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    Clinical Trial Results:
    A Multi-centre, Open-label, Randomised, Two-arm Phase III Trial of Bevacizumab Plus Chemotherapy Versus Chemotherapy Alone in Patients With Platinum-resistant, Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer.

    Summary
    EudraCT number
    2009-011400-33
    Trial protocol
    SE   ES   PT   DE   IT   FR   DK   NL   BE   FI   GR  
    Global end of trial date
    09 Jul 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Apr 2022
    First version publication date
    28 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO22224
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00976911
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    09 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objective of the study was to evaluate the efficacy and safety of bevacizumab added to chemotherapy versus chemotherapy alone in participants with epithelial ovarian, fallopian tube or primary peritoneal cancer with disease progression within 6 months of platinum therapy.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    Both arms in the study received chemotherapy treatment, which was either paclitaxel, topotecan or pegylated liposomal doxorubicin. These treatments were considered to be the standard-of-care non-investigational combination drugs in the study. Liposomal doxorubicin was administered at 40 mg/m^2 intravenously (iv) every 4 weeks. Paclitaxel was administered at 80 mg/m^2 iv on days 1, 8, 15 and 22 of each 4-week cycle. Topotecan was administered at 4 mg/m^2 iv on days 1, 8 and 15 of each 4-week cycle, or 1.25 mg/kg on days 1-5 of each 3-week cycle.
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Oct 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 121
    Country: Number of subjects enrolled
    Germany: 67
    Country: Number of subjects enrolled
    Spain: 56
    Country: Number of subjects enrolled
    Denmark: 19
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Norway: 14
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 11
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Finland: 1
    Worldwide total number of subjects
    361
    EEA total number of subjects
    341
    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)
    228
    From 65 to 84 years
    133
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were recruited at a total of 96 sites in 14 countries in Europe.

    Pre-assignment
    Screening details
    The study enrolled adult subjects with epithelial ovarian cancer (EOC), fallopian tube carcinoma (FTC) or primary peritoneal carcinomas (PPC) who were considered to have platinum-resistant disease (progression <6 months from last platinum-based therapy).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Chemotherapy
    Arm description
    Participants received one of the following chemotherapies at the discretion of the investigator: paclitaxel, 80 milligrams per square meter (mg/m^2) as a 1-hour intravenous (IV) infusion on Days 1, 8, 15, and 22 every 4 weeks (q4w) OR topotecan 4 mg/m^2 as a 30-minute IV infusion on Days 1, 8, and 15 q4w (alternatively, a 1.25 mg/m^2 dose could have been administered over 30 minutes on Days 1-5 every 3 weeks [q3w]) OR pegylated liposomal doxorubicin (PLD) 40 mg/m^2 as a 1 milligram per minute (mg/min) infusion on Day 1 q4w (after Cycle 1 the drug could have been administered as a 1 hour infusion). Depending on chosen chemotherapy, pre-medication was implemented according to local practices.
    Arm type
    Chemotherapy only

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Chemotherapy + Bevacizumab
    Arm description
    Participants received one of the following chemotherapies at the discretion of the investigator: paclitaxel, 80 mg/m^2 as a 1-hour IV infusion on Days 1, 8, 15, and 22 q4w OR topotecan 4 mg/m^2 as a 30-minute IV infusion on Days 1, 8, and 15 q4w (alternatively, a 1.25 mg/m^2 dose could have been administered over 30 minutes on Days 1-5 q3w) OR PLD 40 mg/m^2 as a 1 mg/min infusion on Day 1 q4w (after Cycle 1 the drug could have been administered as a 1 hour infusion. Depending on chosen chemotherapy, pre-medication was implemented according to local practices. The chosen chemotherapy was combined with bevacizumab 10 milligrams per kilogram (mg/kg) IV every 2 weeks (q2w; or bevacizumab 15 mg/kg q3w if used in combination with topotecan 1.25 mg/m^2 on Days 1-5 on a q3w schedule). The initial bevacizumab infusion was over 90 minutes, with subsequent infusions over 60 minutes and then 30 minutes, as tolerated.
    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 was administered at 10 mg/kg iv every 2 weeks or 15 mg/kg iv every 3 weeks.

