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    Clinical Trial Results:
    A Phase III, Multicenter, Placebo-Controlled, Double-Blind, Randomized Clinical Trial to Evaluate the Efficacy of Bevacizumab in Combination With Tarceva (Erlotinib) Compared With Erlotinib Alone for Treatment of Advanced Non-Small Cell Lung Cancer (Nsclc) After Failure of Standard First-Line Chemotherapy

    Summary
    EudraCT number
    		 2006-006626-26
    Trial protocol
    		 DE   BE   BG   SE   IT  
    Global end of trial date
    23 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2021
    First version publication date
    03 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OSI3364g
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00130728
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the efficacy of the combination of bevacizumab with Tarceva (erlotinib) in relation to Tarceva monotherapy in participants receiving second-line therapy for non-small cell lung cancer.
    Protection of trial subjects
    All study subjects were required to read and sign and Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jun 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 11 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Philippines: 4
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    United States: 576
    Worldwide total number of subjects
    636
    EEA total number of subjects
    29
    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)
    309
    From 65 to 84 years
    327
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 636 participants were enrolled at 177 sties worldwide

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 erlotinib HCl + bevacizumab
    Arm description
    		 Oral erlotinib HCl 150 mg/day orally + intravenous infusion of bevacizumab at a dose of 15 mg/kg on the first day of each 3-week cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A 15 miligram (mg)/kilogram (kg) dose of bevacizumab was administered on the first day of each 3-week cycle.

    Investigational medicinal product name
    erlotinib HCl
    Investigational medicinal product code
    Other name
    Tarceva
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib was administered as a 150 mg dose daily.

    Arm title
    		 erlotinib HCl + placebo
    Arm description
    		 Oral erlotinib HCl 150 mg/day orally + intravenous infusion of placebo at a dose of 15 mg/kg on the first day of each 3-week cycle
    Arm type
    		 Placebo

    Investigational medicinal product name
    erlotinib HCl
    Investigational medicinal product code
    Other name
    Tarceva
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib was administered as a 150 mg dose daily.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A 15 mg/kg dose of placebo was administered on the first day of each 3-week cycle.

    Number of subjects in period 1
    		erlotinib HCl + bevacizumab erlotinib HCl + placebo
    Started
    319
    317
    Completed
    57
    57
    Not completed
    262
    260
         Consent withdrawn by subject
    -
    2
         Death
    258
    258
         Lost to follow-up
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    erlotinib HCl + bevacizumab
    Reporting group description
    		 Oral erlotinib HCl 150 mg/day orally + intravenous infusion of bevacizumab at a dose of 15 mg/kg on the first day of each 3-week cycle

    Reporting group title
    erlotinib HCl + placebo
    Reporting group description
    		 Oral erlotinib HCl 150 mg/day orally + intravenous infusion of placebo at a dose of 15 mg/kg on the first day of each 3-week cycle

    Reporting group values
    		 erlotinib HCl + bevacizumab erlotinib HCl + placebo Total
    Number of subjects
    		 319 317 636
    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 (18-59 years)
    		 91 90 181
        From 60-64 years
    		 62 66 128
        From 65-69 years
    		 59 53 112
        >= 70 years
    		 107 108 215
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.8 ( 10.4 ) 65.0 ( 10.3 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 148 147 295
        Male
    		 171 170 341
    Race/Ethnicity
    Units: Subjects
        White
    		 264 257 521
        Black
    		 21 33 54
        Asian or Pacific Islander
    		 23 18 41
        Hispanic
    		 10 8 18
        American Indian or Alaskan Native
    		 0 1 1
        Other
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    erlotinib HCl + bevacizumab
    Reporting group description
    		 Oral erlotinib HCl 150 mg/day orally + intravenous infusion of bevacizumab at a dose of 15 mg/kg on the first day of each 3-week cycle

    Reporting group title
    erlotinib HCl + placebo
    Reporting group description
    		 Oral erlotinib HCl 150 mg/day orally + intravenous infusion of placebo at a dose of 15 mg/kg on the first day of each 3-week cycle

