DCR) was defined as the percentage of subjects whose best response was CR (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), PR (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or stable disease (SD) (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST and RECIST 1.1 criteria. SD had to be maintained for at least 6 weeks from the first demonstration of that rating.
    End point type
    Secondary
    End point timeframe
    From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)
    End point values
    Placebo Regorafenib 160 mg (BAY73-4506)
    Number of subjects analysed
    194
    379
    Units: percentage of subjects
    number (not applicable)
        mRECIST
    36.1
    65.2
        RECIST 1.1
    34.5
    65.7
    Statistical analysis title
    Regorafenib v Placebo-mRECIST
    Statistical analysis description
    Comparison of treatments were calculated.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    -29.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.52
         upper limit
    -21.11
    Statistical analysis title
    Regorafenib v Placebo-RECIST 1.1
    Statistical analysis description
    Comparison of treatments were calculated.
    Comparison groups
    Placebo v Regorafenib 160 mg (BAY73-4506)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    -31.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.57
         upper limit
    -23.22

    Other pre-specified: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause
    End point type
    Other pre-specified
    End point timeframe
    From randomization (Day 1) of the first subject to end of follow upto 1710 days
    End point values
    Placebo Regorafenib 160 mg (BAY73-4506)
    Number of subjects analysed
    194
    379
    Units: days
        median (confidence interval 95%)
    241 (196 to 274)
    326 (278 to 372)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected after start of study drug administration until 30 days after end of study treatment over a period of approximately three years
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Description: Subjects received placebo matched to regorafenib tablets orally every day for 3 weeks followed by 1 week off treatment plus best supportive care(BSC).

    Reporting group title
    Regorafenib (Stivarga, BAY73-4506)
    Reporting group description
    Description: Subjects received regorafenib 160 mg (4 *40 mg tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.