    Number of subjects in period 1
    Chemotherapy Chemotherapy + Bevacizumab
    Started
    182
    179
    Completed
    0
    0
    Not completed
    182
    179
         In Follow-Up as of 25 Jan 2013
    30
    37
         Protocol deviation
    2
    -
         Adverse event, serious fatal
    138
    126
         Adverse event, non-fatal
    -
    1
         Consent withdrawn by subject
    4
    6
         Not Specified
    8
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Participants received one of the following chemotherapies at the discretion of the investigator: paclitaxel, 80 milligrams per square meter (mg/m^2) as a 1-hour intravenous (IV) infusion on Days 1, 8, 15, and 22 every 4 weeks (q4w) OR topotecan 4 mg/m^2 as a 30-minute IV infusion on Days 1, 8, and 15 q4w (alternatively, a 1.25 mg/m^2 dose could have been administered over 30 minutes on Days 1-5 every 3 weeks [q3w]) OR pegylated liposomal doxorubicin (PLD) 40 mg/m^2 as a 1 milligram per minute (mg/min) infusion on Day 1 q4w (after Cycle 1 the drug could have been administered as a 1 hour infusion). Depending on chosen chemotherapy, pre-medication was implemented according to local practices.

    Reporting group title
    Chemotherapy + Bevacizumab
    Reporting group description
    Participants received one of the following chemotherapies at the discretion of the investigator: paclitaxel, 80 mg/m^2 as a 1-hour IV infusion on Days 1, 8, 15, and 22 q4w OR topotecan 4 mg/m^2 as a 30-minute IV infusion on Days 1, 8, and 15 q4w (alternatively, a 1.25 mg/m^2 dose could have been administered over 30 minutes on Days 1-5 q3w) OR PLD 40 mg/m^2 as a 1 mg/min infusion on Day 1 q4w (after Cycle 1 the drug could have been administered as a 1 hour infusion. Depending on chosen chemotherapy, pre-medication was implemented according to local practices. The chosen chemotherapy was combined with bevacizumab 10 milligrams per kilogram (mg/kg) IV every 2 weeks (q2w; or bevacizumab 15 mg/kg q3w if used in combination with topotecan 1.25 mg/m^2 on Days 1-5 on a q3w schedule). The initial bevacizumab infusion was over 90 minutes, with subsequent infusions over 60 minutes and then 30 minutes, as tolerated.

    Reporting group values
    Chemotherapy Chemotherapy + Bevacizumab Total
    Number of subjects
    182 179 361
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    60.7 ± 9.8 60.0 ± 11.1 -
    Sex: Female, Male
    Units: Subjects
        Female
    182 179 361
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Participants received one of the following chemotherapies at the discretion of the investigator: paclitaxel, 80 milligrams per square meter (mg/m^2) as a 1-hour intravenous (IV) infusion on Days 1, 8, 15, and 22 every 4 weeks (q4w) OR topotecan 4 mg/m^2 as a 30-minute IV infusion on Days 1, 8, and 15 q4w (alternatively, a 1.25 mg/m^2 dose could have been administered over 30 minutes on Days 1-5 every 3 weeks [q3w]) OR pegylated liposomal doxorubicin (PLD) 40 mg/m^2 as a 1 milligram per minute (mg/min) infusion on Day 1 q4w (after Cycle 1 the drug could have been administered as a 1 hour infusion). Depending on chosen chemotherapy, pre-medication was implemented according to local practices.

    Reporting group title
    Chemotherapy + Bevacizumab
    Reporting group description
    Participants received one of the following chemotherapies at the discretion of the investigator: paclitaxel, 80 mg/m^2 as a 1-hour IV infusion on Days 1, 8, 15, and 22 q4w OR topotecan 4 mg/m^2 as a 30-minute IV infusion on Days 1, 8, and 15 q4w (alternatively, a 1.25 mg/m^2 dose could have been administered over 30 minutes on Days 1-5 q3w) OR PLD 40 mg/m^2 as a 1 mg/min infusion on Day 1 q4w (after Cycle 1 the drug could have been administered as a 1 hour infusion. Depending on chosen chemotherapy, pre-medication was implemented according to local practices. The chosen chemotherapy was combined with bevacizumab 10 milligrams per kilogram (mg/kg) IV every 2 weeks (q2w; or bevacizumab 15 mg/kg q3w if used in combination with topotecan 1.25 mg/m^2 on Days 1-5 on a q3w schedule). The initial bevacizumab infusion was over 90 minutes, with subsequent infusions over 60 minutes and then 30 minutes, as tolerated.

