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    Clinical Trial Results:
    Phase 3b, Randomized, Open-Label Study of Bevacizumab + Temsirolimus Versus Bevacizumab + Interferon-Alfa as First-Line Treatment in Subjects With Advanced Renal Cell Carcinoma.

    Summary
    EudraCT number
    2007-003793-26
    Trial protocol
    HU   ES   FR   BE   PT   CZ   DE   SK   NL   IT   GB  
    Global end of trial date
    27 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Apr 2016
    First version publication date
    14 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3066K1-3311 (B1771006)
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00631371
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Wyeth Research Division of Wyeth Pharmaceuticals Inc.
    Sponsor organisation address
    500 Arcola Road,, Collegeville, PA, United States, 19426
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    23 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was a comparison of independently assessed progression free survival (PFS) in participants with clear cell advanced RCC (all risk groups) treated with Bevacizumab + Temsirolimus (experimental arm) Versus Bevacizumab + Interferon-Alfa (control arm).
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of study participants.
    Background therapy
    -
    Evidence for comparator
    Roferon (Solution for injection, subcutaneous use).
    Actual start date of recruitment
    10 Apr 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 14
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Brazil: 45
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Chile: 44
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hong Kong: 9
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    India: 42
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 122
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Russian Federation: 111
    Country: Number of subjects enrolled
    Serbia: 36
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Slovakia: 22
    Country: Number of subjects enrolled
    South Africa: 17
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    Taiwan: 25
    Country: Number of subjects enrolled
    Ukraine: 51
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    791
    EEA total number of subjects
    336
    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)
    576
    From 65 to 84 years
    214
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 791 participants were randomized (intent to treat [ITT] population) and 784 participants received at least 1 dose of study treatment (safety population); 7 participants did not receive study drug.

    Pre-assignment
    Screening details
    Participants were randomized in a 1:1 ratio, stratified by prior nephrectomy status (yes/no) and Memorial Sloan Kettering Cancer Center (MSKCC) risk factors (good/intermediate/poor), and received either the combination treatment of Temisirolimus + Bevacizumab (Temsr+Bev) or Interferon-alfa + Bevacizumab (IFN+Bev).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bevacizumab+Temsirolimus
    Arm description
    Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 10 mg/kg was administered as intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along either with either temsirolimus or interferon-alfa.

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    Other name
    Torisel
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Temsirolimus 25 mg was administered as intravenous infusion over at least 30 minutes once a week..

    Arm title
    Bevacizumab+ Interferon-Alfa
    Arm description
    Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
    Arm type
    Active comparator

    Investigational medicinal product name
    Interferon Alfa-2A
    Investigational medicinal product code
    Other name
    Roferon
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Interferon-alfa (IFN) 9 million units (MU) was administered as subcutaneous injection every 3 times a week.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along either with either temsirolimus or interferon-alfa.

    Number of subjects in period 1
    Bevacizumab+Temsirolimus Bevacizumab+ Interferon-Alfa
    Started
    400
    391
    Treated
    393
    391
    Completed
    0
    0
    Not completed
    400
    391
         Deaths
    263
    239
         Discontinuation of study by Sponsor
    70
    76
         Other reason
    5
    12
         Subject request
    38
    45
         Lost to follow-up
    24
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab+Temsirolimus
    Reporting group description
    Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.

    Reporting group title
    Bevacizumab+ Interferon-Alfa
    Reporting group description
    Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.

    Reporting group values
    Bevacizumab+Temsirolimus Bevacizumab+ Interferon-Alfa Total
    Number of subjects
    400 391 791
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    294 282 576
        From 65-84 years
    106 109 215
        85 years and over
    0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    58.6 ± 10.1 58.2 ± 10.4 -
    Gender, Male/Female
    Units: participants
        Female
    114 121 235
        Male
    286 270 556

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab+Temsirolimus
    Reporting group description
    Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.

    Reporting group title
    Bevacizumab+ Interferon-Alfa
    Reporting group description
    Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.

