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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind Study of PF-06439535 Plus Paclitaxel-Carboplatin and Bevacizumab Plus Paclitaxel-Carboplatin for the First-Line Treatment of Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2014-003878-16
    Trial protocol
    		 SK   NL   CZ   DE   ES   PL   HU   GR   HR   IT  
    Global end of trial date
    22 Dec 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 Dec 2018
    First version publication date
    23 May 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    B7391003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the confirmed objective response rate (ORR) by Week 19 following treatment with PF-06439535 in combination with paclitaxel and carboplatin to bevacizumab-EU plus paclitaxel and carboplatin in subjects who had not received previous treatment for advanced non-small cell lung cancer (NSCLC).
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Chile: 10
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Greece: 18
    Country: Number of subjects enrolled
    Hungary: 52
    Country: Number of subjects enrolled
    India: 30
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 19
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    Poland: 40
    Country: Number of subjects enrolled
    Romania: 62
    Country: Number of subjects enrolled
    Russian Federation: 176
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Thailand: 15
    Country: Number of subjects enrolled
    Turkey: 32
    Country: Number of subjects enrolled
    Ukraine: 152
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    719
    EEA total number of subjects
    240
    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)
    456
    From 65 to 84 years
    261
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 719 subjects were enrolled in this study, and 5 of them did not receive any therapy. One (1) additional subject received only chemotherapy, and did not receive blinded bevacizumab.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-06439535
    Arm description
    		 Subjects received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-06439535
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    PF-06439535 was administered on Day 1 of each 21-day cycle. The initial dose was 15 mg/kg delivered over 90 minutes as an intravenous infusion. The length of infusion could be adjusted based on subject's tolerability.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered by intravenous infusion over a minimum of 15 minutes, and could be administered immediately after the paclitaxel infusion had completed. Subjects were administered carboplatin for at least 4 cycles and no more than 6 cycles. Dose reduction was allowed based on occurrence of toxicity. The initial dose was AUC 6, based on subject's pre-existing renal function or renal function and desired platelet nadir.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered at a dose of 200 mg/m*2 by intravenous infusion over 3 hours on Day 1 of each 21-day cycle. In the absence of progressive disease, subjects received paclitaxel treatment for at least 4 cycles but no more than 6 cycles. Dose reduction was allowed based on occurrence of toxicity. Paclitaxel was administered as the first drug when chemotherapy was administered.

    Arm title
    		 Bevacizumab-EU
    Arm description
    		 Subjects received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab-EU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab-EU was administered on Day 1 of each 21-day cycle. The initial dose was 15 mg/kg delivered over 90 minutes as an intravenous infusion. The length of infusion could be adjusted based on subject's tolerability.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered at a dose of 200 mg/m*2 by intravenous infusion over 3 hours on Day 1 of each 21-day cycle. In the absence of progressive disease, subjects received paclitaxel treatment for at least 4 cycles but no more than 6 cycles. Dose reduction was allowed based on occurrence of toxicity. Paclitaxel was administered as the first drug when chemotherapy was administered.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered by intravenous infusion over a minimum of 15 minutes, and could be administered immediately after the paclitaxel infusion had completed. Subjects were administered carboplatin for at least 4 cycles and no more than 6 cycles. Dose reduction was allowed based on occurrence of toxicity. The initial dose was AUC 6, based on subject's pre-existing renal function or renal function and desired platelet nadir.

    Number of subjects in period 1
    		PF-06439535 Bevacizumab-EU
    Started
    358
    361
    Received treatment
    356
    358
    Completed
    193
    188
    Not completed
    165
    173
         Adverse event, serious fatal
    136
    138
         Consent withdrawn by subject
    14
    14
         Randomized but did not receive treatment
    2
    3
         Unspecified
    -
    1
         Lost to follow-up
    10
    15
         Protocol deviation
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PF-06439535
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.

    Reporting group title
    Bevacizumab-EU
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.