    Primary: Percentage of Participants with Disease Progression or Death (Data cutoff 14 November 2011)

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    End point title
    Percentage of Participants with Disease Progression or Death (Data cutoff 14 November 2011) [1]
    End point description
    Progression free survival was defined as the time from the date of randomization to the first documented disease progression or death, whichever occurs first. Progression was based on tumour assessment made by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria (for participants with measurable disease), and for those with non-measurable disease presence or absence of lesions was noted. ITT Population: All participants randomized to study treatment, irrespective of whether or not the assigned treatment was actually received.
    End point type
    Primary
    End point timeframe
    Screening Visit, Every 8 weeks (or 9 weeks if receiving topotecan) until progression reported between day of first participant randomized (29 October 2009) until cutoff date of 14 November 2011
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    Chemotherapy Chemotherapy + Bevacizumab
    Number of subjects analysed
    182
    179
    Units: percentage of participants
        number (not applicable)
    92.3
    78.2
    No statistical analyses for this end point

    Primary: Progression Free Survival (PFS; Data Cutoff 14 November 2011)

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    End point title
    Progression Free Survival (PFS; Data Cutoff 14 November 2011)
    End point description
    PFS was defined as the time from the date of randomization to the first documented disease progression (PD) or death, whichever occurred first. Progression was based on tumor assessment made by the investigators according to the RECIST criteria (for participants with measurable disease), and for those with non-measurable disease presence or absence of lesions was noted. An event was defined as the earliest progressive disease or death that occurred on or before the cutoff date (14Nov2011), regardless of start of non-protocol specified anti-cancer therapy or bevacizumab monotherapy. PD was assessed by investigator according to RECIST or by symptom deterioration, and could not be declared based on rising cancer antigen 125 (CA125) levels alone. ITT Population: All randomized participants. Only participants with an event of progression or death were included in the analysis. Kaplan-Meier methodology was used. 95% CI for median was computed using the method of Brookmeyer and Crowley.
    End point type
    Primary
    End point timeframe
    Screening Visit, Every 8 weeks (or 9 weeks if receiving topotecan) until progression reported between day of first participant randomized (29 October 2009) until cutoff date of 14 November 2011
    End point values
    Chemotherapy Chemotherapy + Bevacizumab
    Number of subjects analysed
    168
    141
    Units: months
        median (confidence interval 95%)
    3.4 (2.10 to 3.75)
    6.8 (5.62 to 7.79)
    Statistical analysis title
    Stratified analysis
    Statistical analysis description
    Cox regression model was used to determine the hazard ratio.
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.379
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.296
         upper limit
    0.485
    Notes
    [2] - Stratified analysis: Strata were: chemotherapy selected (paclitaxel, PLD, or topotecan), prior anti-angiogenic therapy (yes or no), and platinum-free interval (less than [<] 3 or 3-6 months).
    Statistical analysis title
    Unstratified analysis
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.366
         upper limit
    0.577
    Statistical analysis title
    Unstratified analysis p-value Peto-Peto-Prentice
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Peto-Peto-Prentice
    Confidence interval
    Statistical analysis title
    Stratified analysis p-value Peto-Peto-Prentice
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    P-value
    < 0.0001
    Method
    Peto-Peto-Prentice
    Confidence interval
    Notes
    [3] - Stratified analysis: Strata were: chemotherapy selected (paclitaxel, PLD, or topotecan), prior anti-angiogenic therapy (yes or no), and platinum-free interval (less than [<] 3 or 3-6 months).

    Secondary: Percentage of Participants with Best Overall Confirmed Objective Response of Complete Response (CR) or Partial Response (PR) per Modified RECIST (Data Cutoff 14 November 2011)

