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    Clinical Trial Results:
    A randomized phase III 2-arm trial of paclitaxel plus bevacizumab vs. capecitabine plus bevacizumab for the first-line treatment of HER2-negative locally recurrent or metastatic breast cancer

    Summary
    EudraCT number
    		 2007-005828-32
    Trial protocol
    		 AT   CZ   HU   LV   SK   BG  
    Global end of trial date
    15 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Nov 2019
    First version publication date
    08 Nov 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CECOG/BC 1.3.005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00600340
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CECOG (Central European Cooperative Oncology Group)
    Sponsor organisation address
    Schlagergasse 6/6, Vienna, Austria, A-1090
    Public contact
    Waehringer Guertel 18-20 A-1090 Vienna Austria, Prof. Christoph Zielinski, M.D., christoph.zielinski@meduniwien.ac.at
    Scientific contact
    Waehringer Guertel 18-20 A-1090 Vienna Austria, Prof. Christoph Zielinski, M.D., christoph.zielinski@meduniwien.ac.at
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To show non-inferiority of Arm B versus Arm A in terms of overall survival (OS). Overall survival is assessed as time from date of randomization until date of death. Study Treatment, given until progression of disease, unacceptable toxicity of withdrawal of consent: Arm A: Bevacizumab plus Paclitaxel Arm B: Bevacizumab plus Capecitabine
    Protection of trial subjects
    For patients who stopped chemotherapy or the companion drug for any reason before disease progression (e.g. toxicity), the chemotherapy or companion drug was given as monotherapy until disease progression. If toxicity required a dosing delay or interruption of paclitaxel or capecitabine of more than three weeks, the patient was withdrawn from study treatment for toxicity reasons, but continued with the companion drug. In cases of a first occurrence of a serious bevacizumab-related toxicity (grade 3 or 4), bevacizumab treatment was temporarily (for a max of 6 weeks) suspended. Bevacizumab was permanently suspended for a second occurrence of a serious bevacizumab-related toxicity. Additionally, any patient who experienced the following events permanently discontinued bevacizumab: • Reversible Posterior Leucoencephalopathy Syndrome (RPLS) • Grade 3/4 hemorrhagic/bleeding events • Any grade of arterial thromboembolism • Grade 4 hypertension (hypertensive crisis) • Grade 4 proteinuria (nephrotic syndrome) • Grade 3/4 left ventricular dysfunction (CHF) • Any grade of Gastrointestinal perforation • Any grade of Tracheo-esophageal fistula • Any grade 4 non-gastrointestinal fistula • Any grade of hypersensitivity/allergic reactions related to bevacizumab.
    Background therapy
    		 -
    Evidence for comparator
    		 Results from a phase III trial (E2100) indicate that the addition of bevacizumab to first-line paclitaxel significantly improves PFS (hazard ratio 0.48 [95% CI: 0.39–0.59], p=0.0001, median 6.7 vs 13.3 months ). A phase III trial demonstrated that the addition of bevacizumab to capecitabine in heavily pretreated patients significantly improves response rate. In this trial, 462 heavily pre-treated patients were randomised to treatment with standard-dose single-agent capecitabine (1,250 mg/m2 twice daily, days 1–14 every 21 days) or the same capecitabine regimen plus bevacizumab 15 mg/kg on day 1 every 21 days. The response rate was 20% with the combination versus 9% with single-agent capecitabine (p=0.001). However, the significantly superior response rate did not translate into improved PFS (hazard ratio 0.98 [95% CI: 0.77–1.25], p=0.857; median 4.9 vs. 4.2 months, respectively) or overall survival (median 15.1 vs 14.5 months, respectively). The preliminary results of a single-arm phase II study of bevacizumab plus capecitabine in the first-line setting suggest that the combination is more active earlier in the disease course. In this study, patients received capecitabine 1,000 mg/m2 administered twice-daily for 14 days followed by a 7-day rest period in combination with bevacizumab 15 mg/kg every 21 days. Grade 4 adverse events were rare and the only grade 3 toxicities occurring in >5% of patients were hand-foot syndrome (13%), pain (10%), fatigue (7%) and diarrhoea (6%). Interim results for the first part of this crossover study indicated that with a median follow-up of 12.9 months (range 0.5-20.7), the median Time to progression (TTP) for the Intent-to-treat population (n=106) was 5.7 months (range 4.9-8.4) and 8.9 months (range7.5-13.6) in the estrogen receptor (ER) positive patient population. Corresponding results for overall survival for the ITT vs ER positive populations were 16.0+ months vs 16.6+ months, respectively.
    Actual start date of recruitment
    10 Sep 2008
    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
    Poland: 36
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Austria: 75
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Czech Republic: 37
    Country: Number of subjects enrolled
    Hungary: 162
    Country: Number of subjects enrolled
    Latvia: 27
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 26
    Country: Number of subjects enrolled
    Croatia: 12
    Country: Number of subjects enrolled
    Israel: 105
    Country: Number of subjects enrolled
    Romania: 42
    Country: Number of subjects enrolled
    Serbia: 14
    Worldwide total number of subjects
    564
    EEA total number of subjects
    419
    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)
    419
    From 65 to 84 years
    143
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 A total of 604 patients were screened and 564 randomized between September 10, 2008 and August 30, 2010, in 51 sites in 12 countries (Austria: 9, Bosnia: 1, Bulgaria: 3, Croatia: 5, Czech Republic: 4, Hungary: 4, Israel: 5, Latvia: 2, Poland: 6, Romania: 5, Serbia: 3, Slovakia: 4). 564 pats in ITT population, 561 in safety, 533 in per-protocol.

    Pre-assignment
    Screening details
    		 604 patients were screened for eligibility, 40 of these were not randomized: 38 did not meet the inclusion criteria, 2 declined to participate.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Patients in this arm received a combination of bevacizumab plus paclitaxel in cycles of 28 days as first-line treatment. Treatment continued until first progression of disease (PD), unacceptable toxicity or withdrawal of patient's consent. For patients who stopped chemotherapy for any reason before PD, bevacizumab was to be given as monotherapy until PD. Bevacizumab 10mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90mg/m², days 1, 8 and 15, every 4 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab dose of 10 mg/kg on days 1 and 15, every 4 weeks. Patient's weight at screening was used to determine the dose to be used for the duration of the study. In case of weight change by more than 10% during the study, the dose had to be recalculated. Bevacizumab was administered as an i.v. infusion initially over 90 minutes (following the administration of paclitaxel). If the first infusion was well tolerated, the second infusion could be delivered over a 60-minute period. If the 60-minute infusion was well tolerated, all subsequent infusions could be delivered over a 30-minute period. Bevacizumab was to be stored at 2 to 8°C and was to be prepared by a healthcare professional using aseptic technique. Withdraw the necessary amount of bevacizumab and dilute with sodium chloride (0.9%) solution for injection, up to a total volume of 100 mL. For heavier patients receiving doses of 10 or 15 mg/kg, the dose might be made up to 200 or 250 mL with sodium Chloride (0.9%) solution.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel in dose of 90 mg/m² on days 1, 8 and 15, every 4 weeks. Obtained commercially in vials of 30 mg (5.0 mL) and 100 mg (16.7 mL) and supplied with solvent. This was further diluted in 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP or 5% Dextrose in Ringer´s Injection to a final concentration of 0.3 to 1.2 mg/mL, prior to administration. Recommended pretreatment with oral corticosteroids (such as dexametaxone), difenhidramina and H2 antagonists (such as ranitidine) to reduce the severity of hypersensitivity reactions. Paclitaxel was be administered as a 1-hour i.v. infusion before bevacizumab and with the appropriate co-medications.