    Reporting group values
    		 PF-06439535 Bevacizumab-EU Total
    Number of subjects
    		 358 361 719
    Age, Customized
    Units: Subjects
        18-44 years|
    		 19 17 36
        45-64 years|
    		 198 222 420
        >= 65 years|
    		 141 122 263
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.7 ( 9.5 ) 60.9 ( 8.9 ) -
    Sex/Gender, Customized
    Units: Subjects
        Female|
    		 121 131 252
        Male|
    		 237 230 467
    Race/Ethnicity, Customized
    Units: Subjects
        WHITE|
    		 319 319 638
        BLACK|
    		 3 1 4
        ASIAN|
    		 36 40 76
        OTHER|
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    PF-06439535
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.

    Reporting group title
    Bevacizumab-EU
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.

    Primary: Objective Response Rate (ORR) by Week 19

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    End point title
    		 Objective Response Rate (ORR) by Week 19
    End point description
    ORR: percentage of subjects who achieved complete response (CR) or partial response (PR) by Week 19 based on Response Evaluation Criteria in Solid Tumors v 1.1 which was confirmed by Week 25. A subject achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes decreased to normal size); PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes were normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits. The analysis population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    25 weeks
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    358
    361
    Units: percentage of subjects
        number (confidence interval 95%)
    45.3 (40.01 to 50.57)
    44.6 (39.40 to 49.89)
    Statistical analysis title
    		 Risk difference analysis with 95% CI
    Comparison groups
    PF-06439535 v Bevacizumab-EU
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.6531
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.608
         upper limit
    		 7.9082
    Notes
    [1] - Calculated based on 2-sided Miettinen and Nurminen method without strata for risk difference for confirmed response. EU equivalence margins (95% CI in -13% to 13%).
    Statistical analysis title
    		 Risk ratio analysis with 90% CI
    Comparison groups
    PF-06439535 v Bevacizumab-EU
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0146
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8856
         upper limit
    		 1.1625
    Notes
    [2] - Calculated based on 2-sided Miettinen and Nurminen method without strata for risk ratio for confirmed response. US equivalence margins (90% CI in 0.73 to 1.37).
    Statistical analysis title
    		 Risk ratio analysis with 95% CI
    Comparison groups
    PF-06439535 v Bevacizumab-EU
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0146
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8628
         upper limit
    		 1.1933
    Notes
    [3] - Calculated based on 2-sided Miettinen and Nurminen method without strata for risk ratio for confirmed response. Japan equivalence margins (95% CI in 0.729 to 1.371).

    Secondary: Number of Subjects with Treatment-Emergent Adverse Events

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    End point title
    		 Number of Subjects with Treatment-Emergent Adverse Events
    End point description
    AE: any untoward medical occurrence in a clinical investigation subject, without regard to causality. TEAEs: AEs that occurred for the first time during treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were any untoward medical occurrence at any dose that resulted in death; was life-threatening; required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. The analysis population included all subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    55 weeks
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    356
    358
    Units: subjects
        All-causality AE|
    344
    347
        All-causality SAE|
    81
    80
        Bevacizumab-related AE|
    190
    199
        Bevacizumab-related SAE|
    23
    17
        Grade 1 all-causality AE|
    32
    41
        Grade 2 all-causality AE|
    141
    134
        Grade 3 all-causality AE|
    125
    104
        Grade 4 all-causality AE|
    25
    44
        Grade 5 all-causality AE|
    21
    24
    No statistical analyses for this end point

    Secondary: Number of Subjects with Laboratory Abnormalities (Without Regard to Baseline Abnormality)

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    End point title
    		 Number of Subjects with Laboratory Abnormalities (Without Regard to Baseline Abnormality)
    End point description
    Laboratory evaluation included hematology (hemoglobin, white blood cells, platelets and absolute neutrophil count), blood chemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, serum or plasma creatinine, sodium, potassium, total calcium, magnesium, blood urea nitrogen or urea, and albumin ), coagulation (international normalized ratio for prothrombin time and activated partial thromboplastin time) and urinalysis (dipstick followed by a quantitative urine protein analysis for results of 2+ or greater). The analysis population included all subjects who were randomized and received at least 1 dose of study treatment, and had laboratory evaluation done.
    End point type
    Secondary
    End point timeframe
    55 weeks
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    342
    348
    Units: subjects
    303
    304
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause in the absence of documented PD. DOR was based on the Brookmeyer and Crowley method. The analysis population included all randomized subjects who had a confirmed objective response achieved by Week 19.
    End point type
    Secondary
    End point timeframe
    55 weeks
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    162
    161
    Units: weeks
        median (confidence interval 95%)
    36.3 (31.6 to 43.6)
    28.7 (27.0 to 36.3)
    Statistical analysis title
    		 Hazard ratio analysis
    Statistical analysis description
    A hazard ratio =1 indicated no difference in progressive disease(PD)/death between 2 reporting groups; >1 indicated an increase in PD/death in PF-06439535; <1 indicated an increase in PD/death in bevacizumab-EU.
    Comparison groups
    PF-06439535 v Bevacizumab-EU
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.1077
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.608
         upper limit
    		 1.051
    Notes
    [4] - Hazard ratio of PF-06439535 versus Bevacizumab-EU