    Primary: Progression-Free Survival (PFS): Independent-Assessment

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    End point title
    Progression-Free Survival (PFS): Independent-Assessment
    End point description
    PFS was defined as the interval from the date of randomization until the earlier date of progression or death. Progression was assessed by independent imaging reviewers using Response Evaluation Criteria in Solid Tumors (RECIST) criteria which is 20% increase in sum of longest diameter of target lesions from nadir (the smallest sum obtained previously); measurable increase in non-target lesion; appearance of new lesions. The efficacy endpoint analysis is conducted on ITT population (N=791).
    End point type
    Primary
    End point timeframe
    Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)
    End point values
    Bevacizumab+Temsirolimus Bevacizumab+ Interferon-Alfa
    Number of subjects analysed
    400
    391
    Units: months
        median (confidence interval 95%)
    9.1 (8.1 to 10.2)
    9.3 (9 to 11.2)
    Statistical analysis title
    Staistical analysis 1
    Statistical analysis description
    P value was based on 1-sided stratified log-rank test (stratification factors: prior nephrectomy [yes/no] and Memorial Sloan Kettering Cancer Center [MSKCC] risk factors [good/intermediate/poor] at time of randomization). The hazard ratio and corresponding 95 percent (%) confidence interval (CI) from the stratified Cox proportional hazards model were also presented.
    Comparison groups
    Bevacizumab+Temsirolimus v Bevacizumab+ Interferon-Alfa
    Number of subjects included in analysis
    791
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.8
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.3

    Secondary: Progression-Free Survival (PFS): Investigator-Assessment

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    End point title
    Progression-Free Survival (PFS): Investigator-Assessment
    End point description
    PFS was defined as the interval from the date of randomization until the earlier date of progression or death. Progression was assessed by investigator imaging reviewers using RECIST criteria which is 20% increase in sum of longest diameter of target lesions from nadir (the smallest sum obtained previosuly); measurable increase in non-target lesion; appearance of new lesions. The efficacy endpoint analysis is conducted on ITT population (N=791).
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)
    End point values
    Bevacizumab+Temsirolimus Bevacizumab+ Interferon-Alfa
    Number of subjects analysed
    400
    391
    Units: months
        median (confidence interval 95%)
    9.1 (8.1 to 10.5)
    10.8 (9.1 to 11.2)
    Statistical analysis title
    Statisitcal analysis 1
    Statistical analysis description
    P-value was based on 1-sided stratified log-rank test (stratification factors: prior nephrectomy [yes/no] and MSKCC risk factors [good/intermediate/poor] at time of randomization). The hazard ratio and corresponding 95% CI from the stratified Cox proportional hazards model were also presented.
    Comparison groups
    Bevacizumab+Temsirolimus v Bevacizumab+ Interferon-Alfa
    Number of subjects included in analysis
    791
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    1.4

    Secondary: Percentage of Participants With Objective Response (complete response/partial response): Independent-Assessment

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    End point title
    Percentage of Participants With Objective Response (complete response/partial response): Independent-Assessment
    End point description
    Percentage of participants with OR based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. Confirmed response were those that persisted on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and/or non target). PR were those with at least 30% decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non target lesions not increased or absent. The efficacy endpoint analysis is conducted on ITT population (N=791).
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)
    End point values
    Bevacizumab+Temsirolimus Bevacizumab+ Interferon-Alfa
    Number of subjects analysed
    400
    391
    Units: Percentage of participants
        number (confidence interval 95%)
    27 (22.7 to 31.6)
    27.4 (23 to 32.1)
    Statistical analysis title
    Statistical analysis
    Statistical analysis description
    P-value (2-sided), risk ratio and associated 95% CI were based on Cochran-Mantel-Haenszel test stratified by prior nephrectomy and MSKCC risk group as randomized.
    Comparison groups
    Bevacizumab+Temsirolimus v Bevacizumab+ Interferon-Alfa
    Number of subjects included in analysis
    791
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 1
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk ratio (RR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.3

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death due to any cause, censored at the last date known alive. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death). The efficacy endpoint analysis is conducted on ITT population (N=791).
    End point type
    Secondary
    End point timeframe
    Baseline until death due to any cause, assessed every 8 weeks (up to cut-off date: 19 April 2012)
    End point values
    Bevacizumab+Temsirolimus Bevacizumab+ Interferon-Alfa
    Number of subjects analysed
    400
    391
    Units: months
        median (confidence interval 95%)
    25.8 (21.1 to 30.7)
    25.5 (22.4 to 30.8)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    P value was based on 1-sided stratified log-rank test (stratification factors: prior nephrectomy [yes/no] and MSKCC risk factors [good/intermediate/poor] at time of randomization). The hazard ratio and corresponding 95% CI from the stratified Cox proportional hazards model were also presented.
    Comparison groups
    Bevacizumab+Temsirolimus v Bevacizumab+ Interferon-Alfa
    Number of subjects included in analysis
    791
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.6
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication.
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Bevacizumab+ Interferon-Alfa
    Reporting group description
    Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.

