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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Pegfilgrastim Administered to Subjects With Newly Diagnosed, Locally-advanced or Metastatic Colorectal Cancer Treated With Bevacizumab and Either 5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX) or 5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI)

    Summary
    EudraCT number
    		 2009-011899-30
    Trial protocol
    		 LV   HU   CZ   BE   IE   IT   FR   SK   BG  
    Global end of trial date
    02 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2016
    First version publication date
    25 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20080259
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00911170
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    02 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the efficacy of pegfilgrastim, as compared with placebo in reducing the incidence of grade 3/4 febrile neutropenia in subjects with newly diagnosed, locally-advanced or metastatic colorectal cancer (mCRC) treated with bevacizumab and either FOLFOX or FOLFIRI. This study will also investigate the effect of adding pegfilgrastim to bevacizumab and either FOLFOX or FOLFIRI on overall survival, progression-free survival, and overall response rate.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The protocol, informed consent form (ICF), other written subject information were submitted to the Independent Ethics Committee / Institutional Review Board for written approval. Written approval of the protocol and ICF were received by Amgen before recruitment of subjects into the study and shipment of the investigational product (IP). Informed consent forms were signed by the subject or a legally acceptable representative and by the person who conducted the informed consent discussion.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Nov 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 124
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Australia: 27
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    Bulgaria: 25
    Country: Number of subjects enrolled
    Czech Republic: 87
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Hungary: 162
    Country: Number of subjects enrolled
    Ireland: 35
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Latvia: 65
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Poland: 74
    Country: Number of subjects enrolled
    Romania: 27
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    Slovakia: 13
    Country: Number of subjects enrolled
    Ukraine: 82
    Worldwide total number of subjects
    847
    EEA total number of subjects
    549
    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)
    534
    From 65 to 84 years
    311
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first participant was enrolled into the study on 03 November 2009 and the last participant on 03 January 2012 at 114 centers worldwide. This study included a study treatment period (approximately 8 weeks), and a long-term follow-up period (up to 36 months after the last subject enrolled).

    Pre-assignment
    Screening details
    		 A total of 1038 subjects were screened, 191 screen-failed and and 847 subjects were enrolled. Randomization was stratified by region (North America vs Rest of World), subject disease status (locally-advanced vs metastatic), and chemotherapy regimen (bevacizumab plus FOLFOX vs bevacizumab plus FOLFIRI).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle, plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered as a single subcutaneous injection

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg by intravenous (IV) infusion on day 1 of each 14-day cycle.

    Investigational medicinal product name
    Standard Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each participant received one of the following chemotherapy regimens at the discretion of treating physician: FOLFOX: Oxaliplatin, leucovorin, and 5-fluorouracil; FOLFIRI: Irinotecan, leucovorin and 5-flurouracil.

    Arm title
    		 Pegfilgrastim
    Arm description
    		 Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2 and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus pegfilgrastim 6 mg administered as a single subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Pegfilgrastim
    Investigational medicinal product code
    Other name
    Neulasta®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered as a single 6 mg subcutaneous injection

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg by intravenous (IV) infusion on day 1 of each 14-day cycle.

    Investigational medicinal product name
    Standard Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each participant received one of the following chemotherapy regimens at the discretion of treating physician: FOLFOX: Oxaliplatin, leucovorin, and 5-fluorouracil; FOLFIRI: Irinotecan, leucovorin and 5-flurouracil.

    Number of subjects in period 1
    		Placebo Pegfilgrastim
    Started
    424
    423
    Received chemotherapy
    423
    422
    Received bevacizumab
    423
    420
    Received investigational product
    422
    419
    Completed
    397
    386
    Not completed
    27
    37
         Adverse event, serious fatal
    6
    9
         Randomized in error
    1
    1
         Consent withdrawn by subject
    4
    4
         Physician decision
    5
    5
         Disease progression
    -
    2
         Adverse event, non-fatal
    9
    10
         Protocol deviation
    1
    2
         Ineligibility determined
    1
    3
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle, plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.

    Reporting group title
    Pegfilgrastim
    Reporting group description
    		 Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2 and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus pegfilgrastim 6 mg administered as a single subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.