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    End point title
    Percentage of Participants with Best Overall Confirmed Objective Response of Complete Response (CR) or Partial Response (PR) per Modified RECIST (Data Cutoff 14 November 2011)
    End point description
    Objective Response was determined by the investigator using modified RECIST criteria, Version 1.0. An objective response was a complete or partial overall confirmed response as determined by investigators. CR defined as complete disappearance of all target and non-target lesions and no new lesions. PR defined as greater than or equal to (≥) 30 percent (%) decrease in the sum of appropriate diameters of all target measurable lesions, no progress in the non-measurable disease, and no new lesions. ITT Population; only participants with measurable disease at baseline were included in the analysis. 95% CI computed using the normal approximation to the binomial distribution.
    End point type
    Secondary
    End point timeframe
    Screening Visit, Every 8 weeks (or 9 weeks if receiving topotecan) until progression reported between day of first participant randomized (29 October 2009) until cutoff date of 14 November 2011
    End point values
    Chemotherapy Chemotherapy + Bevacizumab
    Number of subjects analysed
    144
    142
    Units: percentage of participants
        number (confidence interval 95%)
    12.5 (7.1 to 17.9)
    28.2 (20.8 to 35.6)
    Statistical analysis title
    Difference in Response Rates
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Difference in Response Rates
    Point estimate
    15.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.5
         upper limit
    24.8
    Statistical analysis title
    Unstratified Analysis p-value
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [4]
    Method
    Pearson's chi-square
    Confidence interval
    Notes
    [4] - Unstratified
    Statistical analysis title
    Stratified Analysis p-value
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007 [5]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - Stratified analysis: Strata were: chemotherapy selected (paclitaxel, PLD, or topotecan), prior anti-angiogenic therapy (yes or no), and platinum-free interval (<3 or 3-6 months).

    Secondary: Duration of Objective Response (Data Cutoff 14 November 2011)

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    End point title
    Duration of Objective Response (Data Cutoff 14 November 2011)
    End point description
    For randomized participants who achieved an objective response per modified RECIST, duration of objective response was defined as the time from the date of the first occurrence of a CR or PR (whichever occurred first) until the date that progressive disease or death was documented (whichever occurred first). Participants who had an objective response and did not experience disease progression or death by the time of analysis were censored at the time of the last tumor assessment. ITT Population; only participants with a best overall confirmed response of CR or PR were included in the analysis. Summaries of duration of objective response (median and percentiles) were estimated from Kaplan−Meier curves. 95% CI for duration of objective response was computed using the method of Brookmeyer and Crowley.
    End point type
    Secondary
    End point timeframe
    Screening Visit, Every 8 weeks (or 9 weeks if receiving topotecan) until progression reported between day of first participant randomized (29 October 2009) until cutoff date of 14 November 2011
    End point values
    Chemotherapy Chemotherapy + Bevacizumab
    Number of subjects analysed
    18
    40
    Units: months
        median (confidence interval 95%)
    5.4 (3.81 to 9.23)
    9.4 (6.60 to 11.63)
    Statistical analysis title
    Unstratified Peto-Peto-Prentice p-value
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0081
    Method
    Peto-Peto-Prentice
    Confidence interval
    Statistical analysis title
    Unstratified Hazard Ratio - Log Rank p-value
    Statistical analysis description
    Cox regression model was used to determine the hazard ratio.
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0202
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.225
         upper limit
    0.9

    Secondary: Percentage of Participants Who Died (Data Cutoff 25 January 2013)

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    End point title
    Percentage of Participants Who Died (Data Cutoff 25 January 2013)
    End point description
    ITT Population: All participants randomized to study treatment, irrespective of whether or not the assigned treatment was actually received.
    End point type
    Secondary
    End point timeframe
    Screening Visit, Every 8 weeks (or 9 weeks if receiving topotecan) until progression reported between day of first participant randomized (29 October 2009) until cutoff date of 25 January 2013
    End point values
    Chemotherapy Chemotherapy + Bevacizumab
    Number of subjects analysed
    182
    179
    Units: percentage of participants
        number (not applicable)
    75.8
    71.5
    No statistical analyses for this end point

    Secondary: Overall Survival (Data Cutoff 25 January 2013)