    Reporting group title
    Bevacizumab+Temsirolimus
    Reporting group description
    Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant’s tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.

    Serious adverse events
    Bevacizumab+ Interferon-Alfa Bevacizumab+Temsirolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    158 / 391 (40.41%)
    184 / 393 (46.82%)
         number of deaths (all causes)
    239
    261
         number of deaths resulting from adverse events
    21
    20
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 391 (0.26%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    4 / 391 (1.02%)
    6 / 393 (1.53%)
         occurrences causally related to treatment / all
    6 / 6
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Peripheral Venous Disease
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Cancer Surgery
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastasis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic pain
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic renal cell carcinoma
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Neoplasm progression
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 391 (0.26%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 12
    0 / 11
    Tumour associated fever
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour ulceration
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 391 (1.28%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    7 / 12
    1 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Chills
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 391 (1.02%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    2 / 5
    0 / 2
    Disease progression
         subjects affected / exposed
    16 / 391 (4.09%)
    13 / 393 (3.31%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 15
         deaths causally related to treatment / all
    0 / 19
    0 / 21
    Fatigue
         subjects affected / exposed
    7 / 391 (1.79%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    6 / 391 (1.53%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Injury associated with device
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 391 (0.00%)
    5 / 393 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Multi-organ failure
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 391 (1.79%)
    9 / 393 (2.29%)
         occurrences causally related to treatment / all
    3 / 8
    4 / 11
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 391 (0.00%)
    5 / 393 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    Condition Aggravated
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    3 / 391 (0.77%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Completed Suicide
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depression
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Head injury
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure systolic decreased
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Protein urine present
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 391 (0.00%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac valve disease
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary ostial stenosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atelectasis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchospasm
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    10 / 391 (2.56%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    2 / 12
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Epistaxis
         subjects affected / exposed
    2 / 391 (0.51%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 391 (0.77%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    5 / 6
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septum disorder
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 391 (0.51%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 391 (0.00%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 391 (1.02%)
    5 / 393 (1.27%)
         occurrences causally related to treatment / all
    7 / 8
    3 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pulmonary hypertension
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 391 (0.26%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Sputum discoloured
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 391 (3.07%)
    10 / 393 (2.54%)
         occurrences causally related to treatment / all
    10 / 31
    7 / 12
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 391 (0.77%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 391 (0.51%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Loss of consciousness
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Spinal cord compression
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 391 (1.02%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    4 / 391 (1.02%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance Disorder
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central Nervous System Haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 391 (0.26%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Toxic Encephalopathy
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Encephalopathy
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous floaters
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 391 (1.53%)
    8 / 393 (2.04%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Anal fissure
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    2 / 391 (0.51%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Constipation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 391 (1.28%)
    7 / 393 (1.78%)
         occurrences causally related to treatment / all
    1 / 6
    9 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Gastric fistula
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 391 (0.26%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Painful defaecation
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    2 / 391 (0.51%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 391 (0.51%)