    Reporting group values
    		 Placebo Pegfilgrastim Total
    Number of subjects
    		 424 423 847
    Age categorical
    Units: Subjects
        < 65 years
    		 267 267 534
        ≥ 65 years
    		 157 156 313
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.6 ± 10.7 60.7 ± 10.4 -
    Gender, Male/Female
    Units: participants
        Female
    		 159 174 333
        Male
    		 265 249 514
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 3 2 5
        Black or African American
    		 6 4 10
        Hispanic or Latino
    		 8 11 19
        Japanese
    		 0 2 2
        Native Hawaiian or Other Pacific Islander
    		 2 0 2
        White
    		 405 403 808
    Chemotherapy Regimen
    Units: Subjects
        FOLFOX
    		 207 207 414
        FOLFIRI
    		 217 216 433
    Region
    North America (Canada and the US) and the Rest of World (Australia, Belgium, Bulgaria, Czech Republic, France, Hungary, Ireland, Italy, Latvia, Mexico, Poland, Romania, Russian Federation, Slovakia, and Ukraine)
    Units: Subjects
        North America
    		 79 78 157
        Rest of World
    		 345 345 690
    Disease Status
    Units: Subjects
        Locally Advanced
    		 18 18 36
        Metastatic
    		 406 405 811
    Primary Tumor Diagnosis
    Units: Subjects
        Colon
    		 284 291 575
        Rectum
    		 139 132 271
        Missing
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle, plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.

    Reporting group title
    Pegfilgrastim
    Reporting group description
    		 Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2 and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus pegfilgrastim 6 mg administered as a single subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). During the long-term follow-up period, further chemotherapy and/or biologic agents (for example, bevacizumab) were to continue at the discretion of the treating physician.

    Primary: Percentage of Participants with Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy

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    End point title
    		 Percentage of Participants with Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy
    End point description
    Grade 3/4 febrile neutropenia (FN) is defined as: • A temperature ≥ 38.0°C (≥ 100.4°F) and absolute neutrophil count (ANC) < 1.0 × 10^9/L, where ANC was measured the same day or within ± 1 calendar day of a temperature ≥ 38.0°C (≥ 100.4°F), or • An ANC < 1.0 × 10^9/L in combination with: – documented sepsis or infection, OR – neutropenia-related hospitalization where ANC was measured the same day or within ± 1 calendar day. Participants monitored their oral temperatures and maintained diaries to record their temperature twice per day: once in the morning and once in the evening, as well as whenever they suspect they had fever throughout the first 4 cycles of chemotherapy treatment. This analysis was performed in the primary analysis set which included all participants with a signed informed consent, and who were randomized and received at least 1 dose of protocol-specified study treatment (chemotherapy, bevacizumab, or investigational product).
    End point type
    Primary
    End point timeframe
    Approximately 2 months duration (daily for 4 cycles of treatment; 2 weeks per cycle)
    End point values
    		 Placebo Pegfilgrastim
    Number of subjects analysed
    423
    422
    Units: percentage of participants
        number (confidence interval 95%)
    5.7 (3.7 to 8.3)
    2.4 (1.1 to 4.3)
    Statistical analysis title
    		 Analysis of Grade 3/4 Febrile Neutropenia
    Statistical analysis description
    The Cochran-Mantel-Haenszel (CMH) test, stratified by the IVRS-recorded randomization factors (geographic region, disease stage, and chemotherapy), was used to test the difference between treatment arms in the proportion of subjects who experienced grade 3/4 FN during the treatment period. The odds ratio (pegfilgrastim to placebo) is adjusted for the randomization stratification factors. An OR < 1.0 indicates a lower event rate for the pegfilgrastim arm relative to the placebo arm.
    Comparison groups
    Placebo v Pegfilgrastim
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.014 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.86
    Notes
    [1] - The primary hypothesis was that the percentage of participants treated with study chemotherapy and bevacizumab who experience grade 3/4 febrile neutropenia (FN) would be lower in participants randomized to the pegfilgrastim arm compared to placebo arm. The study was designed to have at least 90% power at the 2-sided 0.05 significance level to detect a 6% difference in incidence of grade 3/4 FN from 9% to 3%, which is approximately a 66.7% relative reduction.
    [2] - The p-value is adjusted for the randomization stratification factors (chemotherapy regimen, geographic region, disease stage).