    Arm title
    		 Arm B
    Arm description
    		 Patients in Arm B received combination treatment with bevacizumab plus capecitabine as first-line treatment in cycles of 21 days, until first progression of disease (PD), unacceptable toxicity or withdrawal of patient consent. For patients who stopped chemotherapy for any reason before PD, bevacizumab was to be given as montherapy until PD. Bevacizumab 15 mg/kg i.v. on day 1 every 3 weeks Capecitabine 1000 mg/m² twice-daily on days 1-14, every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab dose of 15 mg/kg on day 1, every 3 weeks. Patient's weight at screening was used to determine the dose to be used for the duration of the study. In case of weight change by more than 10% during the study, the dose had to be recalculated. Bevacizumab was administered as an i.v. infusion initially over 90 minutes (following the administration of paclitaxel). If the first infusion was well tolerated, the second infusion could be delivered over a 60-minute period. If the 60-minute infusion was well tolerated, all subsequent infusions could be delivered over a 30-minute period. Bevacizumab was to be stored at 2 to 8°C and was to be prepared by a healthcare professional using aseptic technique. Withdraw the necessary amount of bevacizumab and dilute with sodium chloride (0.9%) solution for injection, up to a total volume of 100 mL. For heavier patients receiving doses of 10 or 15 mg/kg, the dose might be made up to 200 or 250 mL with sodium Chloride (0.9%) solution.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of twice-daily 1000 mg/m² on days 1-14, every 3 weeks. To be taken orally twice daily in equally divided doses morning and evening for a total daily dose of 2000 mg/m² on days 1-14, with the first dose occurring in the morning of day 1 and the last dose occurring on the evening of day 14 for a total of 28 doses. The morning and evening dose should be given approximately 12 hours apart, and taken within 30 minutes after the ingestion of food with approximately 200 mL of water, ideally after the breakfast and evening meal. Patients who were 65 years of age or older had an initial 25% capecitabine dose reduction. The daily dose was derived by determining the body surface area (BSA) from the nomogram in Appendix 5 of the study protocol. If body weight varied during the study, it was assumed that the body surface area would remain approximately constant (i.e. no dose adjustments for changes in body weight were done).

    Number of subjects in period 1
    		Arm A Arm B
    Started
    285
    279
    Completed
    285
    279

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients in this arm received a combination of bevacizumab plus paclitaxel in cycles of 28 days as first-line treatment. Treatment continued until first progression of disease (PD), unacceptable toxicity or withdrawal of patient's consent. For patients who stopped chemotherapy for any reason before PD, bevacizumab was to be given as monotherapy until PD. Bevacizumab 10mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90mg/m², days 1, 8 and 15, every 4 weeks

    Reporting group title
    Arm B
    Reporting group description
    		 Patients in Arm B received combination treatment with bevacizumab plus capecitabine as first-line treatment in cycles of 21 days, until first progression of disease (PD), unacceptable toxicity or withdrawal of patient consent. For patients who stopped chemotherapy for any reason before PD, bevacizumab was to be given as montherapy until PD. Bevacizumab 15 mg/kg i.v. on day 1 every 3 weeks Capecitabine 1000 mg/m² twice-daily on days 1-14, every 3 weeks

