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    Clinical Trial Results:
    A Double-Blind, Randomized Phase III Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer

    Summary
    EudraCT number
    2009-012007-25
    Trial protocol
    DE   GB   ES   IT   NL   FR   DK   SE   BE   AT   SK   BG  
    Global end of trial date
    30 Aug 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    17 Feb 2019
    First version publication date
    30 Aug 2018
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Control of data.

    Trial information

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    Trial identification
    Sponsor protocol code
    14295
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00984282
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this phase III study in subjects with differentiated thyroid cancer (papillary, follicular, Hurthle cell carcinoma) who are refractory to radioactive iodine treatment is to compare the treatment groups in terms of progression free survival (PFS) evaluated by the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Oct 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    5 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    United Kingdom: 43
    Country: Number of subjects enrolled
    United States: 97
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Bulgaria: 11
    Country: Number of subjects enrolled
    China: 56
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    France: 67
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Italy: 83
    Country: Number of subjects enrolled
    Japan: 29
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Poland: 40
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Saudi Arabia: 6
    Worldwide total number of subjects
    556
    EEA total number of subjects
    334
    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)
    310
    From 65 to 84 years
    242
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    Study was conducted at 81 study centers in Austria, Belgium, Bulgaria, China, Germany, Denmark, Spain, France, United Kingdom, Italy, Japan, Republic of Korea, Netherlands, Poland, Russia, Saudi-Arabia, Sweden and United States between 15 Oct 2009 (first subject first visit) and 30 Aug 2017 (last subject last visit)

    Pre-assignment
    Screening details
    A total of 556 subjects were screened. 137 subjects failed screening. 419 subjects were randomized but 2 subjects who did not meet the eligibility criteria were erroneously randomized to sorafenib, these subjects were never treated and were subsequently rescreened and randomized to placebo. 417 subjects were assigned to treatment.

    Period 1
    Period 1 title
    Double blind treatment
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sorafenib (Nexavar, BAY43-9006)
    Arm description
    Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle
    Arm type
    Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    BAY43-9006
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib 400 mg will be administered orally, twice daily (approximately every 12 hours).

    Arm title
    Placebo
    Arm description
    Participants received 2 tablets of Sorafenib-matching placebo orally twice daily (12 hours apart without food), 28 days comprise a cycle
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (2 tablets) will be administered orally, twice daily (approximately every 12 hours).

    Number of subjects in period 1 [1]
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Started
    207
    210
    Completed
    103
    172
    Not completed
    104
    38
         Death
    8
    4
         Progression by clinical judgment
    2
    -
         Noncompliance with study medication
    3
    -
         Transferred to treatment continuation study
    2
    1
         Consent withdrawn by subject
    13
    18
         Not treated
    -
    1
         Physician decision
    1
    2
         Switched to commercial drug
    6
    1
         Protocol driven decision point
    1
    1
         Progression, recurrence or relapse
    25
    3
         Radiological and clinical progression
    -
    1
         Adverse Event
    40
    6
         Lost to follow-up
    3
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all subjects completing double blinded treatment received Open-label treatment.
    Period 2
    Period 2 title
    Open-label treatment
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    DB sorafenib first, then option of OL sorafenib treatment
    Arm description
    Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    BAY43-9006
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib 400 mg will be administered orally, twice daily (approximately every 12 hours).

    Arm title
    DB placebo first, then option of OL sorafenib treatment
    Arm description
    Participants on placebo who switched to sorafenib, received sorafenib 400 mg (2 x 200 mg) orally twice daily, 28 days comprise a cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    BAY43-9006
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib 400 mg will be administered orally, twice daily (approximately every 12 hours).

    Number of subjects in period 2 [2]
    DB sorafenib first, then option of OL sorafenib treatment DB placebo first, then option of OL sorafenib treatment
    Started
    86
    161
    Completed
    0
    0
    Not completed
    86
    161
         Death
    7
    15
         Target lesion removed
    -
    1
         Transferred to treat. continuation study
    -
    3
         Patient convenience
    1
    -
         Non-compliant with study medication
    1
    -
         Transferred to treatment continuation study
    2
    -
         Consent withdrawn by subject
    6
    21
         Physician decision
    1
    -
         Protocol driven decision point
    1
    1
         Switched to commercial drug
    6
    7
         Progression, recurrence or relapse
    40
    82
         Adverse Event
    20
    30
         Lost to follow-up
    1
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all enrolled subjects received treatment. Only treated subjects were included in the baseline period.
    Period 3
    Period 3 title
    Long term follow-up
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    DB sorafenib first, then option of OL sorafenib treatment
    Arm description
    Participants entered long-term follow-up if terminated double-blind or open-label periods
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    DB placebo first, then option of OL sorafenib treatment
    Arm description
    Participants entered long-term follow-up if terminated double-blind or open-label periods
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    DB sorafenib first, then option of OL sorafenib treatment DB placebo first, then option of OL sorafenib treatment
    Started
    72
    124
    Completed
    3
    4
    Not completed
    69
    120
         Death
    27
    68
         Disease program, recurrence or relapse
    -
    1
         Switched to commercial drug
    4
    2
         Protocol driven decision point
    25
    26
         Transferred to treat. continuation study
    2
    -
         Transferred to treatment continuation study
    -
    3
         Consent withdrawn by subject
    8
    14
         Lost to follow-up
    3
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006)
    Reporting group description
    Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle

    Reporting group title
    Placebo
    Reporting group description
    Participants received 2 tablets of Sorafenib-matching placebo orally twice daily (12 hours apart without food), 28 days comprise a cycle