    Serious adverse events
    Placebo Regorafenib (Stivarga, BAY73-4506)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 193 (47.67%)
    194 / 374 (51.87%)
         number of deaths (all causes)
    176
    324
         number of deaths resulting from adverse events
    39
    62
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine benign neoplasm
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 193 (0.00%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertensive crisis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 193 (0.00%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Orthostatic hypotension
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 193 (0.00%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Fatigue
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    25 / 193 (12.95%)
    47 / 374 (12.57%)
         occurrences causally related to treatment / all
    1 / 32
    8 / 73
         deaths causally related to treatment / all
    0 / 17
    1 / 28
    Malaise
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    2 / 193 (1.04%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 193 (0.52%)
    6 / 374 (1.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal oedema
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 193 (1.04%)
    5 / 374 (1.34%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Haemoptysis
         subjects affected / exposed
    2 / 193 (1.04%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 193 (0.52%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 193 (1.55%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Tracheal disorder
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary venous thrombosis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 193 (1.04%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure decreased
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General physical condition abnormal
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Femur fracture
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 193 (0.00%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Acute myocardial infarction
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    3 / 193 (1.55%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    3 / 193 (1.55%)
    9 / 374 (2.41%)
         occurrences causally related to treatment / all
    0 / 6
    5 / 14
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Meningorrhagia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myasthenia gravis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplegia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intracranial venous sinus thrombosis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 193 (0.52%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 3
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 193 (2.07%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    6 / 193 (3.11%)
    10 / 374 (2.67%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Constipation
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 193 (0.00%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastritis
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 193 (1.04%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 193 (0.52%)
    6 / 374 (1.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pancreatitis
         subjects affected / exposed
    0 / 193 (0.00%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 193 (1.55%)
    6 / 374 (1.60%)
         occurrences causally related to treatment / all
    0 / 5
    3 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 193 (0.00%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Bile duct stenosis
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    9 / 193 (4.66%)
    9 / 374 (2.41%)
         occurrences causally related to treatment / all
    5 / 14
    1 / 14
         deaths causally related to treatment / all
    2 / 5
    0 / 3
    Hepatic function abnormal
         subjects affected / exposed
    3 / 193 (1.55%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    2 / 193 (1.04%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disease
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 193 (0.52%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    2 / 193 (1.04%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 193 (0.52%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Precancerous skin lesion
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 193 (1.04%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis noninfective
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 193 (0.52%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 193 (1.04%)
    6 / 374 (1.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 193 (1.04%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 193 (0.00%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peritonitis
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural infection bacterial
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 193 (0.52%)
    8 / 374 (2.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 193 (0.00%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Folliculitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 193 (1.55%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 193 (0.00%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Regorafenib (Stivarga, BAY73-4506)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    162 / 193 (83.94%)
    366 / 374 (97.86%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 193 (7.25%)
    119 / 374 (31.82%)
         occurrences all number
    30
    327
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 193 (9.84%)
    56 / 374 (14.97%)
         occurrences all number
    34
    97
    Fatigue
         subjects affected / exposed
    50 / 193 (25.91%)
    110 / 374 (29.41%)
         occurrences all number
    67
    205
    Malaise
         subjects affected / exposed
    5 / 193 (2.59%)
    23 / 374 (6.15%)
         occurrences all number
    5
    33
    Oedema peripheral
         subjects affected / exposed
    26 / 193 (13.47%)
    63 / 374 (16.84%)
         occurrences all number
    32
    81
    Pyrexia
         subjects affected / exposed
    13 / 193 (6.74%)
    79 / 374 (21.12%)
         occurrences all number
    15
    113
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 193 (6.74%)
    45 / 374 (12.03%)
         occurrences all number
    15
    50
    Dyspnoea
         subjects affected / exposed
    15 / 193 (7.77%)
    26 / 374 (6.95%)
         occurrences all number
    15
    42
    Dysphonia
         subjects affected / exposed
    5 / 193 (2.59%)
    68 / 374 (18.18%)
         occurrences all number
    7
    85
    Pleural effusion
         subjects affected / exposed
    10 / 193 (5.18%)
    13 / 374 (3.48%)
         occurrences all number
    11
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 193 (4.15%)
    30 / 374 (8.02%)
         occurrences all number
    8
    35
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 193 (10.88%)
    56 / 374 (14.97%)
         occurrences all number
    37
    102
    Aspartate aminotransferase increased
         subjects affected / exposed
    40 / 193 (20.73%)
    99 / 374 (26.47%)
         occurrences all number
    89
    234
    Blood alkaline phosphatase increased
         subjects affected / exposed
    9 / 193 (4.66%)
    23 / 374 (6.15%)
         occurrences all number
    21
    43
    Blood bilirubin increased
         subjects affected / exposed
    30 / 193 (15.54%)
    94 / 374 (25.13%)
         occurrences all number
    59
    258
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    14 / 193 (7.25%)
    24 / 374 (6.42%)
         occurrences all number
    32
    73
    Lipase increased
         subjects affected / exposed
    7 / 193 (3.63%)
    27 / 374 (7.22%)
         occurrences all number
    15
    62
    Platelet count decreased
         subjects affected / exposed
    2 / 193 (1.04%)
    39 / 374 (10.43%)
         occurrences all number
    8
    129
    Weight decreased
         subjects affected / exposed
    9 / 193 (4.66%)
    55 / 374 (14.71%)
         occurrences all number
    11
    132
    White blood cell count decreased
         subjects affected / exposed
    2 / 193 (1.04%)
    20 / 374 (5.35%)
         occurrences all number
    7
    40
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 193 (6.22%)
    25 / 374 (6.68%)
         occurrences all number
    12
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 193 (10.88%)
    57 / 374 (15.24%)
         occurrences all number
    40
    114
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    10 / 193 (5.18%)
    20 / 374 (5.35%)
         occurrences all number
    13
    24
    Abdominal pain upper
         subjects affected / exposed
    18 / 193 (9.33%)
    52 / 374 (13.90%)
         occurrences all number
    22
    85
    Abdominal pain
         subjects affected / exposed
    29 / 193 (15.03%)
    85 / 374 (22.73%)
         occurrences all number
    43
    127
    Ascites
         subjects affected / exposed
    31 / 193 (16.06%)
    61 / 374 (16.31%)
         occurrences all number
    57
    91
    Constipation
         subjects affected / exposed
    21 / 193 (10.88%)
    67 / 374 (17.91%)
         occurrences all number
    24
    79
    Diarrhoea
         subjects affected / exposed
    31 / 193 (16.06%)
    163 / 374 (43.58%)
         occurrences all number
    44
    348
    Dry mouth
         subjects affected / exposed
    12 / 193 (6.22%)
    22 / 374 (5.88%)
         occurrences all number
    15
    24
    Nausea
         subjects affected / exposed
    26 / 193 (13.47%)
    72 / 374 (19.25%)
         occurrences all number
    38
    106
    Stomatitis
         subjects affected / exposed
    4 / 193 (2.07%)
    31 / 374 (8.29%)
         occurrences all number
    4
    44
    Vomiting
         subjects affected / exposed
    13 / 193 (6.74%)
    50 / 374 (13.37%)
         occurrences all number
    17
    73
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 193 (3.11%)
    27 / 374 (7.22%)
         occurrences all number
    6
    27
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    15 / 193 (7.77%)
    194 / 374 (51.87%)
         occurrences all number
    27
    554
    Pruritus
         subjects affected / exposed
    14 / 193 (7.25%)
    22 / 374 (5.88%)
         occurrences all number
    19
    34
    Rash
         subjects affected / exposed
    14 / 193 (7.25%)
    21 / 374 (5.61%)
         occurrences all number
    15
    28
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 193 (1.04%)
    34 / 374 (9.09%)
         occurrences all number
    6
    96
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 193 (0.52%)
    29 / 374 (7.75%)
         occurrences all number
    1
    33
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 193 (5.70%)
    15 / 374 (4.01%)
         occurrences all number
    12
    17
    Back pain
         subjects affected / exposed
    16 / 193 (8.29%)
    50 / 374 (13.37%)
         occurrences all number
    18
    73
    Musculoskeletal pain
         subjects affected / exposed
    11 / 193 (5.70%)
    18 / 374 (4.81%)
         occurrences all number
    19
    22
    Muscle spasms
         subjects affected / exposed
    4 / 193 (2.07%)
    38 / 374 (10.16%)
         occurrences all number
    5
    48
    Pain in extremity
         subjects affected / exposed
    5 / 193 (2.59%)
    31 / 374 (8.29%)
         occurrences all number
    6
    51
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 193 (15.03%)
    122 / 374 (32.62%)
         occurrences all number
    37
    186
    Hypoalbuminaemia
         subjects affected / exposed
    14 / 193 (7.25%)
    56 / 374 (14.97%)
         occurrences all number
    19
    152
    Hypokalaemia
         subjects affected / exposed
    6 / 193 (3.11%)
    28 / 374 (7.49%)
         occurrences all number
    22
    62
    Hyponatraemia
         subjects affected / exposed
    7 / 193 (3.63%)
    20 / 374 (5.35%)
         occurrences all number
    17
    30
    Hypophosphataemia
         subjects affected / exposed
    5 / 193 (2.59%)
    36 / 374 (9.63%)
         occurrences all number
    11
    96