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    End point title
    Overall Survival (Data Cutoff 25 January 2013)
    End point description
    Duration of overall survival was defined as the time from randomization to death of any cause. Kaplan-Meier methodology was used. The OS data for participants for whom no death was captured in the clinical database were censored at the last time they were known to be alive. ITT Population; only participants who died were included in the analysis. 95% CI was computed using the method of Brookmeyer and Crowley.
    End point type
    Secondary
    End point timeframe
    Screening Visit, Every 8 weeks (or 9 weeks if receiving topotecan) until progression reported between day of first participant randomized (29 October 2009) until cutoff date of 25 January 2013
    End point values
    Chemotherapy Chemotherapy + Bevacizumab
    Number of subjects analysed
    138
    128
    Units: months
        median (confidence interval 95%)
    13.3 (11.89 to 16.43)
    16.6 (13.70 to 18.99)
    Statistical analysis title
    Unstratified Hazard Ratio - Log Rank p-value
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.136
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.833
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.655
         upper limit
    1.059
    Statistical analysis title
    Unstratified Peto-Peto-Prentice p-value
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0715
    Method
    Peto-Peto-Prentice
    Confidence interval
    Statistical analysis title
    Stratified Hazard Ratio - Log Rank p-value
    Statistical analysis description
    Stratified analysis: Strata were: chemotherapy selected (paclitaxel, PLD, or topotecan), prior anti-angiogenic therapy (yes or no), and platinum-free interval (<3 or 3-6 months).
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2711
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.678
         upper limit
    1.116
    Statistical analysis title
    Stratified Peto-Peto-Prentice p-value
    Statistical analysis description
    Stratified analysis: Strata were: chemotherapy selected (paclitaxel, PLD, or topotecan), prior anti-angiogenic therapy (yes or no), and platinum-free interval (<3 or 3-6 months).
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.089
    Method
    Peto-Peto-Prentice
    Confidence interval

    Secondary: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Ovarian (OV) 28 Abdominal/Gastrointestinal (AB/GI) Symptom Scale - Percentage of Responders (Data Cutoff 14 November 2011)

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    End point title
    European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Ovarian (OV) 28 Abdominal/Gastrointestinal (AB/GI) Symptom Scale - Percentage of Responders (Data Cutoff 14 November 2011)
    End point description
    The EORTC OV-28 module is a questionnaire that focuses on issues specific to ovarian cancer Participants were asked to indicate the extent to which they experienced AB/GI symptoms in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following: Did you have abdominal pain? Did you have a bloated feeling in your abdomen/stomach? Did you have problems with your clothes feeling too tight? Did you experience any change in bowel habit due to your disease or treatment? Were you troubled by passing wind/gas/flatulence? Have you felt full too quickly after beginning to eat? Have you had indigestion/heartburn? Data are transformed to a scale from 0 to 100. Lower scores represent fewer symptoms. Participants were considered a responder if they had a 10 point or more reduction in score from baseline. ITT population; n indicates the number of participants who completed the questionnaire at the specified visit.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 8, 9, 16, 18, 24 and 30 (Data Cutoff 14 November 2011)
    End point values
    Chemotherapy Chemotherapy + Bevacizumab
    Number of subjects analysed
    84
    122
    Units: percentage of participants
    number (confidence interval 95%)
        Weeks 8/9 (n=84,122)
    19.0 (11.3 to 29.1)
    27.9 (20.1 to 36.7)
        Weeks 16/18 (n=43,86)
    23.3 (11.8 to 38.6)
    26.7 (17.8 to 37.4)
        Week 24 (n=22,53)
    22.7 (7.8 to 45.4)
    32.1 (19.9 to 46.3)
        Week 30 (n=12,42)
    33.3 (9.9 to 65.1)
    28.6 (15.7 to 44.6)
    Statistical analysis title
    Responders at Baseline versus Week 8/9
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1859
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    8.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    21.4
    Statistical analysis title
    Responders at Baseline versus Week 16/18
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.8309
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14
         upper limit
    20.9
    Statistical analysis title
    Responders at Baseline versus Week 24
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.579
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    9.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15
         upper limit
    34.1
    Statistical analysis title
    Responders at Baseline versus Week 30
    Comparison groups
    Chemotherapy v Chemotherapy + Bevacizumab
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7339
    Method
    Fisher exact
    Parameter type
    Difference in Response Rates
    Point estimate
    -4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40
         upper limit
    30.6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded at every treatment visit and all follow-up visits until 2 months after the final follow-up visit (up to approximately 4 years).
    Adverse event reporting additional description
    AEs: Safety population: all treated up to 25Jan2013 CCOD. Additional AEs: 26Jan2013 to 09Jul1014 in the primary study period: no SAEs; 8 Grade 2-3 AEs (blurred vision, fatigue, bronchitis, gastroenteritis, dehydration, proteinuria, hypertension, hyponatremia) in 4 subjects in the CT+BV arm. Deaths (all causes): ITT population up to 09Jul2014 CCOD.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Participants received one of the following chemotherapies at the discretion of the investigator: paclitaxel, 80 mg/m^2 as a 1-hour IV infusion on Days 1, 8, 15, and 22 q4w OR topotecan 4 mg/m^2 as a 30-minute IV infusion on Days 1, 8, and 15 q4w (alternatively, a 1.25 mg/m^2 dose could have been administered over 30 minutes on Days 1-5 q3w) OR PLD 40 mg/m^2 as a 1 mg/min infusion on Day 1 q4w (after Cycle 1 the drug could have been administered as a 1 hour infusion). Depending on chosen chemotherapy, pre-medication was implemented according to local practices.