    Reporting group values
    Sorafenib (Nexavar, BAY43-9006) Placebo Total
    Number of subjects
    207 210 417
    Age categorical
    Units: Subjects
        < 60 years
    80 81 161
        >= 60 years
    127 129 256
    Age continuous
    Units: years
        median (standard deviation)
    61.5 ± 11.2 62.0 ± 11.7 -
    Gender categorical
    Units: Subjects
        Female
    103 115 218
        Male
    104 95 199
    Geographic region
    Units: Subjects
        Europe
    124 125 249
        North America
    36 36 72
        Asia
    47 49 96
    ECOG (Eastern Cooperative Oncology Group)
    The ECOG PS required for the study was 0 (fully active), 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), or 2 (ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours).
    Units: Subjects
        Missing
    1 1 2
        Zero
    130 129 259
        One
    69 74 143
        Two
    7 6 13

    End points

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    End points reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006)
    Reporting group description
    Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle

    Reporting group title
    Placebo
    Reporting group description
    Participants received 2 tablets of Sorafenib-matching placebo orally twice daily (12 hours apart without food), 28 days comprise a cycle
    Reporting group title
    DB sorafenib first, then option of OL sorafenib treatment
    Reporting group description
    Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle.

    Reporting group title
    DB placebo first, then option of OL sorafenib treatment
    Reporting group description
    Participants on placebo who switched to sorafenib, received sorafenib 400 mg (2 x 200 mg) orally twice daily, 28 days comprise a cycle.
    Reporting group title
    DB sorafenib first, then option of OL sorafenib treatment
    Reporting group description
    Participants entered long-term follow-up if terminated double-blind or open-label periods

    Reporting group title
    DB placebo first, then option of OL sorafenib treatment
    Reporting group description
    Participants entered long-term follow-up if terminated double-blind or open-label periods

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Set (FAS). The primary population for efficacy analysis was the FAS. The FAS was identical to the intent-to-treat (ITT) population, which was defined as all randomized participants. Participants were analyzed as randomized.

    Subject analysis set title
    Per protocol set (PPS)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per protocol set (PPS). A participant was included in the PPS if he/she was randomized and was evaluable for tumor response based on imaging data, had exposure to study medication, and had no major protocol deviations.

    Subject analysis set title
    Pharmacokinetic (PK) analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Pharmacokinetic (PK) analysis set=participants with PK data collected after 14 days of uninterrupted and unmodified dosing of sorafenib. If an interruption occurred within 14 days prior to the sample, no doses may be missed for 3 days prior to the sample, and no more than 3 doses could be missed 4 to 14 days prior to the sample collection date.

    Primary: Progression-free survival (PFS) based on central assessment incl. clinical progression due to bone irradiation

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    End point title
    Progression-free survival (PFS) based on central assessment incl. clinical progression due to bone irradiation
    End point description
    PFS=time from randomization to first observed disease progression (radiological according to central assessment or clinical due to bone irradiation, whichever is earlier), or death due to any cause, if death occurred before progression. Progression was assessed by RECIST criteria, version 1.0, modified for bone lesions. PFS for participants without disease progression or death at the time of analysis or unblinding were censored at the last date of tumor assessment before unblinding. Participants with no tumor evaluation after baseline were censored at Day 1. PD (Progression Disease)=At least a 20% increase in sum of longest diameters (LD) of measured lesions taking as reference the smallest sum LD on study since the treatment started or the appearance of 1 or more new lesions. New lesions also constituted PD. In exceptional circumstances, unequivocal progression of a nonmeasured lesion may have been accepted as evidence of disease progression in participants with measurable disease.
    End point type
    Primary
    End point timeframe
    Final analysis to be performed when approximately 267 progression-free survival events (centrally assessed) had occurred, study duration approximately three years
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    207 [1]
    210 [2]
    Units: Days
        median (full range (min-max))
    329 (278 to 393)
    175 (160 to 238)
    Notes
    [1] - FAS
    [2] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The two treatment groups were compared using a stratified one-sided log rank test with an overall alpha of 0.01 stratified by age group and region. The null hypothesis that both treatment arms have the same PFS distribution will be tested against the alternative hypothesis that the distribution of PFS times in the sorafenib arm is different from the control arm according to the Lehmann alternative, which is equivalent to the assumption of proportional hazards of the treatment arms.
    Comparison groups
    Placebo v Sorafenib (Nexavar, BAY43-9006)
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Log Rank
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.587
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.454
         upper limit
    0.758

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    Overall survival was defined as the time (days) from date of randomization to date of death due to any cause. Subjects still alive at the time of analysis were censored at their date of last contact. Since the median value could not be estimated due to censored data, the percentage of participants who died is presented.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until the database cut-off (30 AUG 2017), study duration approximately eight years
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    207 [3]
    210 [4]
    Units: Percentage of participants
        number (not applicable)
    52.7
    54.8
    Notes
    [3] - FAS
    [4] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2892
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Sorafenib (Nexavar, BAY43-9006)
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.928
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.713
         upper limit
    1.208

    Secondary: Time to progression (TTP) based on central assessment incl. clinical progression due to bone irradiation

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    End point title
    Time to progression (TTP) based on central assessment incl. clinical progression due to bone irradiation
    End point description
    Time to progression was defined at the time (days) from randomization to progression (based on central assessment [radiological and clinical progression due to bone irradiation])
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    207 [5]
    210 [6]
    Units: days
        median (full range (min-max))
    337 (283 to 451)
    175 (160 to 238)
    Notes
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.557
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.429
         upper limit
    0.724