    Primary: Overall survival (OS) among all randomized patients

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    End point title
    		 Overall survival (OS) among all randomized patients
    End point description
    Overall Survival was defined as the period from the date of randomization until the date of patient death from any cause. For patients who had not died, survival data was censored at the date of last contact.
    End point type
    Primary
    End point timeframe
    From the date of randomization until the date of patient death from any cause, or the date of last contact. (Up to 3.1 years)
    End point values
    		 erlotinib HCl + bevacizumab erlotinib HCl + placebo
    Number of subjects analysed
    319
    317
    Units: Months
        median (confidence interval 95%)
    9.3 (7.39 to 11.47)
    9.2 (7.85 to 11.60)
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    erlotinib HCl + bevacizumab v erlotinib HCl + placebo
    Number of subjects included in analysis
    636
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7583 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.799
         upper limit
    		 1.177
    Notes
    [1] - relative to placebo arm

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    PFS was defined as the time from randomization to documented disease progression, as determined by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST), or death on study treatment, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    From randomization to documented disease progression or death on study treatment, whichever occurred first. (Up to 3.1 years)
    End point values
    		 erlotinib HCl + bevacizumab erlotinib HCl + placebo
    Number of subjects analysed
    319
    317
    Units: Months
        median (confidence interval 95%)
    3.4 (2.79 to 4.27)
    1.7 (1.48 to 2.53)
    Statistical analysis title
    		 Progression-Free Survival
    Comparison groups
    erlotinib HCl + bevacizumab v erlotinib HCl + placebo
    Number of subjects included in analysis
    636
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.623
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.519
         upper limit
    		 0.748
    Notes
    [2] - relative to placebo arm

    Secondary: Percentage of Participants with Objective Response

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    End point title
    		 Percentage of Participants with Objective Response
    End point description
    Objective response was defined as a complete or partial response determined by RECIST on two consecutive occasions >= 4 weeks apart.
    End point type
    Secondary
    End point timeframe
    The median duration of Objective response was up to 9.7 months
    End point values
    		 erlotinib HCl + bevacizumab erlotinib HCl + placebo
    Number of subjects analysed
    301
    306
    Units: Percentage of participants
        number (confidence interval 95%)
    12.6 (9.1 to 16.8)
    6.2 (3.8 to 9.5)
    Statistical analysis title
    		 Objrective Response
    Comparison groups
    erlotinib HCl + bevacizumab v erlotinib HCl + placebo
    Number of subjects included in analysis
    607
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0068 [3]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Perentage difference
    Point estimate
    6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 11.3
    Notes
    [3] - relative to placebo arm

    Secondary: Duration of objective response

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    End point title
    		 Duration of objective response
    End point description
    Duration of objective response was defined as the period from the date of the initial partial or complete response until the date of disease progression or death on study treatment from any cause. For patients who had not died, data was censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    Period from Objective response until disease progression or death on study treatment. (Up to 29.5 months)
    End point values
    		 erlotinib HCl + bevacizumab erlotinib HCl + placebo
    Number of subjects analysed
    38
    19
    Units: Months
        median (confidence interval 95%)
    9.7 (6.90 to 19.48)
    8.4 (3.48 to 14.88)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization to up to 3.8 years (for Adverse Events) From randomization until last patient last visit or 14.5 years from start of study (for Serious Adverse Events)
    Adverse event reporting additional description
    Safety analyses were based on safety-evaluable randomized participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    erlotinib HCl + placebo
    Reporting group description
    		 Oral erlotinib HCl 150 mg/day orally + intravenous infusion of placebo at a dose of 15 mg/kg on the first day of each 3-week cycle

    Reporting group title
    erlotinib HCl + bevacizumab
    Reporting group description
    		 Oral erlotinib HCl 150 mg/day orally + intravenous infusion of bevacizumab at a dose of 15 mg/kg on the first day of each 3-week cycle