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Median time from randomization to date of death caclulated using the Kaplan-Meier method. Participants were censored on the date of last contact (i.e., the date the participant was last known to be alive) if they were not known to have died.
    End point type
    Secondary
    End point timeframe
    From randomization to the end of study. Median time on study was 21.4 months and the maximum was 57.9 months.
    End point values
    		 Placebo Pegfilgrastim
    Number of subjects analysed
    423
    422
    Units: months
        median (confidence interval 95%)
    23.1 (21.2 to 24.6)
    24 (21.6 to 26.3)
    Statistical analysis title
    		 Analysis of Overall Survival
    Statistical analysis description
    Hazard ratio for treatment is estimated based on Cox proportional Hazard model stratified by the stratification factors at randomization. Stratification factors are: chemotherapy regimen (FOLFOX vs. FOLFIRI); region (North America vs. Rest of World) and disease status (Metastatic vs. Locally Advanced). A hazard ratio < 1.0 indicates a lower average event rate and a longer survival time for the pegfilgrastim arm relative to the placebo arm.
    Comparison groups
    Placebo v Pegfilgrastim
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.398 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.09
    Notes
    [3] - P-value based on the log-rank test statistic from the Kaplan-Meier survival analysis stratified by the 3 randomization factors.

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Time from randomization to the date of radiological disease progression or death from any cause, whichever event occurs first, calculated using the Kaplan-Meier method. Participants without either event by the analysis data cutoff date were censored on the date of their last evaluable disease assessment. Disease progression based on the investigator’s assessment of radiographic scans using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Clinical progression without radiological assessment was not be considered a disease progression in this analysis. Progression defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
    End point type
    Secondary
    End point timeframe
    From randomization to the end of study. Median time on study was 21.4 months and the maximum was 57.9 months.
    End point values
    		 Placebo Pegfilgrastim
    Number of subjects analysed
    423
    422
    Units: months
        median (confidence interval 95%)
    10.4 (9.5 to 11.1)
    10.6 (9.4 to 11.2)
    Statistical analysis title
    		 Analysis of Progression-free Survival
    Statistical analysis description
    Hazard ratio for treatment is estimated based on Cox proportional Hazard model stratified by 3 stratification factors at randomization. Stratification factors are: chemotherapy regimen (FOLFOX vs. FOLFIRI); region (North America vs. Rest of World) and disease status (Metastatic vs. Locally Advanced). A hazard ratio < 1.0 indicates a lower average event rate and a longer survival time for the pegfilgrastim arm relative to the placebo arm.
    Comparison groups
    Placebo v Pegfilgrastim
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.224 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.06
    Notes
    [4] - P-value based on the log-rank test statistic from the Kaplan-Meier survival analysis stratified by the 3 randomization factors.

    Secondary: Time to Progression

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    End point title
    		 Time to Progression
    End point description
    Time from randomization to date of radiological disease progression calculated using the Kaplan-Meier method. Participants without progression were censored on the date of their last radiographic tumor assessment. Disease progression based on the investigator’s assessment of scans using the RECIST v1.1. Clinical progression without radiological assessment was not considered a disease progression. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
    End point type
    Secondary
    End point timeframe
    From randomization to the end of study. Median time on study was 21.4 months and the maximum was 57.9 months.
    End point values
    		 Placebo Pegfilgrastim
    Number of subjects analysed
    423
    422
    Units: months
        median (confidence interval 95%)
    12.5 (11.1 to 12.7)
    12.1 (11 to 12.7)
    Statistical analysis title
    		 Analysis of Time to Progression
    Statistical analysis description
    Hazard ratio, stratified by randomization stratification factors at baseline, is estimated based on the proportional subdistribution hazards model proposed by Fine and Gray (1999). Stratification factors are: chemotherapy regimen (FOLFOX vs. FOLFIRI); region (North America vs. Rest of World) and disease status (Metastatic vs. Locally Advanced). A hazard ratio < 1.0 indicates a lower average event rate and a longer survival time for the pegfilgrastim arm relative to the placebo arm.
    Comparison groups
    Placebo v Pegfilgrastim
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.861 [5]
    Method
    		 Fine and Gray Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.15
    Notes
    [5] - Stratified by randomization stratification factors