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 285 279 564
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 218 201 419
        From 65-84 years
    		 66 77 143
        85 years and over
    		 1 1 2
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 59 (49 to 64) 59 (48 to 65) -
    Gender categorical
    Units: Subjects
        Female
    		 284 275 559
        Male
    		 1 4 5
    Race
    Units: Subjects
        Caucasian/White
    		 283 278 561
        Black
    		 1 0 1
        Other
    		 1 1 2
    Menopausal status
    Units: Subjects
        Pre-menopausal
    		 52 52 104
        Post-menopausal
    		 232 223 455
        Male patients
    		 1 4 5
    ECOG PS
    Units: Subjects
        ECOG 0
    		 193 179 372
        ECOG 1
    		 75 91 166
        ECOG 2
    		 16 7 23
        Missing
    		 1 2 3
    Estrogen receptor (ER)
    Units: Subjects
        Positive
    		 215 201 416
        Negative
    		 68 77 145
        Unknown
    		 2 1 3
    Progesterone Receptor (PgR)
    Units: Subjects
        Positive
    		 167 168 335
        Negative
    		 118 109 227
        Unknown
    		 0 2 2
    Estrogen and progesterone receptor
    Units: Subjects
        ER and PgR negative
    		 63 67 130
        ER or PgR positive
    		 221 212 433
        ER and PR unknown or negative
    		 1 0 1
    ECG result
    Units: Subjects
        Normal
    		 243 246 489
        Abnormal
    		 39 30 69
        Not performed
    		 3 3 6
    Method for brain imaging
    No brain CT or MRI was required if the patient did not show signs/symptoms of CNS involvement or other unexplained neurological symptoms.
    Units: Subjects
        CT
    		 18 19 37
        MRI
    		 3 2 5
        No brain CT/MRI
    		 264 258 522
    Result of brain CT/MRI
    No brain CT or MRI was required if the patient did not show signs/symptoms suggestive of CNS involvement or other unexplained neurological symptoms.
    Units: Subjects
        No metastasis
    		 21 21 42
        No brain CT/MRI
    		 264 258 522
    Stage at primary diagnosis: Primary tumor (T)
    Units: Subjects
        Tis
    		 1 2 3
        T1
    		 66 72 138
        T2
    		 130 118 248
        T3
    		 26 32 58
        T4
    		 45 38 83
        TX
    		 16 16 32
        Missing
    		 1 1 2
    Stage at primary diagnosis: Regional lymph nodes (N)
    Units: Subjects
        N0
    		 78 62 140
        N1
    		 97 116 213
        N2
    		 55 51 106
        N3
    		 26 22 48
        NX
    		 28 27 55
        Missing
    		 1 1 2
    Stage at primary diagnosis: Distant metastasis (M)
    Units: Subjects
        M0
    		 222 219 441
        M1
    		 62 59 121
        Missing
    		 1 1 2
    Current stage of locally recurrent/metastatic tumor
    Units: Subjects
        Locally recurrent breast cancer
    		 2 0 2
        Metastatic breast cancer
    		 282 279 561
        Missing
    		 1 0 1
    Disease free interval after therapy of primary breast cancer
    Units: Subjects
        Yes
    		 214 215 429
        No
    		 71 64 135
    Disease free interval
    Disease free interval set to 0 months (No DFI), if the patient did not receive previous therapy fo primary breast cancer or if the patient was not disease free after previous therapy of Primary breast cancer
    Units: Subjects
        No DFI
    		 71 64 135
        DFI <=12 months
    		 14 10 24
        DFI >12 and <=24 months
    		 52 34 86
        DFI >24 months
    		 148 171 319
    Metastatic lesions
    Patients can have multiple sites with metastatic lesions.
    Units: Subjects
        At least one metastatic lesion
    		 282 279 561
        No metastatic lesions
    		 3 0 3
    Imaging methods
    Units: Subjects
        CT
    		 270 261 531
        MRI
    		 8 12 20
        X-ray
    		 7 6 13
    Target and non-target lestions
    Units: Subjects
        Target lesions only
    		 34 22 56
        Non-target lesions only
    		 65 49 114
        Both
    		 185 208 393
        None
    		 1 0 1
    Number of target lesions
    Units: Subjects
        0 lesions
    		 66 49 115
        1 lesion
    		 48 49 97
        2 lesions
    		 41 49 90
        3 lesions
    		 47 39 86
        4-5 lesions
    		 44 57 101
        >=6 lesions
    		 39 36 75
    Number of organs with metastases
    Units: Subjects
        >=3
    		 105 124 229
        <3
    		 180 155 335
    Previous hormonal therapy
    LR/MBC = for locally recurrent / metastatic breast cancer
    Units: Subjects
        Neoadjuvant/adjuvant only
    		 113 112 225
        LR/MBC only
    		 25 33 58
        Both
    		 37 25 62
        Other
    		 0 1 1
        None
    		 110 108 218
    Previous neoadjuvant chemotherapy
    Units: Subjects
        Anthracycline and taxane
    		 16 11 27
        Anthracycline, no taxane
    		 41 33 74
        Taxane, no anthracycline
    		 5 5 10
        No anthracycline, no taxane, other
    		 2 3 5
        none
    		 221 227 448
    Previous adjuvant chemotherapy
    Units: Subjects
        Anthracycline and taxane
    		 21 25 46
        Anthracycline, no taxane
    		 83 89 172
        Taxane, no anthracycline
    		 16 12 28
        No anthracycline, no taxane, other
    		 30 25 55
        None
    		 135 128 263
    Previous neoadjuvant/adjuvant chemotherapy
    Units: Subjects
        Yes
    		 180 176 356
        No
    		 105 103 208
    Previous radiotherapy
    Units: Subjects
        Yes
    		 191 194 385
        No
    		 94 85 179
    Previous surgery
    Units: Subjects
        Yes
    		 241 239 480
        No
    		 44 40 84
    Sum of longest diameter of target lesions
    Units: Subjects
        No lesions
    		 66 49 115
        1 - 5 cm
    		 86 83 169
        >5 - 10 cm
    		 64 77 141
        >10 cm
    		 69 70 139
    Previous neoadjuvant/ adjuvant hormonal therapy only with anti-estrogens
    Units: Subjects
        Yes
    		 87 89 176
        No
    		 198 190 388
    Bone metastatic lesions
    Units: Subjects
        Yes
    		 158 151 309
        No
    		 127 128 255
    Lung metastatic lesions
    Units: Subjects
        Yes
    		 112 122 234
        No
    		 173 157 330
    Liver metastatic lesions
    Units: Subjects
        Yes
    		 113 126 239
        No
    		 172 153 325
    Skin metastatic lesions
    Units: Subjects
        Yes
    		 13 9 22
        No
    		 272 270 542
    Soft tissue metastatic lesions
    Units: Subjects
        Yes
    		 69 63 132
        No
    		 216 216 432
    Lymph node metastatic lesions
    Units: Subjects
        Yes
    		 146 171 317
        No
    		 139 108 247
    Lung and/ or liver metastatic lesions
    Units: Subjects
        Yes
    		 185 203 388
        No
    		 100 76 176
    Soft tissue and/ or bone metastatic lesions only
    Units: Subjects
        Yes
    		 41 23 64
        No
    		 244 256 500
    Other metastatic lesions
    Metastatic lesions in locations other than bone, lung, liver, skin, soft tissue and lymph nodes
    Units: Subjects
        Yes
    		 19 25 44
        No
    		 266 254 520
    Previous neoadjuvant/adjuvant chemotherapy with anthracycline
    Units: Subjects
        Yes
    		 145 144 289
        No
    		 140 135 275
    Previous neoadjuvant/adjuvant chemotherapy with taxane
    Units: Subjects
        Yes
    		 57 50 107
        No
    		 228 229 457
    Previous neoadjuvant/adjuvant chemotherapy with other medications
    Excluding anthracycline and taxane
    Units: Subjects
        Yes
    		 26 26 52
        No
    		 259 253 512
    Previous total mastectomy
    Units: Subjects
        Yes
    		 131 135 266
        No
    		 154 144 298
    Previous breast conserving surgery
    Units: Subjects
        Yes
    		 111 99 210
        No
    		 174 180 354
    Previous biopsy/ aspiration
    Units: Subjects
        Yes
    		 54 48 102
        No
    		 231 231 462
    Other previous surgery
    Surgery other than total mastectomy, breast conserving surgery, biopsy, aspiration
    Units: Subjects
        Yes
    		 35 29 64
        No
    		 250 250 500
    Previous neoadjuvant radiotherapy
    Units: Subjects
        Yes
    		 8 9 17
        No
    		 277 270 547
    Previous adjuvant radiotherapy
    Units: Subjects
        Yes
    		 167 171 338
        No
    		 118 108 226
    Previous radiotherapy for relief of metastatic bone pain
    Units: Subjects
        Yes
    		 32 44 76
        No
    		 253 235 488
    Previous hormonal therapy for LR/MBC only with anti-estrogens
    LR/MBC = locally recurrent/metastatic breast cancer
    Units: Subjects
        Yes
    		 18 29 47
        No
    		 267 250 517
    Previous hormonal therapy for LR/MBC only with aromatase inhibitors
    LR/MBC = locally recurrent/metastatic breast cancer
    Units: Subjects
        Yes
    		 17 23 40
        No
    		 268 256 524
    Previous hormonal therapy for LR/MBC only with LH-RH analogues
    LR/MBC = locally recurrent/metastatic breast cancer
    Units: Subjects
        Yes
    		 1 4 5
        No
    		 284 275 559
    Previous neoadjuvant/ adjuvant hormonal therapy only with aromatase inhibitors
    Units: Subjects
        Yes
    		 56 56 112
        No
    		 229 223 452
    Previous neoadjuvant/ adjuvant hormonal therapy only with LR-RH analogues
    Units: Subjects
        Yes
    		 12 15 27
        No
    		 273 264 537
    Previous neoadjuvant/ adjuvant hormonal therapy only with progesterone
    Units: Subjects
        Yes
    		 0 1 1
        No
    		 285 278 563
    Previous neoadjuvant/ adjuvant hormonal therapy only with other therapies
    Other neoadjuvant/ adjuvant hormonal therapies excluding anti-estrogens, aromatase Inhibitors, LR-RH analogues, and progesterone
    Units: Subjects
        Yes
    		 0 1 1
        No
    		 285 278 563
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 162.0 ± 6.60 162.3 ± 6.48 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 71.97 ± 15.679 72.90 ± 14.350 -
    BSA
    Units: m²
        arithmetic mean (standard deviation)
    		 1.760 ± 0.1834 1.773 ± 0.1688 -
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 127.9 ± 12.91 128.7 ± 13.85 -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 78.1 ± 8.23 77.9 ± 9.34 -
    Heart rate
    Units: beats per minute
        arithmetic mean (standard deviation)
    		 79.7 ± 11.27 79.1 ± 11.41 -
    Body temperature
    Units: °C
        arithmetic mean (standard deviation)
    		 36.55 ± 0.265 36.47 ± 0.305 -
    LVEF
    Units: percent
        arithmetic mean (standard deviation)
    		 63.4 ± 5.32 62.6 ± 6.26 -
    Time since diagnosis of adenocarcinoma
    Adenocarcinoma histologically of cytologically confirmed.
    Units: months
        arithmetic mean (standard deviation)
    		 55.2 ± 56.46 58.9 ± 55.09 -
    Time since diagnosis of LR or MT
    LR or MT = locally recurrent of metastatic tumor
    Units: months
        arithmetic mean (standard deviation)
    		 5.7 ± 14.77 7.6 ± 19.11 -
    Disease free interval
    Disease free interval was set to 0 months (No DFI) if the patient did not receive previous therapy for primary breast cancer or the patient was not disease free after previous therapy for primary breast cancer.
    Units: months
        arithmetic mean (standard deviation)
    		 43.6 ± 48.84 48.0 ± 48.53 -
    Number of target lesions
    Units: number
        arithmetic mean (standard deviation)
    		 2.7 ± 2.52 2.8 ± 2.42 -
    Sum of longest diameters of target lesions
    Units: cm
        arithmetic mean (standard deviation)
    		 6.758 ± 7.4372 6.872 ± 6.6679 -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients in this arm received a combination of bevacizumab plus paclitaxel in cycles of 28 days as first-line treatment. Treatment continued until first progression of disease (PD), unacceptable toxicity or withdrawal of patient's consent. For patients who stopped chemotherapy for any reason before PD, bevacizumab was to be given as monotherapy until PD. Bevacizumab 10mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90mg/m², days 1, 8 and 15, every 4 weeks