    Secondary: Disease control rate (DCR) based on central assessment

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    End point title
    Disease control rate (DCR) based on central assessment
    End point description
    Disease control rate was defined as the proportion of subjects whose best response was complete response (CR), partial response (PR), or stable disease (SD). Per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, CR and PR were to be confirmed by another scan at least 4 weeks later; SD had to be documented at least 4 weeks after date of randomization. CR = Disappearance of all clinical and radiological evidence of tumor (both target and no-target). PR = At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum. SD = steady state of disease which is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    196 [7]
    201 [8]
    Units: Percentage of participants
        median (full range (min-max))
    86.2 (80.6 to 90.7)
    74.6 (68.0 to 80.5)
    Notes
    [7] - PPS
    [8] - PPS
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0015
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference of response rates
    Point estimate
    11.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.9
         upper limit
    19.4

    Secondary: Response rate based on central assessment

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    End point title
    Response rate based on central assessment
    End point description
    Response rate was defined as the proportion of subjects whose best response was CR or PR. Per RECIST, CR and PR was to be confirmed by another scan at least 4 weeks later. CR = Disappearance of all clinical and radiological evidence of tumor (both target and no-target). PR = At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    196 [9]
    201 [10]
    Units: Percentage of participants
        median (full range (min-max))
    12.24 (8.01 to 17.67)
    0.5 (0.01 to 2.74)
    Notes
    [9] - PPS
    [10] - PPS
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in response rate
    Point estimate
    11.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7
         upper limit
    16.5

    Secondary: Duration of response (DOR) based on central assessment

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    End point title
    Duration of response (DOR) based on central assessment
    End point description
    Duration of response was defined as the time from the first documented objective response of PR or CR, whichever was noted earlier, to disease progression or death (if death occurred before progression was documented). CR = Disappearance of all clinical and radiological evidence of tumor (both target and no-target). PR = At least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    24 [11]
    1 [12]
    Units: days
        median (full range (min-max))
    309 (226 to 505)
    99999 (99999 to 99999)
    Notes
    [11] - FAS
    [12] - only one subject with PR. 99999 stands for NA. FAS
    No statistical analyses for this end point

    Secondary: Maximum percent reduction in target lesion size based on central assessment

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    End point title
    Maximum percent reduction in target lesion size based on central assessment
    End point description
    The magnitude of change from baseline in target lesion size in evaluable participants with scans was determined.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until the database cut-off (31 Aug 2012), study duration approximately three years
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    196 [13]
    201 [14]
    Units: Percentage of participants
    number (not applicable)
        Reduction ≥ 30%
    17.3
    1.0
        Reduction ≥ 20% but < 30%
    15.3
    1.5
        Reduction ≥ 10% but < 20%
    22.4
    3.5
        Reduction > 0% but < 10%
    22.4
    21.9
        Growth ≥ 0%
    12.8
    62.7
        Not assessed
    9.7
    9.5
    Notes
    [13] - PPS
    [14] - PPS
    No statistical analyses for this end point

    Secondary: AUC(0-12h),ss (area under the concentration time curve from time 0 to 12 hours at steady state)

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    End point title
    AUC(0-12h),ss (area under the concentration time curve from time 0 to 12 hours at steady state) [15]
    End point description
    Sorafenib AUC(0-12h),ss (area under the concentration time curve from time 0 to 12 hours at steady state) was estimated from the steady state plasma concentration.
    End point type
    Secondary
    End point timeframe
    A single pharmacokinetic plasma sample was collected at steady state (after 14 days of uninterrupted, unmodified sorafenib dosing)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only subjects who received sorafenib treatment in double blind period were included in PK analysis.
    End point values
    Sorafenib (Nexavar, BAY43-9006)
    Number of subjects analysed
    113 [16]
    Units: mg*h/L
        geometric mean (standard deviation)
    75.4 ± 1.5
    Notes
    [16] - Pharmacokinetic (PK) analysis set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After signing the informed consent until the database cut-off 30 AUG 2017, study duration approximately eight years.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Sorafenib (Double Blind Only)
    Reporting group description
    Reporting Group 1: Participants received 2 tablets of Sorafenib (2x200 mg) orally twice daily (12 hours apart without food), 28 days comprise a cycle. Data were collected from randomization to the end of double blind period

    Reporting group title
    Placebo (Double Blind Only)
    Reporting group description
    Reporting Group 2: Participants received 2 tablets of Sorafenib-matching placebo orally twice daily (12 hours apart without food), 28 days comprise a cycle. Data were collected from randomization to the end of double-blind period.

    Reporting group title
    Sorafenib, Open Label Only (Sorafenib continued)
    Reporting group description
    Reporting Group 3: Participants on sorafenib who continued OL sorafenib treat., received sorafenib 400 mg (2 x 200 mg) orally twice daily, 28 days comprise a cycle. Data were collected from the start of OL period to the data cutoff on 31 Aug

    Reporting group title
    Placebo, Open Label Only (Switch to Sorafenib)
    Reporting group description
    Reporting Group 3: Participants on placebo who switched to sorafenib, received sorafenib 400 mg (2 x 200 mg) orally twice daily, 28 days comprise a cycle. Data were collected from the start of open label period to the data cutoff on 31 Aug 20