    Secondary: Percentage of Participants with an Objective Response

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    End point title
    		 Percentage of Participants with an Objective Response
    End point description
    The percentage of participants with a complete response (CR) or partial response (PR) defined by the RECIST v1.1 criteria at any time during the study. Response was determined by the investigator’s assessment of radiographic scans. CR: Disappearance of all non-nodal target lesions and the disappearance of all non-nodal non-target lesions, and no new lesions. All nodal lesions must have reduction of short axis to < 10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters and no new lesions and/or unequivocal progression of existing non-target lesions, or, the disappearance of all non-nodal target lesions with persistence of one or more non-target lesion(s).
    End point type
    Secondary
    End point timeframe
    From randomization to the end of study. Median time on study was 21.4 months and the maximum was 57.9 months.
    End point values
    		 Placebo Pegfilgrastim
    Number of subjects analysed
    420 [6]
    420 [7]
    Units: percentage of participants
        number (confidence interval 95%)
    57.6 (52.7 to 62.4)
    61 (56.1 to 65.6)
    Notes
    [6] - Subjects with measurable disease at baseline
    [7] - Subjects with measurable disease at baseline
    Statistical analysis title
    		 Analysis of Objective Response
    Statistical analysis description
    Odds ratio (OR) adjusted for the randomization stratification factors. An OR > 1.0 indicates a higher event rate for the pegfilgrastim arm relative to the placebo arm.
    Comparison groups
    Placebo v Pegfilgrastim
    Number of subjects included in analysis
    840
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.33 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.51
    Notes
    [8] - The p-value is from the Cochran Mantel Haenszel (CMH) test adjusting for the randomization stratification factors.

    Secondary: Percentage of Participants with Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy

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    End point title
    		 Percentage of Participants with Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy
    End point description
    Grade 4 febrile neutropenia (FN) is defined as: • A temperature ≥ 38.0ºC (≥ 100.4ºF) and absolute neutrophil count (ANC) < 0.5 × 10^9/L, where ANC is measured the same day or within +/- 1 calendar day of a temperature ≥ 38.0ºC (≥ 100.4ºF), or • An ANC < 0.5 × 10^9/L in combination with: o Documented sepsis or infection, OR o Neutropenia-related hospitalization where ANC is measured the same day or within +/- 1 calendar day.
    End point type
    Secondary
    End point timeframe
    Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)
    End point values
    		 Placebo Pegfilgrastim
    Number of subjects analysed
    423
    422
    Units: percentage of participants
        number (confidence interval 95%)
    3.5 (2 to 5.8)
    2.4 (1.1 to 4.3)
    Statistical analysis title
    		 Analysis of Grade 4 Febrile Neutropenia
    Statistical analysis description
    Odds ratio (OR) adjusted for the randomization stratification factors. An OR < 1.0 indicates a lower event rate for the pegfilgrastim arm relative to the placebo arm.
    Comparison groups
    Placebo v Pegfilgrastim
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.312 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.49
    Notes
    [9] - The study was not planned nor adequately powered to test the secondary endpoints for statistical significance. Therefore, estimations of these secondary endpoints were provided without formal hypothesis testing; p-values are nominal.
    [10] - The p-value is from the Cochran Mantel Haenszel (CMH) test adjusting for the randomization stratification factors.

    Secondary: Percentage of Participants with Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy

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    End point title
    		 Percentage of Participants with Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy
    End point description
    Grade 3/4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) < 1.0 x 10^9/L.
    End point type
    Secondary
    End point timeframe
    Approximately 2 months duration (daily for 4 cycles of treatment; 2 weeks per cycle)
    End point values
    		 Placebo Pegfilgrastim
    Number of subjects analysed
    423
    422
    Units: percentage of participants
        number (confidence interval 95%)
    17 (13.6 to 20.9)
    3.6 (2 to 5.8)
    Statistical analysis title
    		 Analysis of Grade 3/4 Severe Neutropenia
    Statistical analysis description
    Odds ratio (OR) adjusted for the randomization stratification factors. An OR < 1.0 indicates a lower event rate for the pegfilgrastim arm relative to the placebo arm.
    Comparison groups
    Placebo v Pegfilgrastim
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.32
    Notes
    [11] - The p-value is from the Cochran Mantel Haenszel (CMH) test adjusting for the randomization stratification factors.