    Reporting group title
    Arm B
    Reporting group description
    		 Patients in Arm B received combination treatment with bevacizumab plus capecitabine as first-line treatment in cycles of 21 days, until first progression of disease (PD), unacceptable toxicity or withdrawal of patient consent. For patients who stopped chemotherapy for any reason before PD, bevacizumab was to be given as montherapy until PD. Bevacizumab 15 mg/kg i.v. on day 1 every 3 weeks Capecitabine 1000 mg/m² twice-daily on days 1-14, every 3 weeks

    Primary: Overall Survival (PP population)

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    End point title
    		 Overall Survival (PP population)
    End point description
    OS defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. For the adjusted HR, the stratification factors at randomization were used. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at interim after 47% of information was 0.0010. Alpha spent at final analysis after 99% of information was 0.0250.
    End point type
    Primary
    End point timeframe
    Median Overall Survival (OS), associated stratified Hazard Ratio(HR) (pre-specified primary endpoint) and unstratified HR (sensitivity analysis) assessed after a median observation time of 54.3 months in arm A and 55.7 months in arm B.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    266 [1]
    265 [2]
    Units: months
        median (confidence interval 95%)
    30.2 (25.6 to 32.6)
    26.1 (22.3 to 29.0)
    Attachments
    		 Kaplan-Meier Plot for OS by Arm (PP Population)
    Notes
    [1] - Per protocol population
    [2] - Per-protocol population
    Statistical analysis title
    		 HR of Arm B vs. Arm A for OS (interim, stratified)
    Statistical analysis description
    Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age) HR is the hazard rate of Arm B divided by hazard rate of Arm A.
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.1983 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.042
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.689
    Notes
    [3] - Based on approach using repeated confidence intervals, with one-sided 97.5% repeated confidence intervals
    Statistical analysis title
    		 HR of Arm B vs. Arm A for OS (final, stratified)
    Statistical analysis description
    Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age) HR is the hazard rate of Arm B divided by hazard rate of Arm A.
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.007 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.018
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.261
    Notes
    [4] - Based on approach using repeated confidence intervals, with one-sided 97.5% repeated confidence intervals. Non-inferiority margin was a HR of 1.33.
    Statistical analysis title
    		 HR of Arm B vs. Arm A for OS (interim, unstrat.)
    Statistical analysis description
    Based on unadjusted Cox proportional hazards model. HR is the hazard rate of Arm B divided by hazard rate of Arm A.
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.2024 [5]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.058
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.674
    Notes
    [5] - Based on approach using repeated confidence intervals, with one-sided 97.5% repeated confidence intervals. Non-inferiority margin was a HR of 1.33.
    Statistical analysis title
    		 HR of Arm B vs. Arm A for OS (final, unstratified)
    Statistical analysis description
    Based on unadjusted Cox proportional hazards model. HR is the hazard rate of Arm B divided by hazard rate of Arm A.
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0612 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.134
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.386
    Notes
    [6] - Based on approach using repeated confidence intervals, with one-sided 97.5% repeated confidence intervals. Non-inferiority margin was a HR of 1.33.