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 May 2013
    -The term study drug treatment was substituted for regorafenib treatment in a sentence describing whether a subject could continue treatment if considered to be achieving a benefit from the treatment according to the investigator. - An inclusion criterion was modified according to the mRECIST and RECIST 1.1 in order to include subjects who demonstrated progression in previously treated lesions. - An exclusion criteria requiring the assessment of esophageal varices by endoscopy within 6 months and 12 months of the start of the study was modified to require that endoscopy be performed as per local standard of care. - In treatment assignment, text was modified stipulating that subjects should start treatment no later than 3 days after randomization. - Antiviral treatment for hepatitis C virus was included under “not permissible concomitant medication,” in order to not include these subjects due to the unfavorable risk benefit assessment. - The measurement of vital signs was included separately from the physical examinations due to differences in the timing of those assessments. - Vital signs examinations were included to be carried out on Day 15 of each cycle consistent with the design of the electronic case report form (eCRF). - The section on Tumor response Criteria (RECIST 1.1 and mRECIST) was divided into subsections for clarity. Slight modifications were made to the introductory text for the RECIST 1.1 and the mRECIST criteria section for clarity.
    13 Dec 2013
    - Rewording was done for clarity regarding the planning of the formal futility and formal efficacy analyses stating that there would be one of type of analysis and that data reviews were to be performed according to the data monitoring committee (DMC) charter. - The text excluding subjects from the study who permanently discontinued sorafenib treatment due to any cause more than 8 weeks before randomization was changes to 10 weeks. This change was to allow additional time to recruit subjects who were transferred from other sites. - Under the subsection “Emergency unblinding by the investigator”, text was added following ICH guidelines (ICH Topic E 6 [R1] Guideline for Good Clinical Practice) and in accordance with the Site User Manual for unblinding a subject's treatment assignment. - Text was added for clarification specifying exploratory pharmacokinetic (PK) analyses and an explanation of the timing of sample collection and the calculation of PK parameters. In addition a new subsection was added for completeness entitled “Validity of PK samples” describing the conditions under which PK samples were to be considered acceptable for analysis.
    11 Nov 2014
    - The number of subjects to be recruited into the study was increased from 530 to 560. - A change was introduced allowing the use of a separate non-genetic biomarker consent form in exceptional cases according to site-specific requirements. This change was introduced in order to cover the case where study sites required a separate non-genetic biomarker consent form. - Administrative changes
    02 Nov 2015
    -Changes regarding the planned interim analysis: The protocol requirement for performing a second interim efficacy analysis of the study results was removed. Due to the unexpectedly slow recruitment of subjects in China, the second interim analysis would have been conducted before full subject accrual into the study had been reached. It was considered important to optimize subject enrollment in China in light of a Health Authority guidance regarding enrollment. -Changes regarding monthly survival assessments: A requirement was added stating that monthly survival assessments were to continue until the approximate date of unblinding for primary completion of the study. If needed, survival assessments (for example via additional phone contacts) were to be allowed to continue past the primary analysis until the end of the study. This modification was included because overall survival data might be required after the primary completion of the study; additional analyses might be required to include the data from the data cut-off date (date at which approximately 370 events are achieved) up to or beyond the date of unblinding.
    01 Dec 2015
    -Information was added regarding interactions of regorafenib with neomycin, breast cancer resistant protein (BCRP), UGT1A1, UGT1A9, P-glycoprotein substrates, and bile saltsequestering agents. -The recommendation to proactively monitor subjects taking digoxin was removed. This information was added in light of new information that became available as documented in the latest version of the regorafenib IB. -References to Cytochrome P450 1A2 inhibitors and inducers were removed from the header and in the text since all of the substances were Cytochrome P450 3A4 (CYP 3A4) inhibitors. This change was introduced in order to clarify that only CYP 3A4 inhibitors and inducers. The underlining of the substances listed in the table was removed since there was no need to differentiate between these substances since all are either inhibitors or inducers of CYP34A.

    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.
    Decimal places were automatically truncated if last decimal equals zero.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/29704513
    http://www.ncbi.nlm.nih.gov/pubmed/27932229
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