    7 / 393 (1.78%)
         occurrences causally related to treatment / all
    1 / 2
    5 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Renal and urinary disorders
    Nephrectasia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    2 / 391 (0.51%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    2 / 2
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    3 / 391 (0.77%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 391 (0.51%)
    5 / 393 (1.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral disorder
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Kidney Injury
         subjects affected / exposed
    3 / 391 (0.77%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    0 / 5
    2 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 391 (0.00%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 391 (0.26%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 391 (0.77%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bone lesion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 391 (0.51%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 391 (0.77%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Diabetes mellitus
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 391 (0.51%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    0 / 391 (0.00%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 391 (0.77%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hyponatraemia
         subjects affected / exposed
    2 / 391 (0.51%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 391 (0.51%)
    5 / 393 (1.27%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal cellulitis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 391 (0.26%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cellulitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Erysipelas
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhoid infection
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infection
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung abscess
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal abscess
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 391 (0.51%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 3
    Pharyngitis
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 391 (1.28%)
    16 / 393 (4.07%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 24
         deaths causally related to treatment / all
    0 / 2
    2 / 8
    Post procedural infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 391 (0.26%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 391 (1.02%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    5 / 6
    3 / 3
         deaths causally related to treatment / all
    3 / 4
    1 / 1
    Septic shock
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 391 (1.02%)
    5 / 393 (1.27%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmodium Malariae Infection
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Bevacizumab+ Interferon-Alfa Bevacizumab+Temsirolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    378 / 391 (96.68%)
    383 / 393 (97.46%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    102 / 391 (26.09%)
    128 / 393 (32.57%)
         occurrences all number
    307
    427
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    113 / 391 (28.90%)
    95 / 393 (24.17%)
         occurrences all number
    492
    371
    Chills
         subjects affected / exposed
    44 / 391 (11.25%)
    15 / 393 (3.82%)
         occurrences all number
    95
    18
    Fatigue
         subjects affected / exposed
    122 / 391 (31.20%)
    92 / 393 (23.41%)
         occurrences all number
    559
    272
    Influenza like illness
         subjects affected / exposed
    48 / 391 (12.28%)
    14 / 393 (3.56%)
         occurrences all number
    335
    17
    Mucosal inflammation
         subjects affected / exposed
    40 / 391 (10.23%)
    105 / 393 (26.72%)
         occurrences all number
    101
    391
    Oedema peripheral
         subjects affected / exposed
    32 / 391 (8.18%)
    67 / 393 (17.05%)
         occurrences all number
    55
    189
    Pyrexia
         subjects affected / exposed
    154 / 391 (39.39%)
    79 / 393 (20.10%)
         occurrences all number
    508
    166
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    21 / 391 (5.37%)
    7 / 393 (1.78%)
         occurrences all number
    39
    16
    Depression
         subjects affected / exposed
    22 / 391 (5.63%)
    11 / 393 (2.80%)
         occurrences all number
    48
    39
    Insomnia
         subjects affected / exposed
    31 / 391 (7.93%)
    28 / 393 (7.12%)
         occurrences all number
    65
    66
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    35 / 391 (8.95%)
    38 / 393 (9.67%)
         occurrences all number
    96
    91
    Aspartate aminotransferase increased
         subjects affected / exposed
    41 / 391 (10.49%)
    33 / 393 (8.40%)
         occurrences all number
    125
    69
    Blood creatinine increased
         subjects affected / exposed
    25 / 391 (6.39%)
    40 / 393 (10.18%)
         occurrences all number
    76
    166
    Weight decreased
         subjects affected / exposed
    93 / 391 (23.79%)
    90 / 393 (22.90%)
         occurrences all number
    346
    286
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    14 / 391 (3.58%)
    20 / 393 (5.09%)
         occurrences all number
    40
    51
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    66 / 391 (16.88%)
    80 / 393 (20.36%)
         occurrences all number
    281
    326
    Leukopenia
         subjects affected / exposed
    40 / 391 (10.23%)
    17 / 393 (4.33%)
         occurrences all number
    299
    61
    Lymphopenia
         subjects affected / exposed
    38 / 391 (9.72%)
    24 / 393 (6.11%)
         occurrences all number
    268
    70
    Neutropenia
         subjects affected / exposed
    66 / 391 (16.88%)
    18 / 393 (4.58%)
         occurrences all number
    369
    82
    Thrombocytopenia
         subjects affected / exposed
    40 / 391 (10.23%)