    Secondary: Progression Free Survival Rate at 55 Weeks

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    End point title
    		 Progression Free Survival Rate at 55 Weeks
    End point description
    This outcome measure refers to the possibility of being progression free at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method. The analysis population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    55 weeks
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    358
    361
    Units: percentage of subjects
        number (confidence interval 95%)
    32.3 (26.9 to 37.8)
    30.5 (25.3 to 35.8)
    Statistical analysis title
    		 Hazard ratio analysis
    Statistical analysis description
    A hazard ratio =1 indicated no difference in progressive disease(PD)/death between 2 reporting groups; >1 indicated an increase in PD/death in PF-06439535; <1 indicated an increase in PD/death in bevacizumab-EU.
    Comparison groups
    PF-06439535 v Bevacizumab-EU
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.4492
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.931
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.777
         upper limit
    		 1.116
    Notes
    [5] - Hazard ratio of PF-06439535 versus Bevacizumab-EU

    Secondary: Survival Rate at 55 Weeks

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    End point title
    		 Survival Rate at 55 Weeks
    End point description
    This outcome measure refers to the possibility of being alive at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method. The analysis population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    55 weeks
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    358
    361
    Units: percentage of subjects
        number (confidence interval 95%)
    65.8 (60.5 to 70.6)
    64.1 (58.6 to 69.0)
    Statistical analysis title
    		 Hazard ratio analysis
    Statistical analysis description
    A hazard ratio =1 indicated no difference in progressive disease(PD)/death between 2 reporting groups; >1 indicated an increase in PD/death in PF-06439535; <1 indicated an increase in PD/death in bevacizumab-EU.
    Comparison groups
    PF-06439535 v Bevacizumab-EU
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.4726
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.918
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.729
         upper limit
    		 1.157
    Notes
    [6] - Hazard ratio of PF-06439535 versus Bevacizumab-EU

    Secondary: Serum Concentration of Bevacizumab up to 1 Year

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    End point title
    		 Serum Concentration of Bevacizumab up to 1 Year
    End point description
    The analysis population included all subjects who were randomized and received study treatment as planned and had no major protocol deviations, and had at least 1 drug concentration measurement after administration of study treatment. Not all subjects had measurements at each time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose from Cycle 1 to Cycle 17, 2.5 hours post-dose in Cycle 1, and 1.5 hours post-dose in Cycle 5
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    351
    354
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-dose in Cycle 1|
    68.08 ( 705.53 )
    116.4 ( 1032.1 )
        2.5 hours post-dose in Cycle 1|
    280000 ( 103260 )
    302200 ( 100360 )
        Pre-dose in Cycle 2|
    54350 ( 44479 )
    58930 ( 49452 )
        Pre-dose in Cycle 3|
    81090 ( 48671 )
    83350 ( 32384 )
        Pre-dose in Cycle 4|
    100900 ( 54979 )
    99750 ( 50531 )
        Pre-dose in Cycle 5|
    105300 ( 48469 )
    110000 ( 65416 )
        1.5 hours post-dose in Cycle 5|
    360700 ( 131170 )
    377200 ( 142250 )
        Pre-dose in Cycle 6|
    112000 ( 40825 )
    116700 ( 53844 )
        Pre-dose in Cycle 7|
    117300 ( 53844 )
    122100 ( 47793 )
        Pre-dose in Cycle 8|
    123600 ( 48893 )
    126400 ( 52985 )
        Pre-dose in Cycle 9|
    127200 ( 46200 )
    140900 ( 62548 )
        Pre-dose in Cycle 10|
    125700 ( 50769 )
    135900 ( 53975 )
        Pre-dose in Cycle 11|
    129500 ( 61329 )
    135600 ( 54531 )
        Pre-dose in Cycle 12|
    135200 ( 64560 )
    136300 ( 51312 )
        Pre-dose in Cycle 13|
    130900 ( 58093 )
    139700 ( 53750 )
        Pre-dose in Cycle 14|
    128000 ( 50840 )
    136200 ( 53439 )
        Pre-dose in Cycle 15|
    134000 ( 55933 )
    134000 ( 49663 )
        Pre-dose in Cycle 16|
    137000 ( 54813 )
    128600 ( 49742 )
        Pre-dose in Cycle 17|
    134800 ( 86847 )
    127500 ( 52784 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-Drug Antibody (ADA)