    Primary: Overall Survival (ITT population)

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    End point title
    		 Overall Survival (ITT population)
    End point description
    OS defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. For the adjusted HR, the stratification factors at randomization were used. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at interim after 50% of information was 0.0014. Alpha spent at final analysis after 99% of information was 0.0250.
    End point type
    Primary
    End point timeframe
    Median Overall Survival (OS), associated stratified Hazard Ratio(HR) (pre-specified primary endpoint) and unstratified HR (sensitivity analysis) assessed after a median observation time of 54.3 months in arm A and 55.7 months in arm B.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    285 [7]
    279 [8]
    Units: months
        median (confidence interval 95%)
    29.5 (25.3 to 32.4)
    26.0 (22.3 to 29.0)
    Attachments
    		 Kaplan-Meier Plot for OS by Arm (ITT Population)
    Notes
    [7] - ITT population
    [8] - ITT population
    Statistical analysis title
    		 HR of Arm B vs. Arm A for OS (interim, stratified)
    Statistical analysis description
    Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age) HR is the hazard rate of Arm B divided by hazard rate of Arm A.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.1534 [9]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.027
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.606
    Notes
    [9] - Based on approach using repeated confidence intervals, with one-sided 97.5% repeated confidence intervals
    Statistical analysis title
    		 HR of Arm B vs. Arm A for OS (final, stratified)
    Statistical analysis description
    Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age) HR is the hazard rate of Arm B divided by hazard rate of Arm A.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0085 [10]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.035
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.273
    Notes
    [10] - Based on approach using repeated confidence intervals, with one-sided 97.5% repeated confidence intervals
    Statistical analysis title
    		 HR of Arm B vs. Arm A for OS (interim, unstrat.)
    Statistical analysis description
    Based on unadjusted Cox proportional hazards model. HR is the hazard rate of Arm B divided by hazard rate of Arm A.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.1778 [11]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.058
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.623
    Notes
    [11] - Based on approach using repeated confidence intervals, with one-sided 97.5% repeated confidence intervals
    Statistical analysis title
    		 HR of Arm B vs. Arm A for OS (final, unstratified)
    Statistical analysis description
    Based on unadjusted Cox proportional hazards model. HR is the hazard rate of Arm B divided by hazard rate of Arm A.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.049 [12]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.126
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.37
    Notes
    [12] - Based on approach using repeated confidence intervals, with one-sided 97.5% repeated confidence intervals

    Secondary: Observation time (ITT population)

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    End point title
    		 Observation time (ITT population)
    End point description
    Median observation time estimated with reverse Kaplan-Meier methods
    End point type
    Secondary
    End point timeframe
    Observation time (in months) is defined as time from randomization to the day the patient was last confirmed to be alive. In case of patient death the time was censored at the day of death.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    285 [13]
    279 [14]
    Units: months
        median (confidence interval 95%)
    54.3 (53.1 to 57.5)
    55.7 (53.7 to 58.1)
    Notes
    [13] - ITT population
    [14] - ITT population
    No statistical analyses for this end point

    Secondary: Best overall response (ITT population)

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    End point title
    		 Best overall response (ITT population)
    End point description
    End point type
    Secondary
    End point timeframe
    The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    285 [15]
    279 [16]
    Units: Patients
        Complete response
    10
    2
        Partial response
    115
    74
        Stable disease
    127
    138
        Progressive disease
    18
    47
        Not evaluable
    15
    18
    Notes
    [15] - ITT population
    [16] - ITT population
    No statistical analyses for this end point

    Secondary: Best overall response (PP population)

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    End point title
    		 Best overall response (PP population)
    End point description
    End point type
    Secondary
    End point timeframe
    The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    266 [17]
    265 [18]
    Units: Patients
        Complete response
    10
    2
        Partial response
    111
    72
        Stable disease
    117
    130
        Progressive disease
    17
    45
        Not evaluable
    11
    16
    Notes
    [17] - PP population
    [18] - PP population
    No statistical analyses for this end point

    Secondary: Unconfirmed best overall response (ITT population)

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    End point title
    		 Unconfirmed best overall response (ITT population)
    End point description
    Complete and partial response in this summary did not require a confirmation by a second tumor assessment
    End point type
    Secondary
    End point timeframe
    The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    285 [19]
    279 [20]
    Units: patients
        Complete response
    16
    4
        Partial response
    147
    101
        Stable disease
    89
    109
        Progressive disease
    18
    47
        Not evaluable
    15
    18
    Notes
    [19] - ITT population
    [20] - ITT population
    No statistical analyses for this end point

    Secondary: Unconfirmed best overall response (PP population)

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    End point title
    		 Unconfirmed best overall response (PP population)
    End point description
    Complete and partial response in this summary did not require a confirmation by a second tumor assessment
    End point type
    Secondary
    End point timeframe
    The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    266 [21]
    265 [22]
    Units: patients
        Complete response
    16
    4
        Partial response
    141
    96
        Stable disease
    81
    104
        Progressive disease
    17
    45
        Not evaluable
    11
    16
    Notes
    [21] - PP population
    [22] - PP population
    No statistical analyses for this end point

    Secondary: Objective response rate and disease control rate (ITT population)

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    End point title
    		 Objective response rate and disease control rate (ITT population)
    End point description
    Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease
    End point type
    Secondary
    End point timeframe
    The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    285 [23]
    279 [24]
    Units: patients
        Objective response
    125
    76
        Disease control
    252
    214
    Notes
    [23] - ITT population
    [24] - ITT population
    Statistical analysis title
    		 OR of objective response and CMH test (stratified)
    Statistical analysis description
    OR is the odds for objective response of Arm B divided by the odds for objective response of Arm A Based on Cochran-Mantel-Haenszel test adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.67
    Statistical analysis title
    		 OR of disease control and CMH test (stratified)
    Statistical analysis description
    OR is the odds for disease control of Arm B divided by the odds for disease control of Arm A Based on Cochran-Mantel-Haenszel test adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.7
    Statistical analysis title
    		 Difference in ORR in Arm B vs. Arm A
    Statistical analysis description
    Difference calculated as ORR in Arm B minus ORR in Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24
         upper limit
    		 -9
    Statistical analysis title
    		 Difference in DCR in Arm B vs. Arm A
    Statistical analysis description
    Difference calculated as DCR in Arm B minus DCR in Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18
         upper limit
    		 -6

    Secondary: Objective response rate and disease control rate (PP population)