    50 / 393 (12.72%)
         occurrences all number
    226
    167
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    70 / 391 (17.90%)
    79 / 393 (20.10%)
         occurrences all number
    191
    160
    Dysphonia
         subjects affected / exposed
    30 / 391 (7.67%)
    13 / 393 (3.31%)
         occurrences all number
    52
    34
    Dyspnoea
         subjects affected / exposed
    49 / 391 (12.53%)
    36 / 393 (9.16%)
         occurrences all number
    106
    71
    Epistaxis
         subjects affected / exposed
    82 / 391 (20.97%)
    110 / 393 (27.99%)
         occurrences all number
    225
    315
    Oropharyngeal pain
         subjects affected / exposed
    16 / 391 (4.09%)
    28 / 393 (7.12%)
         occurrences all number
    42
    42
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    37 / 391 (9.46%)
    29 / 393 (7.38%)
         occurrences all number
    88
    49
    Dysgeusia
         subjects affected / exposed
    21 / 391 (5.37%)
    33 / 393 (8.40%)
         occurrences all number
    62
    104
    Headache
         subjects affected / exposed
    82 / 391 (20.97%)
    77 / 393 (19.59%)
         occurrences all number
    237
    182
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    20 / 391 (5.12%)
    4 / 393 (1.02%)
         occurrences all number
    45
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    42 / 391 (10.74%)
    48 / 393 (12.21%)
         occurrences all number
    79
    82
    Abdominal pain upper
         subjects affected / exposed
    21 / 391 (5.37%)
    31 / 393 (7.89%)
         occurrences all number
    38
    54
    Diarrhoea
         subjects affected / exposed
    86 / 391 (21.99%)
    126 / 393 (32.06%)
         occurrences all number
    200
    254
    Constipation
         subjects affected / exposed
    48 / 391 (12.28%)
    43 / 393 (10.94%)
         occurrences all number
    96
    80
    Gingival bleeding
         subjects affected / exposed
    21 / 391 (5.37%)
    5 / 393 (1.27%)
         occurrences all number
    61
    23
    Haemorrhoids
         subjects affected / exposed
    13 / 391 (3.32%)
    28 / 393 (7.12%)
         occurrences all number
    21
    82
    Nausea
         subjects affected / exposed
    78 / 391 (19.95%)
    69 / 393 (17.56%)
         occurrences all number
    210
    123
    Stomatitis
         subjects affected / exposed
    39 / 391 (9.97%)
    102 / 393 (25.95%)
         occurrences all number
    89
    292
    Toothache
         subjects affected / exposed
    14 / 391 (3.58%)
    37 / 393 (9.41%)
         occurrences all number
    16
    57
    Vomiting
         subjects affected / exposed
    53 / 391 (13.55%)
    53 / 393 (13.49%)
         occurrences all number
    112
    79
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    111 / 391 (28.39%)
    143 / 393 (36.39%)
         occurrences all number
    571
    727
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    13 / 391 (3.32%)
    27 / 393 (6.87%)
         occurrences all number
    29
    62
    Pruritus
         subjects affected / exposed
    26 / 391 (6.65%)
    60 / 393 (15.27%)
         occurrences all number
    70
    144
    Rash
         subjects affected / exposed
    32 / 391 (8.18%)
    126 / 393 (32.06%)
         occurrences all number
    91
    392
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    49 / 391 (12.53%)
    52 / 393 (13.23%)
         occurrences all number
    118
    102
    Back pain
         subjects affected / exposed
    53 / 391 (13.55%)
    47 / 393 (11.96%)
         occurrences all number
    125
    115
    Bone pain
         subjects affected / exposed
    22 / 391 (5.63%)
    18 / 393 (4.58%)
         occurrences all number
    57
    58
    Musculoskeletal chest pain
         subjects affected / exposed
    19 / 391 (4.86%)
    27 / 393 (6.87%)
         occurrences all number
    49
    62
    Musculoskeletal pain
         subjects affected / exposed
    28 / 391 (7.16%)
    14 / 393 (3.56%)
         occurrences all number
    47
    32
    Myalgia
         subjects affected / exposed
    60 / 391 (15.35%)
    19 / 393 (4.83%)
         occurrences all number
    178
    28
    Pain in extremity
         subjects affected / exposed
    35 / 391 (8.95%)
    43 / 393 (10.94%)
         occurrences all number
    72
    101
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    127 / 391 (32.48%)
    103 / 393 (26.21%)
         occurrences all number
    415
    309
    Hypercholesterolaemia
         subjects affected / exposed
    39 / 391 (9.97%)
    126 / 393 (32.06%)
         occurrences all number
    144
    578
    Hyperglycaemia
         subjects affected / exposed
    19 / 391 (4.86%)
    86 / 393 (21.88%)
         occurrences all number
    50
    332
    Hyperkalaemia
         subjects affected / exposed
    37 / 391 (9.46%)
    29 / 393 (7.38%)
         occurrences all number
    145
    85
    Hypocalcaemia
         subjects affected / exposed
    13 / 391 (3.32%)
    24 / 393 (6.11%)
         occurrences all number
    57
    74
    Hypertriglyceridaemia
         subjects affected / exposed
    82 / 391 (20.97%)
    114 / 393 (29.01%)
         occurrences all number
    399
    587
    Hypomagnesaemia
         subjects affected / exposed
    16 / 391 (4.09%)
    20 / 393 (5.09%)
         occurrences all number
    34
    37
    Hyponatraemia
         subjects affected / exposed
    21 / 391 (5.37%)
    23 / 393 (5.85%)
         occurrences all number
    47
    88
    Hypophosphataemia
         subjects affected / exposed
    18 / 391 (4.60%)
    40 / 393 (10.18%)
         occurrences all number
    44
    123
    Hypokalaemia
         subjects affected / exposed
    4 / 391 (1.02%)
    20 / 393 (5.09%)
         occurrences all number
    7
    49
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 391 (3.84%)
    20 / 393 (5.09%)
         occurrences all number
    28
    34
    Urinary tract infection
         subjects affected / exposed
    21 / 391 (5.37%)
    23 / 393 (5.85%)
         occurrences all number
    38
    38