    Serious adverse events
    Sorafenib (Double Blind Only) Placebo (Double Blind Only) Sorafenib, Open Label Only (Sorafenib continued) Placebo, Open Label Only (Switch to Sorafenib)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 207 (42.03%)
    58 / 209 (27.75%)
    51 / 86 (59.30%)
    96 / 161 (59.63%)
         number of deaths (all causes)
    71
    25
    38
    90
         number of deaths resulting from adverse events
    14
    8
    9
    23
    Vascular disorders
    CNS hemorrhage
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hematoma
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hemorrhage - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Hemorrhage pulmonary, Bronchopulmonary NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 209 (0.96%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage pulmonary, Bronchus
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage pulmonary, Larynx
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage pulmonary, Lung
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    3 / 161 (1.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Hemorrhage pulmonary, Respiratory tract NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage, GI, Anus
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage, GI, Colon
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage, GI, Varices (rectal)
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage, GU, Urinary NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage, GU, Uterus
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis/Embolism (vascular access)
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis/Thrombus/Embolism
         subjects affected / exposed
    1 / 207 (0.48%)
    4 / 209 (1.91%)
    2 / 86 (2.33%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Vascular - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Secondary malignancy (possibly related to cancer treatment)
         subjects affected / exposed
    11 / 207 (5.31%)
    6 / 209 (2.87%)
    4 / 86 (4.65%)
    3 / 161 (1.86%)
         occurrences causally related to treatment / all
    5 / 13
    1 / 6
    3 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Allergy - Other
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Constitutional symptoms - Other
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Death not associated with CTCAE term, Death NOS
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    2 / 3
    0 / 0
    1 / 1
    0 / 0
    Death not associated with CTCAE term, Disease progression NOS
         subjects affected / exposed
    2 / 207 (0.97%)
    2 / 209 (0.96%)
    3 / 86 (3.49%)
    9 / 161 (5.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    2 / 2
    2 / 2
    3 / 3
    9 / 9
    Death not associated with CTCAE term, Multi-Organ Failure
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    Death not associated with CTCAE term, Sudden death
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 207 (1.45%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    4 / 207 (1.93%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flu-like syndrome
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    No code in CTCAE
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    2 / 86 (2.33%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Not coded yet
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pain, Abdomen NOS
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Back
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 209 (0.96%)
    0 / 86 (0.00%)
    4 / 161 (2.48%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Bone
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    1 / 86 (1.16%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Chest wall
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Chest/Thorax NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Dental/Teeth/peridontal
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Extremity - limb
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Head/Headache
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Joint
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Liver
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Lymph node
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Neuralgia/Peripheral nerve
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Pelvis
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Stomach
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Throat/Pharynx/Larynx
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain, Tumor pain
         subjects affected / exposed
    2 / 207 (0.97%)
    2 / 209 (0.96%)
    1 / 86 (1.16%)
    3 / 161 (1.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syndromes - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Tumor flare
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight loss
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Sexual - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intraop injury, Artery-aorta
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraop injury, Bone
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraop injury, Meninges
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraop injury, Neck NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraop injury, Thyroid
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraop injury, Trachea
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrhythmia - Other
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 209 (0.48%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac general - Other
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    4 / 161 (2.48%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Cardiac ischemia/infarction
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 209 (0.00%)
    2 / 86 (2.33%)
    3 / 161 (1.86%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Cardiopulmonary arrest
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular arrhythmia, Atrial fibrillation
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 209 (0.96%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular arrhythmia, Atrial flutter
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular arrhythmia, Supraventricular tachycardia
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 209 (0.00%)
    2 / 86 (2.33%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Valvular heart disease
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia, Ventricular tachycardia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Airway obstruction, Larynx
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Airway obstruction, Pharynx
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Airway obstruction, Trachea