    Serious adverse events
    		 erlotinib HCl + placebo erlotinib HCl + bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    121 / 313 (38.66%)
    146 / 313 (46.65%)
         number of deaths (all causes)
    258
    258
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant Pleural Effusion
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (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
    6 / 313 (1.92%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular Vein Thrombosis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 313 (0.00%)
    4 / 313 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trousseau's Syndrome
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous Thrombosis Limb
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         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 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Venous Thrombosis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Discomfort
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    2 / 313 (0.64%)
    3 / 313 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Influenza Like Illness
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    4 / 313 (1.28%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 313 (0.96%)
    3 / 313 (0.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Food Allergy
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         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
    Bronchial Obstruction
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 313 (0.00%)
    6 / 313 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dyspnoea
         subjects affected / exposed
    24 / 313 (7.67%)
    12 / 313 (3.83%)
         occurrences causally related to treatment / all
    1 / 24
    1 / 12
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydropneumothorax
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    4 / 313 (1.28%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dyspnoea at Rest
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    5 / 313 (1.60%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infiltration
         subjects affected / exposed
    2 / 313 (0.64%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    8 / 313 (2.56%)
    12 / 313 (3.83%)
         occurrences causally related to treatment / all
    3 / 8
    9 / 12
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pleural Effusion
         subjects affected / exposed
    9 / 313 (2.88%)
    3 / 313 (0.96%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Pulmonary Haemorrhage
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary Oedema
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory Failure
         subjects affected / exposed
    0 / 313 (0.00%)
    3 / 313 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Congestion
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    2 / 313 (0.64%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    2 / 313 (0.64%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood Culture Positive
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart Rate Increased
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International Normalised Ratio Increased
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Function Test Abnormal
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 313 (0.96%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation Retinopathy
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal Injury
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Wound Dehiscence
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 313 (0.00%)
    4 / 313 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Angina Pectoris
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    4 / 313 (1.28%)
    3 / 313 (0.96%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Stenosis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 313 (0.00%)
    5 / 313 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (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
    Ataxia
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    0 / 313 (0.00%)
    3 / 313 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Haemorrhage Intracranial
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial Pressure Increased
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy Peripheral
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reversible Posterior Leukoencephalopathy Syndrome
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic Encephalopathy
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal Cord Paralysis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness Unilateral
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal Haemorrhage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision Blurred
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 313 (0.00%)
    3 / 313 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 313 (1.28%)
    7 / 313 (2.24%)
         occurrences causally related to treatment / all
    3 / 4
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Diverticulum
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis Erosive
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    2 / 313 (0.64%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Perforation
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia, Obstructive
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Perforation