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2008
    Protocol amendment 1 included minor clarifications to inclusion/exclusion criteria and study required assessments. Long-Term Follow-up no longer required as part of the study. Protocol-defined tumor assessments were no longer required, rather assessments were performed according to local standard of care at the discretion of the treating investigator. Tumor assessments no longer required to be submitted to the independent imaging vendor.Plasma samples for biomarker analysis were no longer required. Health Outcome questionnaires were no longer required. Serious adverse events (SAEs) of which the investigator became aware of after the active safety reporting period should be reported to Pfizer with certain exceptions. Appendix regarding Crossover in response to E-DMC Recommendation to prematurely discontinue the Bevacizumab + Temsirolimus arm was deleted. Final OS analysis as stated in Amendment 3 (15 December 2011) eliminated.Use of the External Data Monitoring Committee (E-DMC) was no longer required.
    22 Mar 2010
    Protocol Amendment 2 included an interim analysis. Sponsor and Study Team information removed; Document History section added; Abbreviations and definitions sections revised; Single Reference Safety Document (SRSD) is the investigator’s brochure for temsirolimus and the product label for bevacizumab and interferon-alfa (various sections); Clarification added in subject selection as to collection of retrospective data; Clinical Operations Randomization Environment (CORE) system language regarding subject discontinuation removed. Language regarding preparation and dispensing Updated Medication Errors language to align with EU CT3 added. Updated language as to drug storage conditions. Revised language as to Electronic Case Report Form documentation of Adverse Event.Updated Subject withdrawal language; Added language regarding required assessments when not performed; updated due to alignment with EU CT3 guidance (effective 11 June 2011) and US FDA (Food and Drug Administration) Final Rule (effective 28 September 2011) and more specifically adverse event follow-up clarified to align with CT3 and Final Rule. Active reporting period and necessity to report all SAEs post-active reporting period clarifying language added to align with CT3 and Final Rule. Definition of AE updated to align under CT3 guidance and revised Pfizer corporate policy AEM01, including addition of medication error.
    09 Dec 2011
    Protocol Amendment 3 included alignment of the SAE reporting criteria with EU-CT3 and US FDA final rule guidances. Addition of an Interim Analysis which was planned at approximately 236 observed events (corresponding to 50% information) and recommendation to stop the trial early was given for futility only. The endpoint used at the interim analysis would be the investigator-assessed PFS (tumor progression + death only excluding symptomatic deterioration).
    07 Nov 2012
    Protocol mendment 4 inlcuded the results of the primary analysis, revised study flowchart and long-term follow-up was removed, Plasma samples and tumor tissue were collected for biomarker samples and health outcome questionnaires. Participants (men and women) must be agreed to use medically accepted contraceptive methods during the treatment phase and for 6 months after the last dose of bevacizumab. Participants with a history of cervical carcinoma in situ (CIS) or breast ductal CIS or breast lobular CIS were considered eligible provided they have completed definitive therapy. Participants developing tracheo-oesophageal fistulae or any grade 4 fistula were permanently removed from the treatment phase. The sponsor might request to perform additional unscheduled survival contacts, or to shift the schedule of survival data collection, if needed for data analysis.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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