         subjects affected / exposed
    3 / 207 (1.45%)
    3 / 209 (1.44%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnea (Shortness of breath)
         subjects affected / exposed
    8 / 207 (3.86%)
    7 / 209 (3.35%)
    2 / 86 (2.33%)
    8 / 161 (4.97%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
    0 / 2
    3 / 11
         deaths causally related to treatment / all
    2 / 2
    2 / 2
    1 / 1
    2 / 2
    Hypoxia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    6 / 207 (2.90%)
    4 / 209 (1.91%)
    9 / 86 (10.47%)
    5 / 161 (3.11%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
    0 / 13
    0 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    3 / 3
    Pneumonitis
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary - Other
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    Blood - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemoglobin
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphatics - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophils
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CNS ischemia
         subjects affected / exposed
    3 / 207 (1.45%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    CSF leak
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disturbance
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal nerve
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mood Alteration, Anxiety
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mood alteration, Depression
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurology - Other
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 209 (0.96%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy: Cranial, CN II Vision
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy: motor
         subjects affected / exposed
    0 / 207 (0.00%)
    3 / 209 (1.44%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy: sensory
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope (Fainting)
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ocular - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic disc edema
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 207 (0.97%)
    1 / 209 (0.48%)
    2 / 86 (2.33%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fistula, GI, Abdomen NOS
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fistula, GI, Esophagus
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GI - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 209 (0.48%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 1
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucositis (functional/symptomatic), Oral cavity
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucositis (functional/symptomatic), Trachea
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction, GI, Esophagus
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction, GI, Gallbladder
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perforation, GI, Colon
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stricture, GI, Esophagus
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Teeth
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulcer, GI, Rectum
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal - Other
         subjects affected / exposed
    3 / 207 (1.45%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary - Other
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver dysfunction
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatology - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand-foot skin reaction
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash/desquamation
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    3 / 161 (1.86%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulceration
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound complication, non-infectious
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extremity - upper (Function)
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    4 / 207 (1.93%)
    6 / 209 (2.87%)
    2 / 86 (2.33%)
    4 / 161 (2.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spine ROM
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle weakness, Extremity - lower
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle weakness, Extremity - upper
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle weakness, Whole body/generalized
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal - Other
         subjects affected / exposed
    4 / 207 (1.93%)
    3 / 209 (1.44%)
    5 / 86 (5.81%)
    4 / 161 (2.48%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    2 / 86 (2.33%)
    3 / 161 (1.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Amylase
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Creatinine
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcemia
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcemia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesemia
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic/Lab - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Colitis, infectious
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection (Documented clinically), Lung (Pneumonia)
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Infection (Documented clinically), Soft tissue NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection (Documented clinically), Upper airway NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection (Documented clinically), Wound
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection - Other
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    2 / 86 (2.33%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Anal/perianal
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Bladder (urinary)
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Blood
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Bone (Osteomyelitis)
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Colon
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Kidney
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Lung (Pneumonia)
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 209 (0.96%)
    0 / 86 (0.00%)
    2 / 161 (1.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Mediastinum NOS
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Scrotum
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Soft tissue NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Upper airway NOS
         subjects affected / exposed
    2 / 207 (0.97%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Urinary tract NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with normal ANC, Wound
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with unknown ANC, Abdomen NOS