    Secondary: Percentage of Participants with Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy

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    End point title
    		 Percentage of Participants with Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy
    End point description
    Grade 4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) < 0.5 x 10^9/L.
    End point type
    Secondary
    End point timeframe
    Approximately 2 months duration (daily for 4 cycles of treatment; 2 weeks per cycle)
    End point values
    		 Placebo Pegfilgrastim
    Number of subjects analysed
    423
    422
    Units: percentage of participants
        number (confidence interval 95%)
    8.3 (5.8 to 11.3)
    2.4 (1.1 to 4.3)
    Statistical analysis title
    		 Analysis of Grade 4 Severe Neutropenia
    Statistical analysis description
    Odds ratio (OR) adjusted for the randomization stratification factors. An OR < 1.0 indicates a lower event rate for the pegfilgrastim arm relative to the placebo arm.
    Comparison groups
    Placebo v Pegfilgrastim
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.56
    Notes
    [12] - The p-value is from the Cochran Mantel Haenszel (CMH) test adjusting for the randomization stratification factors.

    Secondary: Number of Participants With Adverse Events (AEs)

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    End point title
    		 Number of Participants With Adverse Events (AEs)
    End point description
    A serious adverse event (SAE) is defined as an adverse event that - is fatal; - is life threatening (places the participant at immediate risk of death); - requires inpatient hospitalization or prolongation of existing hospitalization; - results in persistent or significant disability/incapacity; - is a congenital anomaly/birth defect; - other significant medical hazard. AEs were assessed for severity according to National Cancer Institute, Common Terminology Criteria for Adverse Events, Version 3.0, based on this general guideline: Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to AE.
    End point type
    Secondary
    End point timeframe
    Approximately 8 weeks (4 treatment cycles)
    End point values
    		 Placebo Pegfilgrastim
    Number of subjects analysed
    421
    420
    Units: participants
    number (not applicable)
        Any adverse event
    355
    344
        Worst Grade of ≥ 2
    254
    240
        Worst Grade of ≥ 3
    119
    115
        Worst Grade of ≥ 4
    45
    31
        Serious adverse events
    55
    68
        Severe adverse events
    103
    106
        Life-threatening adverse events
    43
    27
        Fatal adverse events
    11
    10
        Leading to discontinuation of IP
    1
    3
        Leading to discontinuation from study treatment
    9
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 8 weeks (4 treatment cycles)
    Adverse event reporting additional description
    All participants in the Primary Analysis Set who received at least 1 dose of investigational product were included in the safety analysis set. One participant was randomized to the placebo arm but actually received pegfilgrastim and is included in the pegfilgrastim arm for the safety analyses.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, plus bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).

    Reporting group title
    Pegfilgrastim
    Reporting group description
    		 Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2 and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus pegfilgrastim 6 mg administered as a single subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4).