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    End point title
    		 Objective response rate and disease control rate (PP population)
    End point description
    Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease
    End point type
    Secondary
    End point timeframe
    The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    266 [25]
    265 [26]
    Units: patients
        Objective response
    121
    74
        Disease control
    238
    204
    Notes
    [25] - PP population
    [26] - PP population
    Statistical analysis title
    		 OR of objective response and CMH test (stratified)
    Statistical analysis description
    OR is the odds for objective response of Arm B divided by the odds for objective response of Arm A Based on Cochran-Mantel-Haenszel test adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age) OR is the odds of Arm B divided by the odds of Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.65
    Statistical analysis title
    		 OR of disease control and CMH test (stratified)
    Statistical analysis description
    OR is the odds for disease control of Arm B divided by the odds for disease control of Arm A Based on Cochran-Mantel-Haenszel test adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age) OR is the odds of Arm B divided by the odds of Arm A.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.65
    Statistical analysis title
    		 Difference in ORR in Arm B vs. Arm A
    Statistical analysis description
    Difference calculated as ORR in Arm B minus ORR in Arm A
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26
         upper limit
    		 -10
    Statistical analysis title
    		 Difference in DCR in Arm B vs. Arm A
    Statistical analysis description
    Difference calculated as DCR in Arm B minus DCR in Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19
         upper limit
    		 -6

    Secondary: Unconfirmed objective response rate and disease control rate (ITT population)

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    End point title
    		 Unconfirmed objective response rate and disease control rate (ITT population)
    End point description
    Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. Complete and partial response in this summary did not require a confirmation by a second tumor assessment
    End point type
    Secondary
    End point timeframe
    The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    285 [27]
    279 [28]
    Units: patients
        Objective response
    163
    105
        Disease control
    252
    214
    Notes
    [27] - ITT population
    [28] - ITT population
    Statistical analysis title
    		 OR of objective response and CMH test (stratified)
    Statistical analysis description
    OR is the odds for objective response of Arm B divided by the odds for objective response of Arm A Based on Cochran-Mantel-Haenszel test adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age) OR is the odds of Arm B divided by the odds of Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.63
    Statistical analysis title
    		 OR of disease control and CMH test (stratified)
    Statistical analysis description
    OR is the odds for disease control of Arm B divided by the odds for disease control of Arm A Based on Cochran-Mantel-Haenszel test adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age) OR is the odds of Arm B divided by the odds of Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.7
    Statistical analysis title
    		 Difference in ORR in Arm B vs. Arm A
    Statistical analysis description
    Difference calculated as ORR in Arm B minus ORR in Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28
         upper limit
    		 -11
    Statistical analysis title
    		 Difference in DCR in Arm B vs. Arm A
    Statistical analysis description
    Difference calculated as DCR in Arm B minus DCR in Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18
         upper limit
    		 -6

    Secondary: Unconfirmed objective response rate and disease control rate (PP population)

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    End point title
    		 Unconfirmed objective response rate and disease control rate (PP population)
    End point description
    Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. Complete and partial response in this summary did not require a confirmation by a second tumor assessment
    End point type
    Secondary
    End point timeframe
    The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    266 [29]
    265 [30]
    Units: patients
        Objective response
    157
    100
        Disease control
    238
    204
    Notes
    [29] - PP population
    [30] - PP population
    Statistical analysis title
    		 OR of objective response and CMH test (stratified)
    Statistical analysis description
    OR is the odds for objective response of Arm B divided by the odds for objective response of Arm A Based on Cochran-Mantel-Haenszel test adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.6
    Statistical analysis title
    		 OR of disease control and CMH test (stratified)
    Statistical analysis description
    OR is the odds for disease control of Arm B divided by the odds for disease control of Arm A Based on Cochran-Mantel-Haenszel test adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.65
    Statistical analysis title
    		 Difference in ORR in Arm B vs. Arm A
    Statistical analysis description
    Difference calculated as ORR in Arm B minus ORR in Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30
         upper limit
    		 -13
    Statistical analysis title
    		 Difference in DCR in Arm B vs. Arm A
    Statistical analysis description
    Difference calculated as DCR in Arm B minus DCR in Arm A
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19
         upper limit
    		 -6

    Secondary: Progression Free Survival (ITT population)

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    End point title
    		 Progression Free Survival (ITT population)
    End point description
    Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization.
    End point type
    Secondary
    End point timeframe
    Median PFS, associated stratified Hazard Ratio (HR).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    285 [31]
    279 [32]
    Units: months
        median (confidence interval 95%)
    10.9 (10.3 to 12.9)
    8.1 (6.8 to 8.9)
    Attachments
    		 KM plots for PFS (ITT population)
    Notes
    [31] - ITT population
    [32] - ITT population
    Statistical analysis title
    		 HR of Arm B vs. Arm A for PFS (stratified)
    Statistical analysis description
    HR is the hazard rate of Arm B divided by hazard rate of Arm A. Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0066 [33]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 1.61
    Notes
    [33] - Two-sided log-rank test adjusted by stratification factors at randomization

    Secondary: Progression Free Survival (PP population)

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    End point title
    		 Progression Free Survival (PP population)
    End point description
    Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization.
    End point type
    Secondary
    End point timeframe
    Median PFS, associated stratified Hazard Ratio (HR).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    266 [34]
    265 [35]
    Units: months
        median (confidence interval 95%)
    10.9 (10.3 to 12.9)
    8.2 (7.1 to 9.2)
    Attachments
    		 KM-Plot_PFS (PP population)
    Notes
    [34] - PP population
    [35] - PP population
    Statistical analysis title
    		 HR of Arm B vs. Arm A for PFS (stratified).
    Statistical analysis description
    HR is the hazard rate of Arm B divided by hazard rate of Arm A. Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of age)
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0094 [36]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 1.61
    Notes
    [36] - Two-sided log-rank test adjusted by stratification factors at randomization

    Secondary: Time to treatment failure (ITT population)

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    End point title
    		 Time to treatment failure (ITT population)
    End point description
    Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last.
    End point type
    Secondary
    End point timeframe
    Median TTF, associated stratified Hazard Ratio (HR).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    285 [37]
    279 [38]
    Units: months
        median (confidence interval 95%)
    8.4 (8.0 to 9.7)
    7.2 (6.0 to 8.1)
    Attachments
    		 KM Plot TTF (ITT population)
    Notes
    [37] - ITT population
    [38] - ITT population
    Statistical analysis title
    		 HR of Arm B vs. Arm A for TTF (stratified)
    Statistical analysis description
    HR is the hazard rate of Arm B divided by hazard rate of Arm A. Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age)
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1957 [39]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.35
    Notes
    [39] - Two-sided log-rank test adjusted by stratification factors at randomization

    Secondary: Time to treatment failure (PP population)

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    End point title
    		 Time to treatment failure (PP population)
    End point description
    Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last.
    End point type
    Secondary
    End point timeframe
    Median TTF, associated stratified Hazard Ratio (HR).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    266 [40]
    265 [41]
    Units: months
        median (confidence interval 95%)
    8.3 (8.0 to 9.4)
    7.3 (5.9 to 8.2)
    Attachments
    		 KM plot for TTF (PP population)
    Notes
    [40] - PP population
    [41] - PP population
    Statistical analysis title
    		 HR of Arm B vs. Arm A for TTF (stratified)
    Statistical analysis description
    HR is the hazard rate of Arm B divided by hazard rate of Arm A. Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2583 [42]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.34
    Notes
    [42] - Two-sided log-rank test adjusted by stratification factors at randomization