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with unknown ANC, Appendix
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with unknown ANC, Bladder (urinary)
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with unknown ANC, Blood
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Infection with unknown ANC, Bronchus
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with unknown ANC, Lung (Pneumonia)
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 209 (0.48%)
    1 / 86 (1.16%)
    3 / 161 (1.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Infection with unknown ANC, Pleura (Empyema)
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection with unknown ANC, Prostate
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Opportunistic infection
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 209 (0.00%)
    0 / 86 (0.00%)
    1 / 161 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Sorafenib (Double Blind Only) Placebo (Double Blind Only) Sorafenib, Open Label Only (Sorafenib continued) Placebo, Open Label Only (Switch to Sorafenib)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    202 / 207 (97.58%)
    173 / 209 (82.78%)
    74 / 86 (86.05%)
    159 / 161 (98.76%)
    Vascular disorders
    Hemorrhage pulmonary, Nose
         subjects affected / exposed
    15 / 207 (7.25%)
    2 / 209 (0.96%)
    2 / 86 (2.33%)
    8 / 161 (4.97%)
         occurrences all number
    17
    3
    2
    11
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    85 / 207 (41.06%)
    28 / 209 (13.40%)
    10 / 86 (11.63%)
    51 / 161 (31.68%)
         occurrences all number
    103
    35
    13
    57
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    34 / 207 (16.43%)
    34 / 209 (16.27%)
    9 / 86 (10.47%)
    23 / 161 (14.29%)
         occurrences all number
    43
    39
    10
    28
    Dyspnea (Shortness of breath)
         subjects affected / exposed
    31 / 207 (14.98%)
    27 / 209 (12.92%)
    10 / 86 (11.63%)
    25 / 161 (15.53%)
         occurrences all number
    36
    32
    14
    32
    Pulmonary - Other
         subjects affected / exposed
    7 / 207 (3.38%)
    7 / 209 (3.35%)
    7 / 86 (8.14%)
    7 / 161 (4.35%)
         occurrences all number
    8
    7
    11
    9
    Voice changes
         subjects affected / exposed
    25 / 207 (12.08%)
    6 / 209 (2.87%)
    2 / 86 (2.33%)
    12 / 161 (7.45%)
         occurrences all number
    33
    6
    2
    13
    Immune system disorders
    Rhinitis
         subjects affected / exposed
    9 / 207 (4.35%)
    7 / 209 (3.35%)
    2 / 86 (2.33%)
    9 / 161 (5.59%)
         occurrences all number
    11
    10
    2
    10
    Blood and lymphatic system disorders
    Blood - Other
         subjects affected / exposed
    6 / 207 (2.90%)
    6 / 209 (2.87%)
    6 / 86 (6.98%)
    10 / 161 (6.21%)
         occurrences all number
    6
    10
    20
    23
    Edema: Limb
         subjects affected / exposed
    13 / 207 (6.28%)
    6 / 209 (2.87%)
    8 / 86 (9.30%)
    8 / 161 (4.97%)
         occurrences all number
    17
    7
    9
    11
    Hemoglobin
         subjects affected / exposed
    18 / 207 (8.70%)
    10 / 209 (4.78%)
    8 / 86 (9.30%)
    26 / 161 (16.15%)
         occurrences all number
    24
    11
    9
    32
    Leukocytes
         subjects affected / exposed
    9 / 207 (4.35%)
    4 / 209 (1.91%)
    5 / 86 (5.81%)
    8 / 161 (4.97%)
         occurrences all number
    13
    8
    6
    15
    Lymphopenia
         subjects affected / exposed
    7 / 207 (3.38%)
    6 / 209 (2.87%)
    1 / 86 (1.16%)
    10 / 161 (6.21%)
         occurrences all number
    7
    8
    1
    13
    Platelets
         subjects affected / exposed
    8 / 207 (3.86%)
    2 / 209 (0.96%)
    3 / 86 (3.49%)
    11 / 161 (6.83%)
         occurrences all number
    12
    2
    4
    15
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 207 (6.76%)
    7 / 209 (3.35%)
    1 / 86 (1.16%)
    12 / 161 (7.45%)
         occurrences all number
    17
    8
    1
    13
    Mood Alteration, Anxiety
         subjects affected / exposed
    7 / 207 (3.38%)
    6 / 209 (2.87%)
    0 / 86 (0.00%)
    9 / 161 (5.59%)
         occurrences all number
    8
    6
    0
    10
    Neuropathy: sensory
         subjects affected / exposed
    32 / 207 (15.46%)
    13 / 209 (6.22%)
    5 / 86 (5.81%)
    21 / 161 (13.04%)
         occurrences all number
    42
    16
    6
    26
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    102 / 207 (49.28%)
    52 / 209 (24.88%)
    19 / 86 (22.09%)
    68 / 161 (42.24%)
         occurrences all number
    132
    58
    23
    87
    Fever
         subjects affected / exposed
    22 / 207 (10.63%)
    10 / 209 (4.78%)
    8 / 86 (9.30%)
    21 / 161 (13.04%)
         occurrences all number
    30
    11
    10
    26
    Flu-like syndrome
         subjects affected / exposed
    18 / 207 (8.70%)
    10 / 209 (4.78%)
    4 / 86 (4.65%)
    11 / 161 (6.83%)
         occurrences all number
    32
    14
    5
    14
    Insomnia
         subjects affected / exposed
    14 / 207 (6.76%)
    6 / 209 (2.87%)
    5 / 86 (5.81%)
    16 / 161 (9.94%)
         occurrences all number
    16
    6
    5
    17
    Pain, Abdomen NOS
         subjects affected / exposed
    30 / 207 (14.49%)
    10 / 209 (4.78%)
    6 / 86 (6.98%)
    30 / 161 (18.63%)
         occurrences all number
    42
    10
    7
    38
    Pain, Back
         subjects affected / exposed
    24 / 207 (11.59%)
    21 / 209 (10.05%)
    10 / 86 (11.63%)
    15 / 161 (9.32%)
         occurrences all number
    28
    24
    11
    19
    Pain, Bone
         subjects affected / exposed
    14 / 207 (6.76%)
    18 / 209 (8.61%)
    7 / 86 (8.14%)
    12 / 161 (7.45%)
         occurrences all number
    21
    22
    12
    13
    Pain, Chest wall
         subjects affected / exposed
    6 / 207 (2.90%)
    3 / 209 (1.44%)
    2 / 86 (2.33%)
    9 / 161 (5.59%)
         occurrences all number
    8
    3
    2
    9
    Pain, Chest/Thorax NOS
         subjects affected / exposed
    16 / 207 (7.73%)
    5 / 209 (2.39%)
    1 / 86 (1.16%)
    17 / 161 (10.56%)
         occurrences all number
    20
    5
    1
    18
    Pain, Dental/Teeth/peridontal
         subjects affected / exposed
    11 / 207 (5.31%)
    4 / 209 (1.91%)
    2 / 86 (2.33%)
    11 / 161 (6.83%)
         occurrences all number
    15
    4
    2
    16
    Pain, Extremity - limb
         subjects affected / exposed
    31 / 207 (14.98%)
    19 / 209 (9.09%)
    3 / 86 (3.49%)
    28 / 161 (17.39%)
         occurrences all number
    49
    27
    3
    43
    Pain, Head/Headache
         subjects affected / exposed
    38 / 207 (18.36%)
    16 / 209 (7.66%)