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    End point title
    		 Number of Subjects with Anti-Drug Antibody (ADA)
    End point description
    ADA assay was performed using a sensitive, specific, and semi-quantitative electrochemiluminescent (ECL) method, which used biotinylated- and ruthenium-labeled PF-06439535 as reagents. Samples with ADA titer greater than or equal to (>=) 2.29 were considered positive. The analysis population included all subjects who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    55 weeks
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    356
    358
    Units: subjects
        Cycle 1 pre-dose|
    1
    3
        Overall (post-treatment)|
    5
    5
    No statistical analyses for this end point

    Secondary: Number of Subjects with Neutralizing Antibody (NAb)

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    End point title
    		 Number of Subjects with Neutralizing Antibody (NAb)
    End point description
    Only samples that were confirmed positive for ADA were further tested for NAb. The NAb analysis was conducted using a single validated quasi-quantitative enzyme-linked immunosorbent assay (ELISA) that utilized PF-06439535 as a reagent. Samples with NAb titer >=1.70 were considered positive.
    End point type
    Secondary
    End point timeframe
    55 weeks
    End point values
    		 PF-06439535 Bevacizumab-EU
    Number of subjects analysed
    6
    7
    Units: number of subjects
        Cycle 1 pre-dose|
    1
    0
        Overall (post-treatment)|
    0
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    55 weeks
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    PF-06439535
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.

    Reporting group title
    Total
    Reporting group description
    		 This reporting group include all subjects who received at least 1 dose of study treatment from PF-06439535 and Bevacizumab-EU groups.

    Reporting group title
    Bevacizumab-EU
    Reporting group description
    		 Subjects received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m*2) and carboplatin (initial dose was AUC 6, based on subject’s pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.