    Reporting group title
    Chemotherapy + Bevacizumab
    Reporting group description
    Participants received one of the following chemotherapies at the discretion of the investigator: paclitaxel, 80 mg/m^2 as a 1-hour IV infusion on Days 1, 8, 15, and 22 q4w OR topotecan 4 mg/m^2 as a 30-minute IV infusion on Days 1, 8, and 15 q4w (alternatively, a 1.25 mg/m^2 dose could have been administered over 30 minutes on Days 1-5 q3w) OR PLD 40 mg/m^2 as a 1 mg/min infusion on Day 1 q4w (after Cycle 1 the drug could have been administered as a 1 hour infusion). Depending on chosen chemotherapy, pre-medication was implemented according to local practices. The chosen chemotherapy was combined with bevacizumab 10 mg/kg IV q2w (or bevacizumab 15 mg/kg q3w if used in combination with topotecan 1.25 mg/m^2 on Days 1-5 on a q3w schedule). The initial bevacizumab infusion was over 90 minutes, with subsequent infusions over 60 minutes and then 30 minutes, as tolerated.

    Serious adverse events
    Chemotherapy Chemotherapy + Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 181 (27.07%)
    56 / 179 (31.28%)
         number of deaths (all causes)
    152
    144
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 181 (0.00%)
    4 / 179 (2.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Venous thrombosis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cytoreductive surgery
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Food allergy
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 181 (1.66%)
    3 / 179 (1.68%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 181 (0.55%)
    3 / 179 (1.68%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Fatigue
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site necrosis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General symptom
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Wrong drug administered
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 181 (1.66%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 181 (2.76%)
    4 / 179 (2.23%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pleural effusion
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 181 (2.76%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 181 (2.76%)
    4 / 179 (2.23%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 181 (1.10%)
    4 / 179 (2.23%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    6 / 181 (3.31%)
    4 / 179 (2.23%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 181 (1.10%)
    3 / 179 (1.68%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 181 (3.87%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic ascites
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         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 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal stenosis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Vesical fistula
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (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
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (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
    Skin ulcer
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone disorder
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 181 (1.10%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious peritonitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Postoperative wound infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (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
    Chemotherapy Chemotherapy + Bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    129 / 181 (71.27%)
    146 / 179 (81.56%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 181 (5.52%)
    32 / 179 (17.88%)
         occurrences all number
    10
    43
    Investigations
    Weight decreased
         subjects affected / exposed
    5 / 181 (2.76%)
    11 / 179 (6.15%)
         occurrences all number
    5
    11
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 181 (0.00%)
    9 / 179 (5.03%)
         occurrences all number
    0
    9
    Dyspnoea
         subjects affected / exposed
    9 / 181 (4.97%)
    10 / 179 (5.59%)
         occurrences all number
    9
    12
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    46 / 181 (25.41%)
    35 / 179 (19.55%)
         occurrences all number
    74
    54
    Leukopenia
         subjects affected / exposed
    25 / 181 (13.81%)
    23 / 179 (12.85%)
         occurrences all number
    41
    49
    Neutropenia
         subjects affected / exposed
    44 / 181 (24.31%)
    55 / 179 (30.73%)
         occurrences all number
    78
    171
    Thrombocytopenia
         subjects affected / exposed
    12 / 181 (6.63%)
    10 / 179 (5.59%)
         occurrences all number
    23
    20
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    13 / 181 (7.18%)
    32 / 179 (17.88%)
         occurrences all number
    17
    35
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    10 / 181 (5.52%)
    23 / 179 (12.85%)
         occurrences all number
    16
    25
    Fatigue
         subjects affected / exposed
    46 / 181 (25.41%)
    49 / 179 (27.37%)
         occurrences all number
    57
    66
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 181 (2.21%)
    9 / 179 (5.03%)
         occurrences all number
    4
    10
    Abdominal pain
         subjects affected / exposed
    15 / 181 (8.29%)
    17 / 179 (9.50%)
         occurrences all number
    16
    23
    Diarrhoea
         subjects affected / exposed
    10 / 181 (5.52%)
    17 / 179 (9.50%)
         occurrences all number
    17
    26
    Constipation
         subjects affected / exposed
    17 / 181 (9.39%)
    13 / 179 (7.26%)
         occurrences all number
    21
    14
    Nausea
         subjects affected / exposed
    13 / 181 (7.18%)
    17 / 179 (9.50%)
         occurrences all number
    17
    19
    Vomiting
         subjects affected / exposed
    15 / 181 (8.29%)
    14 / 179 (7.82%)
         occurrences all number
    21
    17
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 181 (0.55%)
    22 / 179 (12.29%)
         occurrences all number
    1
    42
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    11 / 181 (6.08%)
    15 / 179 (8.38%)
         occurrences all number
    11
    15
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    9 / 181 (4.97%)
    19 / 179 (10.61%)
         occurrences all number
    10
    20
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 181 (7.73%)
    10 / 179 (5.59%)
         occurrences all number
    19
    12
    Infections and infestations
    Infection
         subjects affected / exposed
    6 / 181 (3.31%)
    19 / 179 (10.61%)
         occurrences all number
    8
    22
    Urinary tract infection
         subjects affected / exposed
    13 / 181 (7.18%)
    15 / 179 (8.38%)
         occurrences all number
    17
    20