    Secondary: Time to response (ITT population)

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    End point title
    		 Time to response (ITT population)
    End point description
    Time to Response (TR) was defined as time from randomization until occurrence of response (CR or PR) according to RECIST criteria. Patients without response were censored after the longest time actually observed. Since the median TR was not observed, the number of subjects with a response at given timepoints were reported.
    End point type
    Secondary
    End point timeframe
    Median TR, associated stratified Hazard Ratio (HR).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    285 [43]
    279 [44]
    Units: subjects
        Month 3
    83
    57
        Month 6
    111
    69
        Month 9
    121
    74
        Month 12
    123
    75
        Month 15
    123
    75
    Attachments
    		 KM Plot TR (ITT population)
    Notes
    [43] - ITT population
    [44] - ITT population
    Statistical analysis title
    		 HR of Arm B vs. Arm A for TR (stratified)
    Statistical analysis description
    HR is the hazard rate of Arm B divided by hazard rate of Arm A. Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [45]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.77
    Notes
    [45] - Two-sided log-rank test adjusted by stratification factors at randomization

    Secondary: Time to response (PP population)

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    End point title
    		 Time to response (PP population)
    End point description
    Time to Response (TR) was defined as time from randomization until occurrence of response (CR or PR) according to RECIST criteria. Patients without response were censored after the longest time actually observed. Since the median TR was not observed, the number of subjects with a response at given timepoints were reported.
    End point type
    Secondary
    End point timeframe
    Median TR, associated stratified Hazard Ratio (HR).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    266 [46]
    265 [47]
    Units: subjects
        Month 3
    81
    56
        Month 6
    108
    68
        Month 9
    118
    72
        Month 12
    119
    73
        Month 15
    119
    73
    Attachments
    		 KM plot for TR (PP population)
    Notes
    [46] - PP population
    [47] - PP population
    Statistical analysis title
    		 HR of Arm B vs. Arm A for TR (stratified)
    Statistical analysis description
    HR is the hazard rate of Arm B divided by hazard rate of Arm A. Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [48]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.75
    Notes
    [48] - Two-sided log-rank test adjusted by stratification factors at randomization

    Secondary: Duration of response (ITT population)

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    End point title
    		 Duration of response (ITT population)
    End point description
    Duration of response (DR) was defined as time from date of first occurrence of any response (CR or PR) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment.
    End point type
    Secondary
    End point timeframe
    Median DR, associated stratified Hazard Ratio (HR).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    125 [49]
    76 [50]
    Units: months
        median (confidence interval 95%)
    11.2 (10.1 to 14.0)
    10.3 (8.6 to 12.4)
    Attachments
    		 KM Plot DR
    Notes
    [49] - ITT population restricted to patients who experienced a partial or complete response
    [50] - ITT population restricted to patients who experienced a partial or complete response
    Statistical analysis title
    		 HR of Arm B vs. Arm A for DR (stratified)
    Statistical analysis description
    HR is the hazard rate of Arm B divided by hazard rate of Arm A. Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0582 [51]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 2.02
    Notes
    [51] - Two-sided log-rank test adjusted by stratification factors at randomization

    Secondary: Duration of response (PP population)

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    End point title
    		 Duration of response (PP population)
    End point description
    Duration of response (DR) was defined as time from date of first occurrence of any response (CR or PR) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment.
    End point type
    Secondary
    End point timeframe
    Median DR, associated stratified Hazard Ratio (HR).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    121 [52]
    74 [53]
    Units: months
        median (confidence interval 95%)
    11.2 (9.5 to 14.2)
    10.3 (8.4 to 12.4)
    Attachments
    		 KM Plot DR
    Notes
    [52] - PP population restricted to patients who experienced a partial or complete response
    [53] - PP population restricted to patients who experienced a partial or complete response
    Statistical analysis title
    		 HR of Arm B vs. Arm A for DR (stratified)
    Statistical analysis description
    HR is the hazard rate of Arm B divided by hazard rate of Arm A. Based on Cox proportional hazards model adjusted by stratification factors at randomization: 1) estrogen and/or progesterone status (positive vs. other) 2) country 3) menopausal status (premenopausal or male <=50 years of age vs. postmenopausal or male >50 years of Age)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0429 [54]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.1
    Notes
    [54] - Two-sided log-rank test adjusted by stratification factors at randomization

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events recording for a patient was started with the first dose of any of the study drugs until the 28-day post-treatment follow up visit. Pre-existing conditions which worsened during the study were reported as Adverse Events.
    Adverse event reporting additional description
    After the 28-day follow up visit only new and ongoing serious adverse events considered to be related to study drug or protocol procedures were recorded by the investigator
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Patients in this arm received a combination of bevacizumab plus paclitaxel in cycles of 28 days as first-line treatment. Treatment continued until first progression of disease (PD), unacceptable toxicity or withdrawal of patients consent. For patients who stopped chemotherapy for any reason before PD, bevacizumab was to be given as monotherapy until PD. Bevacizumab 10mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90mg/m², days 1, 8 and 15, every 4 weeks The safety population comprised all patients randomized who received at least one dose of study medication. For the purpose of safety analyses, patients were included in the treatment groups of their actually received treatment. However, if patients received only one component of the assigned combination treatment (e.g. only paclitaxel in group A), then they were analyzed under the treatment group randomized.

    Reporting group title
    Arm B
    Reporting group description
    		 Patients in Arm B received combination treatment with bevacizumab plus capecitabine as first-line treatment in cycles of 21 days, until first progression of disease (PD), unacceptable toxicity or withdrawal of patient consent. For patients who stopped chemotherapy for any reason before PD, bevacizumab was to be given as montherapy until PD. Bevacizumab 15 mg/kg i.v. on day 1 every 3 weeks Capecitabine 1000 mg/m² twice-daily on days 1-14, every 3 weeks The safety population comprised all patients randomized who received at least one dose of study medication. For the purpose of safety analyses, patients were included in the treatment groups of their actually received treatment. However, if patients received only one component of the assigned combination treatment (e.g. only paclitaxel in group A), then they were analyzed under the treatment group randomized.