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (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
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Obstruction
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Perforation
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Stenosis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 313 (0.00%)
    4 / 313 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 313 (1.28%)
    3 / 313 (0.96%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    1 / 313 (0.32%)
    6 / 313 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hiatus Hernia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Function Abnormal
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Exfoliative Rash
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Ulcer
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (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
    Nephrolithiasis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         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
    Arthralgia
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    5 / 313 (1.60%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    2 / 313 (0.64%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Breast Cellulitis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 313 (0.32%)
    4 / 313 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 313 (0.96%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lung Infection
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal Abscess
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 313 (3.19%)
    15 / 313 (4.79%)
         occurrences causally related to treatment / all
    1 / 11
    2 / 16
         deaths causally related to treatment / all
    4 / 4
    2 / 2
    Pyelonephritis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 313 (0.64%)
    4 / 313 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to Thrive
         subjects affected / exposed
    2 / 313 (0.64%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 313 (0.64%)
    0 / 313 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 313 (0.96%)
    7 / 313 (2.24%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Ketoacidosis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (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
    		 erlotinib HCl + placebo erlotinib HCl + bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    306 / 313 (97.76%)
    310 / 313 (99.04%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 313 (8.31%)
    77 / 313 (24.60%)
         occurrences all number
    27
    79
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    23 / 313 (7.35%)
    33 / 313 (10.54%)
         occurrences all number
    26
    36
    Fatigue
         subjects affected / exposed
    124 / 313 (39.62%)
    146 / 313 (46.65%)
         occurrences all number
    125
    147
    Chest Pain
         subjects affected / exposed
    24 / 313 (7.67%)
    27 / 313 (8.63%)
         occurrences all number
    25
    29
    Asthenia
         subjects affected / exposed
    20 / 313 (6.39%)
    34 / 313 (10.86%)
         occurrences all number
    22
    36
    Oedema Peripheral
         subjects affected / exposed
    32 / 313 (10.22%)
    18 / 313 (5.75%)
         occurrences all number
    34
    18
    Mucosal Inflammation
         subjects affected / exposed
    16 / 313 (5.11%)
    35 / 313 (11.18%)
         occurrences all number
    16
    35
    Pain
         subjects affected / exposed
    18 / 313 (5.75%)
    15 / 313 (4.79%)
         occurrences all number
    21
    17
    Chills
         subjects affected / exposed
    11 / 313 (3.51%)
    23 / 313 (7.35%)
         occurrences all number
    11
    23
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    76 / 313 (24.28%)
    73 / 313 (23.32%)
         occurrences all number
    77
    73
    Dyspnoea
         subjects affected / exposed
    64 / 313 (20.45%)
    61 / 313 (19.49%)
         occurrences all number
    80
    70
    Epistaxis
         subjects affected / exposed
    30 / 313 (9.58%)
    63 / 313 (20.13%)
         occurrences all number
    31
    63
    Dysphonia
         subjects affected / exposed
    6 / 313 (1.92%)
    33 / 313 (10.54%)
         occurrences all number
    6
    34
    Pharyngolaryngeal Pain
         subjects affected / exposed
    14 / 313 (4.47%)
    27 / 313 (8.63%)
         occurrences all number
    14
    27
    Haemoptysis
         subjects affected / exposed
    14 / 313 (4.47%)
    22 / 313 (7.03%)
         occurrences all number
    16
    24
    Wheezing
         subjects affected / exposed
    9 / 313 (2.88%)
    17 / 313 (5.43%)
         occurrences all number
    10
    19
    Dyspnoea Exertional
         subjects affected / exposed
    17 / 313 (5.43%)
    6 / 313 (1.92%)
         occurrences all number
    17
    6
    Rhinorrhoea
         subjects affected / exposed
    6 / 313 (1.92%)
    16 / 313 (5.11%)
         occurrences all number
    6
    16
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    25 / 313 (7.99%)
    38 / 313 (12.14%)
         occurrences all number
    26
    39
    Anxiety
         subjects affected / exposed
    30 / 313 (9.58%)
    26 / 313 (8.31%)
         occurrences all number
    32
    26
    Depression
         subjects affected / exposed
    19 / 313 (6.07%)
    31 / 313 (9.90%)
         occurrences all number
    20
    31
    Investigations
    Weight Decreased
         subjects affected / exposed
    41 / 313 (13.10%)
    65 / 313 (20.77%)