    Serious adverse events
    		 PF-06439535 Total Bevacizumab-EU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    81 / 356 (22.75%)
    161 / 714 (22.55%)
    80 / 358 (22.35%)
         number of deaths (all causes)
    144
    293
    149
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone cancer metastatic
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    2 / 356 (0.56%)
    4 / 714 (0.56%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
    Tumour necrosis
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Vascular disorders
    Brachiocephalic vein thrombosis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Subgaleal haematoma
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 356 (1.12%)
    5 / 714 (0.70%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    3 / 5
    3 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 356 (0.56%)
    5 / 714 (0.70%)
    3 / 358 (0.84%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    1 / 2
    1 / 5
    0 / 3
    Disease progression
         subjects affected / exposed
    4 / 356 (1.12%)
    9 / 714 (1.26%)
    5 / 358 (1.40%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 6
    0 / 4
    General physical health deterioration
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 356 (0.56%)
    3 / 714 (0.42%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 356 (0.56%)
    4 / 714 (0.56%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 356 (0.56%)
    3 / 714 (0.42%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 356 (0.56%)
    4 / 714 (0.56%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 5
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 356 (0.56%)
    3 / 714 (0.42%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 356 (1.97%)
    9 / 714 (1.26%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    2 / 7
    4 / 9
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    3 / 356 (0.84%)
    6 / 714 (0.84%)
    3 / 358 (0.84%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 6
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    2 / 5
    1 / 3
    Pulmonary oedema
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
    Angina unstable
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 356 (0.00%)
    2 / 714 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 356 (0.00%)
    3 / 714 (0.42%)
    3 / 358 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Mononeuropathy
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 356 (0.56%)
    7 / 714 (0.98%)
    5 / 358 (1.40%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 10
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 356 (1.40%)
    12 / 714 (1.68%)
    7 / 358 (1.96%)
         occurrences causally related to treatment / all
    2 / 7
    3 / 14
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 356 (0.56%)
    2 / 714 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 356 (1.12%)
    10 / 714 (1.40%)
    6 / 358 (1.68%)
         occurrences causally related to treatment / all
    1 / 5
    6 / 13
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 356 (0.84%)
    6 / 714 (0.84%)
    3 / 358 (0.84%)
         occurrences causally related to treatment / all
    2 / 5
    4 / 8
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 356 (0.00%)
    2 / 714 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 356 (0.56%)
    4 / 714 (0.56%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 356 (0.00%)
    2 / 714 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    2 / 356 (0.56%)
    2 / 714 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 356 (0.00%)
    2 / 714 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal infection
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 356 (1.12%)
    4 / 714 (0.56%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 356 (0.28%)
    3 / 714 (0.42%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 356 (0.28%)
    2 / 714 (0.28%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral fungal infection
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 356 (2.25%)
    14 / 714 (1.96%)
    6 / 358 (1.68%)
         occurrences causally related to treatment / all
    3 / 11
    3 / 17
    0 / 6
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 356 (0.56%)
    2 / 714 (0.28%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 356 (0.00%)
    2 / 714 (0.28%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 356 (0.28%)
    3 / 714 (0.42%)
    2 / 358 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 356 (0.28%)
    1 / 714 (0.14%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 356 (0.00%)
    1 / 714 (0.14%)
    1 / 358 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 356 (1.12%)
    4 / 714 (0.56%)
    0 / 358 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PF-06439535 Total Bevacizumab-EU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    328 / 356 (92.13%)
    661 / 714 (92.58%)
    333 / 358 (93.02%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    49 / 356 (13.76%)
    88 / 714 (12.32%)
    39 / 358 (10.89%)
         occurrences all number
    95
    148
    53
    Aspartate aminotransferase increased
         subjects affected / exposed
    44 / 356 (12.36%)
    81 / 714 (11.34%)
    37 / 358 (10.34%)
         occurrences all number
    94
    153
    59
    Blood alkaline phosphatase increased
         subjects affected / exposed
    29 / 356 (8.15%)
    61 / 714 (8.54%)
    32 / 358 (8.94%)
         occurrences all number
    46
    94
    48
    Blood creatinine increased
         subjects affected / exposed
    16 / 356 (4.49%)
    37 / 714 (5.18%)
    21 / 358 (5.87%)
         occurrences all number
    28
    61
    33
    Platelet count decreased
         subjects affected / exposed
    23 / 356 (6.46%)