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    65 / 284 (22.89%)
    68 / 277 (24.55%)
         number of deaths (all causes)
    196
    209
         number of deaths resulting from adverse events
    9
    10
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 284 (0.35%)
    5 / 277 (1.81%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic thrombosis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    2 / 284 (0.70%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheterisation venous
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast lump removal
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 284 (0.70%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 284 (1.06%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site pain
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gait disturbance
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         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
    2 / 284 (0.70%)
    6 / 277 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pulmonary embolism
         subjects affected / exposed
    2 / 284 (0.70%)
    4 / 277 (1.44%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 284 (0.00%)
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, olfactory
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizoaffective disorder
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (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
    Fracture
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Systolic dysfunction
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 284 (0.70%)
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain hypoxia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain oedema
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 284 (0.00%)
    4 / 277 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 284 (0.70%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 284 (0.35%)
    4 / 277 (1.44%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (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 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    1 / 284 (0.35%)
    3 / 277 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    3 / 284 (1.06%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 284 (1.06%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 277 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 277 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 277 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    264 / 284 (92.96%)
    240 / 277 (86.64%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    102 / 284 (35.92%)
    83 / 277 (29.96%)
         occurrences all number
    192
    130
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    33 / 284 (11.62%)
    17 / 277 (6.14%)
         occurrences all number
    39
    19
    Dysgeusia
         subjects affected / exposed
    17 / 284 (5.99%)
    10 / 277 (3.61%)
         occurrences all number
    19
    14
    Headache
         subjects affected / exposed
    37 / 284 (13.03%)
    27 / 277 (9.75%)
         occurrences all number
    46
    32
    Neuropathy peripheral
         subjects affected / exposed
    86 / 284 (30.28%)
    9 / 277 (3.25%)
         occurrences all number
    105
    9
    Paraesthesia
         subjects affected / exposed
    17 / 284 (5.99%)
    12 / 277 (4.33%)
         occurrences all number
    18
    12
    Peripheral sensory neuropathy
         subjects affected / exposed
    23 / 284 (8.10%)
    5 / 277 (1.81%)
         occurrences all number
    25
    5
    Polyneuropathy
         subjects affected / exposed
    27 / 284 (9.51%)
    6 / 277 (2.17%)
         occurrences all number
    35
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    35 / 284 (12.32%)
    17 / 277 (6.14%)
         occurrences all number
    59
    20
    Leukopenia
         subjects affected / exposed
    46 / 284 (16.20%)
    6 / 277 (2.17%)
         occurrences all number
    127
    8
    Neutropenia
         subjects affected / exposed
    87 / 284 (30.63%)
    13 / 277 (4.69%)
         occurrences all number
    204
    24
    Thrombocytopenia
         subjects affected / exposed
    9 / 284 (3.17%)
    19 / 277 (6.86%)
         occurrences all number
    12
    26
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    44 / 284 (15.49%)
    34 / 277 (12.27%)
         occurrences all number
    50
    37
    Fatigue
         subjects affected / exposed
    97 / 284 (34.15%)
    76 / 277 (27.44%)
         occurrences all number
    127
    89
    Mucosal inflammation
         subjects affected / exposed
    23 / 284 (8.10%)
    13 / 277 (4.69%)
         occurrences all number
    29
    13
    Oedema peripheral
         subjects affected / exposed
    27 / 284 (9.51%)
    11 / 277 (3.97%)
         occurrences all number
    28
    13
    Pyrexia
         subjects affected / exposed
    23 / 284 (8.10%)
    17 / 277 (6.14%)
         occurrences all number
    27
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 284 (7.04%)
    18 / 277 (6.50%)
         occurrences all number
    26
    21
    Abdominal pain upper
         subjects affected / exposed
    18 / 284 (6.34%)
    14 / 277 (5.05%)
         occurrences all number
    24
    17
    Constipation
         subjects affected / exposed
    27 / 284 (9.51%)
    25 / 277 (9.03%)
         occurrences all number
    32
    32
    Diarrhoea
         subjects affected / exposed
    58 / 284 (20.42%)
    59 / 277 (21.30%)
         occurrences all number
    83
    83
    Dyspepsia
         subjects affected / exposed
    17 / 284 (5.99%)
    15 / 277 (5.42%)
         occurrences all number
    24
    17
    Nausea
         subjects affected / exposed
    57 / 284 (20.07%)
    70 / 277 (25.27%)
         occurrences all number
    82
    94
    Stomatitis
         subjects affected / exposed
    22 / 284 (7.75%)
    20 / 277 (7.22%)
         occurrences all number
    27
    24
    Vomiting
         subjects affected / exposed
    29 / 284 (10.21%)
    34 / 277 (12.27%)
         occurrences all number
    40
    46
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 284 (1.06%)
    16 / 277 (5.78%)
         occurrences all number
    3
    18
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    32 / 284 (11.27%)
    20 / 277 (7.22%)
         occurrences all number
    37
    22
    Dysphonia
         subjects affected / exposed
    35 / 284 (12.32%)
    10 / 277 (3.61%)
         occurrences all number
    37
    11
    Dyspnoea
         subjects affected / exposed
    32 / 284 (11.27%)
    24 / 277 (8.66%)
         occurrences all number
    39
    27
    Epistaxis
         subjects affected / exposed
    89 / 284 (31.34%)
    39 / 277 (14.08%)
         occurrences all number
    122
    46
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    87 / 284 (30.63%)
    5 / 277 (1.81%)
         occurrences all number
    88
    5
    Nail disorder
         subjects affected / exposed
    48 / 284 (16.90%)
    10 / 277 (3.61%)
         occurrences all number
    50
    10
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    8 / 284 (2.82%)
    155 / 277 (55.96%)
         occurrences all number
    8
    197
    Rash
         subjects affected / exposed
    17 / 284 (5.99%)
    11 / 277 (3.97%)
         occurrences all number
    20
    14
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    10 / 284 (3.52%)
    16 / 277 (5.78%)
         occurrences all number
    13
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    30 / 284 (10.56%)
    18 / 277 (6.50%)
         occurrences all number
    58
    20
    Back pain
         subjects affected / exposed
    27 / 284 (9.51%)
    29 / 277 (10.47%)
         occurrences all number
    35
    29
    Bone pain
         subjects affected / exposed
    28 / 284 (9.86%)
    29 / 277 (10.47%)
         occurrences all number
    33
    31
    Musculoskeletal pain
         subjects affected / exposed
    3 / 284 (1.06%)
    14 / 277 (5.05%)
         occurrences all number
    5
    15
    Myalgia
         subjects affected / exposed
    20 / 284 (7.04%)
    9 / 277 (3.25%)
         occurrences all number
    26
    9
    Pain in extremity
         subjects affected / exposed
    25 / 284 (8.80%)
    24 / 277 (8.66%)
         occurrences all number
    32
    28
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    24 / 284 (8.45%)
    14 / 277 (5.05%)
         occurrences all number
    29
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    35 / 284 (12.32%)
    33 / 277 (11.91%)
         occurrences all number
    38
    38

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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