    3 / 86 (3.49%)
    24 / 161 (14.91%)
         occurrences all number
    48
    17
    3
    29
    Pain, Joint
         subjects affected / exposed
    20 / 207 (9.66%)
    14 / 209 (6.70%)
    5 / 86 (5.81%)
    19 / 161 (11.80%)
         occurrences all number
    23
    19
    7
    25
    Pain, Muscle
         subjects affected / exposed
    19 / 207 (9.18%)
    15 / 209 (7.18%)
    6 / 86 (6.98%)
    11 / 161 (6.83%)
         occurrences all number
    23
    17
    6
    17
    Pain, Neck
         subjects affected / exposed
    9 / 207 (4.35%)
    6 / 209 (2.87%)
    1 / 86 (1.16%)
    9 / 161 (5.59%)
         occurrences all number
    10
    6
    1
    9
    Pain, Oral cavity
         subjects affected / exposed
    7 / 207 (3.38%)
    2 / 209 (0.96%)
    0 / 86 (0.00%)
    9 / 161 (5.59%)
         occurrences all number
    7
    2
    0
    11
    Pain, Other
         subjects affected / exposed
    24 / 207 (11.59%)
    16 / 209 (7.66%)
    8 / 86 (9.30%)
    27 / 161 (16.77%)
         occurrences all number
    30
    17
    13
    31
    Pain, Throat/Pharynx/Larynx
         subjects affected / exposed
    21 / 207 (10.14%)
    9 / 209 (4.31%)
    1 / 86 (1.16%)
    19 / 161 (11.80%)
         occurrences all number
    26
    11
    3
    24
    Weight loss
         subjects affected / exposed
    102 / 207 (49.28%)
    29 / 209 (13.88%)
    29 / 86 (33.72%)
    75 / 161 (46.58%)
         occurrences all number
    114
    30
    33
    85
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    67 / 207 (32.37%)
    12 / 209 (5.74%)
    7 / 86 (8.14%)
    48 / 161 (29.81%)
         occurrences all number
    89
    12
    9
    52
    Constipation
         subjects affected / exposed
    32 / 207 (15.46%)
    18 / 209 (8.61%)
    4 / 86 (4.65%)
    27 / 161 (16.77%)
         occurrences all number
    38
    19
    4
    29
    Diarrhea
         subjects affected / exposed
    142 / 207 (68.60%)
    32 / 209 (15.31%)
    22 / 86 (25.58%)
    96 / 161 (59.63%)
         occurrences all number
    226
    40
    26
    165
    Dry mouth
         subjects affected / exposed
    16 / 207 (7.73%)
    8 / 209 (3.83%)
    2 / 86 (2.33%)
    7 / 161 (4.35%)
         occurrences all number
    16
    8
    2
    7
    Dysphagia
         subjects affected / exposed
    14 / 207 (6.76%)
    9 / 209 (4.31%)
    5 / 86 (5.81%)
    12 / 161 (7.45%)
         occurrences all number
    17
    9
    7
    14
    GI - Other
         subjects affected / exposed
    9 / 207 (4.35%)
    4 / 209 (1.91%)
    2 / 86 (2.33%)
    10 / 161 (6.21%)
         occurrences all number
    11
    4
    3
    11
    Heartburn
         subjects affected / exposed
    10 / 207 (4.83%)
    10 / 209 (4.78%)
    1 / 86 (1.16%)
    13 / 161 (8.07%)
         occurrences all number
    11
    10
    1
    14
    Mucositis (functional/symptomatic), Oral cavity
         subjects affected / exposed
    49 / 207 (23.67%)
    7 / 209 (3.35%)
    6 / 86 (6.98%)
    41 / 161 (25.47%)
         occurrences all number
    58
    7
    14
    49
    Nausea
         subjects affected / exposed
    43 / 207 (20.77%)
    25 / 209 (11.96%)
    10 / 86 (11.63%)
    52 / 161 (32.30%)
         occurrences all number
    55
    29
    12
    56
    Taste Alteration
         subjects affected / exposed
    16 / 207 (7.73%)
    0 / 209 (0.00%)
    1 / 86 (1.16%)
    11 / 161 (6.83%)
         occurrences all number
    16
    0
    1
    12
    Vomiting
         subjects affected / exposed
    23 / 207 (11.11%)
    13 / 209 (6.22%)
    3 / 86 (3.49%)
    18 / 161 (11.18%)
         occurrences all number
    36
    14
    3
    25
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    141 / 207 (68.12%)
    18 / 209 (8.61%)
    4 / 86 (4.65%)
    96 / 161 (59.63%)
         occurrences all number
    155
    18
    4
    103
    Dermatology - Other
         subjects affected / exposed
    30 / 207 (14.49%)
    6 / 209 (2.87%)
    12 / 86 (13.95%)
    31 / 161 (19.25%)
         occurrences all number
    56
    8
    14
    43
    Dry skin
         subjects affected / exposed
    30 / 207 (14.49%)
    12 / 209 (5.74%)
    6 / 86 (6.98%)
    17 / 161 (10.56%)
         occurrences all number
    36
    14
    7
    17
    Hand-foot skin reaction
         subjects affected / exposed
    158 / 207 (76.33%)
    20 / 209 (9.57%)
    13 / 86 (15.12%)
    109 / 161 (67.70%)
         occurrences all number
    223
    24
    15
    136
    Pruritus
         subjects affected / exposed
    44 / 207 (21.26%)
    22 / 209 (10.53%)
    3 / 86 (3.49%)
    21 / 161 (13.04%)
         occurrences all number
    52
    24
    6
    25
    Rash/desquamation
         subjects affected / exposed
    107 / 207 (51.69%)
    25 / 209 (11.96%)
    9 / 86 (10.47%)
    67 / 161 (41.61%)
         occurrences all number
    166
    29
    10
    94
    Musculoskeletal and connective tissue disorders
    Musculoskeletal - Other
         subjects affected / exposed
    19 / 207 (9.18%)
    9 / 209 (4.31%)
    7 / 86 (8.14%)
    11 / 161 (6.83%)
         occurrences all number
    21
    9
    10
    16
    Metabolism and nutrition disorders
    ALT
         subjects affected / exposed
    26 / 207 (12.56%)
    9 / 209 (4.31%)
    0 / 86 (0.00%)
    15 / 161 (9.32%)
         occurrences all number
    29
    10
    0
    19
    AST
         subjects affected / exposed
    23 / 207 (11.11%)
    5 / 209 (2.39%)
    1 / 86 (1.16%)
    11 / 161 (6.83%)
         occurrences all number
    26
    6
    2
    14
    Hypoalbuminemia
         subjects affected / exposed
    2 / 207 (0.97%)
    4 / 209 (1.91%)
    5 / 86 (5.81%)
    7 / 161 (4.35%)
         occurrences all number
    3
    4
    7
    7
    Hypocalcemia
         subjects affected / exposed
    38 / 207 (18.36%)
    11 / 209 (5.26%)
    12 / 86 (13.95%)
    30 / 161 (18.63%)
         occurrences all number
    54
    13
    21
    47
    Hypokalemia
         subjects affected / exposed
    14 / 207 (6.76%)
    5 / 209 (2.39%)
    4 / 86 (4.65%)
    14 / 161 (8.70%)
         occurrences all number
    21
    6
    6
    17
    Hypophosphatemia
         subjects affected / exposed
    7 / 207 (3.38%)
    1 / 209 (0.48%)
    0 / 86 (0.00%)
    11 / 161 (6.83%)
         occurrences all number
    11
    1
    0
    12
    Metabolic/Lab - Other
         subjects affected / exposed
    79 / 207 (38.16%)
    37 / 209 (17.70%)
    21 / 86 (24.42%)
    56 / 161 (34.78%)
         occurrences all number
    123
    50
    34
    101
    Infections and infestations
    Infection - Other
         subjects affected / exposed
    22 / 207 (10.63%)
    12 / 209 (5.74%)
    8 / 86 (9.30%)
    12 / 161 (7.45%)
         occurrences all number
    29
    19
    11
    17