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Nov 2009
    The definition of platinum resistance was made more specific: progression within < 6 months from completion of a minimum of 4 platinum therapy cycles, with the date calculated from the last administered dose of platinum therapy. The definition of prior therapies was clarified to include all previous anti-cancer therapy, including those received in the front-line or recurrent settings. It was clarified that it was not a requirement in RECIST for the same investigator to evaluate the participant at each assessment. The statistical analysis for the primary endpoint was updated from a one- to a two-sided log-rank test. The numbers of participants randomized to chemotherapy cohorts was amended because of statistical changes to include 120 participants per chemotherapy cohort. The timing of QoL assessments was amended to be more suited to the scheduling of cycle visits, the 3 worst symptom questionnaire was collected at baseline only, and the use of the 3 worst symptom questionnaire methodology was described in more detail. The protocol was updated so that all Grade 2 adverse events were collected. It was clarified how a participant who had been previously enrolled in a blinded study with an anti-angiogenic was to be stratified. The frequency of CA-125 assessments was corrected to be performed every cycle, not at every visit. It was clarified that the “optional post-study phase” for participants randomized to the CT arm was for the CT arm only and that bevacizumab was to be given as part of the study to those participants who opted to receive crossover bevacizumab monotherapy. Additional safety guidance was provided for the management of bevacizumab in the event of CNS bleeding, proteinuria management, and hypersensitivity with paclitaxel. The definition of residual disease was amended based on the presence or absence of macroscopic disease. Definitions of progression for participants with measurable and non-measurable disease at randomization were further detailed.
    28 Oct 2010
    Clarification regarding the exclusion criteria for platinum refractory disease, peripheral neuropathy, and previous malignancies. Addition of left ventricular ejection fraction (LVEF) assessments every fourth cycle for participants receiving pegylated liposomal doxorubicin (PLD). Additional requirement to capture certain concomitant medication in the electronic Case Report Form (eCRF), particularly supportive medication prescribed for the treatment of cancer-related symptoms or potential side effects of chemotherapy. Clarification that only serious adverse events caused by protocol-mandated interventions needed to be collected prior to initiation of study medication and that all serious adverse events needed to be collected before, during, and after study drug dosing. Guidance on dose modification to reflect the bevacizumab safety profile. Clarification to ensure that only those participants who experienced disease progression on chemotherapy alone were able to subsequently receive bevacizumab on the bevacizumab crossover option.
    23 Jan 2013
    Allow for a potential retrospective scan collection and a review of scans by an independent review committee (IRC). Clarify that the duration of survival follow-up should continue for a minimum of 12 months after end of treatment for all participants.
    05 Dec 2013
    The amendment defined that the study would be closed as soon as the protocol amendment was approved by regulatory authorities and Ethics Committees. The amendment clarified that participants who were still receiving investigational study medication (bevacizumab) would end their AURELIA study participation. If the Avastin Long Term Extension study (AvaLTE, MO25757) was approved in the participant’s country, the participant would be offered participation in this study. Alternatively the participant would be offered continued bevacizumab treatment with commercial drug until disease progression, unacceptable toxicity or participant request for discontinuation as initially planned by the protocol.

    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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