    42 / 714 (5.88%)
    19 / 358 (5.31%)
         occurrences all number
    31
    69
    38
    Weight decreased
         subjects affected / exposed
    36 / 356 (10.11%)
    65 / 714 (9.10%)
    29 / 358 (8.10%)
         occurrences all number
    43
    83
    40
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    19 / 356 (5.34%)
    41 / 714 (5.74%)
    22 / 358 (6.15%)
         occurrences all number
    26
    52
    26
    Vascular disorders
    Hypertension
         subjects affected / exposed
    60 / 356 (16.85%)
    122 / 714 (17.09%)
    62 / 358 (17.32%)
         occurrences all number
    83
    193
    110
    Nervous system disorders
    Headache
         subjects affected / exposed
    30 / 356 (8.43%)
    67 / 714 (9.38%)
    37 / 358 (10.34%)
         occurrences all number
    35
    80
    45
    Neuropathy peripheral
         subjects affected / exposed
    53 / 356 (14.89%)
    118 / 714 (16.53%)
    65 / 358 (18.16%)
         occurrences all number
    67
    153
    86
    Paraesthesia
         subjects affected / exposed
    40 / 356 (11.24%)
    71 / 714 (9.94%)
    31 / 358 (8.66%)
         occurrences all number
    64
    100
    36
    Peripheral sensory neuropathy
         subjects affected / exposed
    34 / 356 (9.55%)
    80 / 714 (11.20%)
    46 / 358 (12.85%)
         occurrences all number
    45
    115
    70
    Polyneuropathy
         subjects affected / exposed
    23 / 356 (6.46%)
    42 / 714 (5.88%)
    19 / 358 (5.31%)
         occurrences all number
    34
    56
    22
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    26 / 356 (7.30%)
    56 / 714 (7.84%)
    30 / 358 (8.38%)
         occurrences all number
    44
    100
    56
    Neutropenia
         subjects affected / exposed
    59 / 356 (16.57%)
    125 / 714 (17.51%)
    66 / 358 (18.44%)
         occurrences all number
    130
    274
    144
    Thrombocytopenia
         subjects affected / exposed
    55 / 356 (15.45%)
    121 / 714 (16.95%)
    66 / 358 (18.44%)
         occurrences all number
    122
    247
    125
    Anaemia
         subjects affected / exposed
    102 / 356 (28.65%)
    208 / 714 (29.13%)
    106 / 358 (29.61%)
         occurrences all number
    196
    396
    200
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    46 / 356 (12.92%)
    89 / 714 (12.46%)
    43 / 358 (12.01%)
         occurrences all number
    78
    143
    65
    Fatigue
         subjects affected / exposed
    73 / 356 (20.51%)
    144 / 714 (20.17%)
    71 / 358 (19.83%)
         occurrences all number
    110
    197
    87
    Pyrexia
         subjects affected / exposed
    24 / 356 (6.74%)
    47 / 714 (6.58%)
    23 / 358 (6.42%)
         occurrences all number
    31
    72
    41
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    39 / 356 (10.96%)
    66 / 714 (9.24%)
    27 / 358 (7.54%)
         occurrences all number
    45
    81
    36
    Diarrhoea
         subjects affected / exposed
    46 / 356 (12.92%)
    94 / 714 (13.17%)
    48 / 358 (13.41%)
         occurrences all number
    59
    125
    66
    Nausea
         subjects affected / exposed
    71 / 356 (19.94%)
    140 / 714 (19.61%)
    69 / 358 (19.27%)
         occurrences all number
    111
    223
    112
    Vomiting
         subjects affected / exposed
    41 / 356 (11.52%)
    74 / 714 (10.36%)
    33 / 358 (9.22%)
         occurrences all number
    52
    94
    42
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    41 / 356 (11.52%)
    88 / 714 (12.32%)
    47 / 358 (13.13%)
         occurrences all number
    53
    111
    58
    Dyspnoea
         subjects affected / exposed
    32 / 356 (8.99%)
    67 / 714 (9.38%)
    35 / 358 (9.78%)
         occurrences all number
    38
    79
    41
    Epistaxis
         subjects affected / exposed
    40 / 356 (11.24%)
    72 / 714 (10.08%)
    32 / 358 (8.94%)
         occurrences all number
    51
    99
    48
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    166 / 356 (46.63%)
    331 / 714 (46.36%)
    165 / 358 (46.09%)
         occurrences all number
    216
    448
    232
    Rash
         subjects affected / exposed
    9 / 356 (2.53%)
    30 / 714 (4.20%)
    21 / 358 (5.87%)
         occurrences all number
    10
    39
    29
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    28 / 356 (7.87%)
    62 / 714 (8.68%)
    34 / 358 (9.50%)
         occurrences all number
    50
    126
    76
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    40 / 356 (11.24%)
    83 / 714 (11.62%)
    43 / 358 (12.01%)
         occurrences all number
    82
    153
    71
    Bone pain
         subjects affected / exposed
    25 / 356 (7.02%)
    48 / 714 (6.72%)
    23 / 358 (6.42%)
         occurrences all number
    58
    105
    47
    Myalgia
         subjects affected / exposed
    54 / 356 (15.17%)
    103 / 714 (14.43%)
    49 / 358 (13.69%)
         occurrences all number
    131
    240
    109
    Pain in extremity
         subjects affected / exposed
    16 / 356 (4.49%)
    39 / 714 (5.46%)
    23 / 358 (6.42%)
         occurrences all number
    23
    52
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    48 / 356 (13.48%)
    94 / 714 (13.17%)
    46 / 358 (12.85%)
         occurrences all number
    76
    141
    65

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2015
    Protocol was amended to incorporate feedback from investigators, regulatory agencies, and protocol template updates.
    10 Jun 2016
    For EU, primary analysis was changed to risk difference; inclusion and exclusion criteria were updated.

    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
    For support, Contact us.
    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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