    Serious adverse events
    		 Placebo Pegfilgrastim
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 421 (13.06%)
    68 / 420 (16.19%)
         number of deaths (all causes)
    116
    120
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour necrosis
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 421 (0.71%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 421 (0.24%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis deep
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 421 (0.00%)
    3 / 420 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 421 (0.24%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 421 (0.48%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 421 (0.48%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Local swelling
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (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
    1 / 421 (0.24%)
    0 / 420 (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 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 421 (0.95%)
    5 / 420 (1.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 421 (0.24%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 421 (0.71%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 421 (0.48%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 421 (0.24%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 421 (0.24%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 421 (0.24%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granulocytopenia
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 421 (0.24%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 421 (0.95%)
    3 / 420 (0.71%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 421 (0.71%)
    5 / 420 (1.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 421 (0.00%)
    3 / 420 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic stenosis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 421 (0.24%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 421 (1.19%)
    10 / 420 (2.38%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 421 (0.00%)
    4 / 420 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal fistula
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 421 (0.48%)
    3 / 420 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    2 / 421 (0.48%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Nausea
         subjects affected / exposed
    1 / 421 (0.24%)
    3 / 420 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    3 / 421 (0.71%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 421 (0.24%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 421 (0.24%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    3 / 421 (0.71%)
    4 / 420 (0.95%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 421 (0.00%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal failure
         subjects affected / exposed
    1 / 421 (0.24%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess rupture
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (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
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candidiasis
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (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
    2 / 421 (0.48%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 421 (0.24%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 421 (0.48%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral fungal infection
         subjects affected / exposed
    1 / 421 (0.24%)
    0 / 420 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 421 (0.00%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         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 / 421 (0.24%)
    4 / 420 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 421 (0.48%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 421 (0.48%)
    2 / 420 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 421 (0.71%)
    5 / 420 (1.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 421 (0.24%)
    4 / 420 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 421 (0.00%)
    1 / 420 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Pegfilgrastim
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    307 / 421 (72.92%)
    290 / 420 (69.05%)
    Investigations
    Weight decreased
         subjects affected / exposed
    18 / 421 (4.28%)
    25 / 420 (5.95%)
         occurrences all number
    21
    27
    Vascular disorders
    Hypertension
         subjects affected / exposed
    25 / 421 (5.94%)
    33 / 420 (7.86%)
         occurrences all number
    29
    38
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 421 (4.99%)
    21 / 420 (5.00%)
         occurrences all number
    25
    22
    Neuropathy peripheral
         subjects affected / exposed
    24 / 421 (5.70%)
    28 / 420 (6.67%)
         occurrences all number
    27
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 421 (4.75%)
    31 / 420 (7.38%)
         occurrences all number
    25
    42
    Neutropenia
         subjects affected / exposed
    115 / 421 (27.32%)
    30 / 420 (7.14%)
         occurrences all number
    206
    36
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    33 / 421 (7.84%)
    30 / 420 (7.14%)
         occurrences all number
    42
    37
    Fatigue
         subjects affected / exposed
    63 / 421 (14.96%)
    67 / 420 (15.95%)
         occurrences all number
    87
    101
    Pyrexia
         subjects affected / exposed
    30 / 421 (7.13%)
    55 / 420 (13.10%)
         occurrences all number
    37
    79
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    19 / 421 (4.51%)
    24 / 420 (5.71%)
         occurrences all number
    22
    30
    Constipation
         subjects affected / exposed
    45 / 421 (10.69%)
    44 / 420 (10.48%)
         occurrences all number
    52
    52
    Diarrhoea
         subjects affected / exposed
    103 / 421 (24.47%)
    105 / 420 (25.00%)
         occurrences all number
    147
    177
    Nausea
         subjects affected / exposed
    91 / 421 (21.62%)
    113 / 420 (26.90%)
         occurrences all number
    119
    160
    Stomatitis
         subjects affected / exposed
    24 / 421 (5.70%)
    9 / 420 (2.14%)
         occurrences all number
    33
    13
    Vomiting
         subjects affected / exposed
    45 / 421 (10.69%)
    46 / 420 (10.95%)
         occurrences all number
    53
    54
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    23 / 421 (5.46%)
    30 / 420 (7.14%)
         occurrences all number
    25
    33
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    17 / 421 (4.04%)
    23 / 420 (5.48%)
         occurrences all number
    17
    24
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    13 / 421 (3.09%)
    22 / 420 (5.24%)
         occurrences all number
    15
    22
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    31 / 421 (7.36%)
    39 / 420 (9.29%)
         occurrences all number
    33
    52
    Hypokalaemia
         subjects affected / exposed
    15 / 421 (3.56%)
    31 / 420 (7.38%)
         occurrences all number
    17
    37

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2011
    The protocol was updated to include that subjects were required to maintain diaries to record their temperature. The eCRF was also updated to create a field for patient-reported temperature recording. The definition of grade 3/4 FN was expanded to ensure all cases of clinical FN were captured. Chemotherapy Dose Adjustments were updated to notify that the subject had to end all study treatments if all components of chemotherapy were suspended for > 6 weeks Exclusion criteria were updated regarding the use of radiosensitizing chemoradiation and implantation of venous device was removed, as it was not safety concern per Avastin® prescribing information. Updated Study Design and Schedule of Assessments to clarify that routine, non- study specific, screening assessments were allowed if they were completed within 28 days of randomization, and the values did not lie outside of the protocol-specified range. Updated Synopsis, Subject enrollment, Study procedures, and Schedule of assessments to specify that randomization was to take place on or before cycle 1, day 1 to ensure all relevant safety data were captured. Clarified definition of CR in protocol 'Appendix F: Guide to using Revised RECIST guideline'. The time period for measuring temperature was updated in Synopsis and Objective to ensure that primary endpoint was correctly identified in cases where data for the time was missing. PTT assessment was replaced and INR range was updated in inclusion criteria and study procedures as PTTs are not a reliable predictor for bleeding diatheses and were not routinely performed nor recommended for patients receiving Avastin®. Also updated inclusion criteria to clarify that if bleeding diathesis was suspected, a bleeding time was to be performed. Updated Study design to clarify that CBC was to be completed within 7 days before initiating study chemotherapy.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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