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2009
    Protocol amendment 1, dated 01 JUL 2009, introduced the following key changes: • Clarified ambiguous wording that did not take into account certain elements of clinical practice • Some inclusion criteria of the protocol were revised to allow enrollment of appropriate patients for the indication studied.
    12 Aug 2009
    Protocol amendment 2, 12 AUG 2009, implemented the US Food and Drug Administration’s recommendations after the End-of-Phase-2 Meeting. These included: • A change in the definition of RAI refractory • Changes in secondary efficacy endpoints (to OS as the first secondary endpoint, and the addition of DoR as a secondary endpoint) • The measurement of total T3 instead of fT3 • Removal of the requirement for urine samples for pharmacogenetic biomarker analysis.
    15 Mar 2010
    Protocol amendment 4, 15 MAR 2010, revised the following: • The inclusion and exclusion criteria were updated to clarify contraception, pregnancy, and breastfeeding requirements • Specification of permitted doses of dexamethasone as well as consistency throughout the protocol of permitted/not-permitted concomitant medications was made. • A criterion for re-screening was added to specify how to handle subjects who had previously failed screening but were later eligible. • Study procedures were revised, including study removal criteria language, dose modifications, blood pressure measurements, cycle numbers and assessments, the requirement for FDG-PET scan at screening, and the study flow chart Revisions and additions were made in biomarkers and genetic testing.
    09 Dec 2010
    Protocol amendment 7, 09 DEC 2010, clarified or revised the following: • The definition of cycle length was redefined to the beginning of the cycle when the specific treatment course changes (e.g., when the blinded phase becomes the open-label phase) • An inclusion criterion was added to specify that subjects with poorly differentiated and other thyroid variants (eg, Insular, tall cell) were eligible for the study provided that the histology had no medullary differentiation nor anaplastic features. • Text was changed to specify that the use of biologic response modifiers were prohibited within 21 days of randomization, not 21 days of study entry. • Clarification was added to the inclusion criterion requiring subjects to have progression within 14 months that the progression was prior to 14 months of enrolment • In the definition of RAI refractory subjects in the inclusion criteria, specification was added that the post-radioactive-iodine scan could have been a diagnostic or therapeutic whole body scan. • An exception was added to the reason that subjects may be discontinued from study treatment if there is an interruption in study drug administration for more than 30 days (ie, if the interruption was due to PD that required interventions that precluded the use of sorafenib in the open-label phase [e.g., radiotherapy or surgery], the subject was permitted to continue on the study upon agreement between the investigator and the sponsor). • The dosing regimen and modifications to dosing were clarified. • Clarification on blood pressure monitoring of unblinded subjects was made. • Clarification on prior and concomitant therapy for long-term follow-up and survival subjects was made. • It was erroneously stated that the baseline CT/MRI scan was required prior to enrollment. It was corrected to state that the scan was required 28 days prior to randomization. (Continued)
    09 Dec 2010
    (Continued) Protocol amendment 7, 09 DEC 2010, clarified or revised the following: Text was added to allow up to 3 extra days added for randomization after signing informed consent in the event that the 28th day was on a weekend or was a holiday • A correction was made that study drug and the blood pressure monitoring form was distributed after randomization, not before. • Clarification was made that laboratory assessments were not required on day 1 of cycle 1 • Text was added to allow a subject who discontinued study drug, but did not progress, to continue with tumor assessments and survival assessments if he/she was in the long-term follow-up period • Clarification was added to specify that there is continued monitoring for subjects who discontinued study treatment but did not hit any study endpoint. • Clarification was made to the study flow chart that height was not required at the EOT visit and imaging tumor assessment were every 56 days during the follow-up.
    24 Aug 2011
    Protocol amendment 8, 24 AUG 2011, clarified or revised the following: • Increase the sample size of randomized subjects • Distinguish the primary endpoint analysis from the end of the study • Clarify that curable skin malignancies do not require removal from study • Clarify the definition of non-radiographically defined progression that can qualify for open-label crossover eligibility • Revise PK analysis methodology.
    26 Feb 2013
    Protocol amendment 9, 26 FEB 2013, clarified or revised the following: • Study procedures to be used following the primary completion date of the study, in order to enable subjects to receive treatment with sorafenib, if deemed appropriate by the investigator, and continue to be evaluated • Give subjects the opportunity to benefit from sorafenib treatment, minimize protocol deviations by clarification of procedures, and enable a more comprehensive evaluation of the efficacy of sorafenib for the treatment of thyroid cancer • Clarify the methods used to address the potential bias in the estimate of the treatment effect for OS due to crossover, with reference to the statistical analysis plan, as these correction methods would also be used for the follow-up OS analysis.
    10 Jan 2014
    Protocol amendment 10, 10 JAN 2014, revised and clarified the study procedures following the primary completion date of the study: • Lower the required tumor assessments from every 2 months to at the investigator’s discretion, up to a threshold of at least one tumor assessment per year • Guidance for use of dose modification was added • Skin toxicity criteria were clarified to include that an occurrence can be any grade of the AE • Statistical analysis methodology for the event-driven overall survival analysis was added • Collection of the genetic plasma sample was removed • Text revised to state the AUCs would also be confirmed by population PK modelling.
    21 Jul 2015
    Protocol amendment 11, 21 JUL 2015, clarified or revised the following: • The Food and Drug Administration (FDA) agreed that it would be sufficient to conduct the final survival analysis with only 210 death events • Text was added indicating that the study will terminate when the final overall survival event number is reached • All subjects receiving clinical benefit of the study drug were assured to have continued access to it even beyond study closure.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26370187
    http://www.ncbi.nlm.nih.gov/pubmed/24768112
    http://www.ncbi.nlm.nih.gov/pubmed/21834960
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