         occurrences all number
    41
    65
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 313 (8.95%)
    53 / 313 (16.93%)
         occurrences all number
    28
    55
    Dizziness
         subjects affected / exposed
    31 / 313 (9.90%)
    41 / 313 (13.10%)
         occurrences all number
    31
    41
    Dysgeusia
         subjects affected / exposed
    19 / 313 (6.07%)
    29 / 313 (9.27%)
         occurrences all number
    19
    29
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    29 / 313 (9.27%)
    19 / 313 (6.07%)
         occurrences all number
    30
    20
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    162 / 313 (51.76%)
    203 / 313 (64.86%)
         occurrences all number
    162
    206
    Nausea
         subjects affected / exposed
    99 / 313 (31.63%)
    121 / 313 (38.66%)
         occurrences all number
    101
    121
    Constipation
         subjects affected / exposed
    45 / 313 (14.38%)
    49 / 313 (15.65%)
         occurrences all number
    45
    50
    Vomiting
         subjects affected / exposed
    49 / 313 (15.65%)
    57 / 313 (18.21%)
         occurrences all number
    52
    61
    Stomatitis
         subjects affected / exposed
    27 / 313 (8.63%)
    40 / 313 (12.78%)
         occurrences all number
    27
    40
    Abdominal Pain
         subjects affected / exposed
    25 / 313 (7.99%)
    29 / 313 (9.27%)
         occurrences all number
    26
    32
    Dyspepsia
         subjects affected / exposed
    16 / 313 (5.11%)
    21 / 313 (6.71%)
         occurrences all number
    17
    22
    Dysphagia
         subjects affected / exposed
    12 / 313 (3.83%)
    19 / 313 (6.07%)
         occurrences all number
    12
    19
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    10 / 313 (3.19%)
    18 / 313 (5.75%)
         occurrences all number
    10
    18
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    184 / 313 (58.79%)
    193 / 313 (61.66%)
         occurrences all number
    184
    195
    Dry Skin
         subjects affected / exposed
    58 / 313 (18.53%)
    63 / 313 (20.13%)
         occurrences all number
    59
    63
    Dermatitis Acneiform
         subjects affected / exposed
    42 / 313 (13.42%)
    58 / 313 (18.53%)
         occurrences all number
    42
    58
    Pruritus
         subjects affected / exposed
    40 / 313 (12.78%)
    47 / 313 (15.02%)
         occurrences all number
    40
    48
    Alopecia
         subjects affected / exposed
    16 / 313 (5.11%)
    18 / 313 (5.75%)
         occurrences all number
    16
    18
    Erythema
         subjects affected / exposed
    11 / 313 (3.51%)
    16 / 313 (5.11%)
         occurrences all number
    11
    16
    Skin Exfoliation
         subjects affected / exposed
    16 / 313 (5.11%)
    8 / 313 (2.56%)
         occurrences all number
    16
    8
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    6 / 313 (1.92%)
    16 / 313 (5.11%)
         occurrences all number
    6
    16
    Proteinuria
         subjects affected / exposed
    8 / 313 (2.56%)
    18 / 313 (5.75%)
         occurrences all number
    8
    18
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    41 / 313 (13.10%)
    46 / 313 (14.70%)
         occurrences all number
    44
    47
    Arthralgia
         subjects affected / exposed
    27 / 313 (8.63%)
    37 / 313 (11.82%)
         occurrences all number
    28
    38
    Musculoskeletal Pain
         subjects affected / exposed
    23 / 313 (7.35%)
    34 / 313 (10.86%)
         occurrences all number
    24
    34
    Pain in Extremity
         subjects affected / exposed
    20 / 313 (6.39%)
    24 / 313 (7.67%)
         occurrences all number
    22
    24
    Musculoskeletal Chest Pain
         subjects affected / exposed
    15 / 313 (4.79%)
    19 / 313 (6.07%)
         occurrences all number
    15
    20
    Muscle Spasms
         subjects affected / exposed
    17 / 313 (5.43%)
    16 / 313 (5.11%)
         occurrences all number
    17
    16
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    26 / 313 (8.31%)
    33 / 313 (10.54%)
         occurrences all number
    28
    36
    Upper Respiratory Tract Infection
         subjects affected / exposed
    30 / 313 (9.58%)
    30 / 313 (9.58%)
         occurrences all number
    30
    30
    Pneumonia
         subjects affected / exposed
    16 / 313 (5.11%)
    9 / 313 (2.88%)
         occurrences all number
    24
    23
    Bronchitis
         subjects affected / exposed
    18 / 313 (5.75%)
    10 / 313 (3.19%)
         occurrences all number
    19
    12
    Sinusitis
         subjects affected / exposed
    8 / 313 (2.56%)
    16 / 313 (5.11%)
         occurrences all number
    8
    16
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    24 / 313 (7.67%)
    35 / 313 (11.18%)
         occurrences all number
    27
    40
    Anorexia
         subjects affected / exposed
    75 / 313 (23.96%)
    104 / 313 (33.23%)
         occurrences all number
    76
    105
    Decreased Appetite
         subjects affected / exposed
    21 / 313 (6.71%)
    36 / 313 (11.50%)
         occurrences all number
    21
    36
    Hypokalaemia
         subjects affected / exposed
    21 / 313 (6.71%)
    17 / 313 (5.43%)
         occurrences all number
    21
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2005
    Inclusion and exclusion criteria were revised; secondary outcome measures were revised; pharmacokinetic outcome measures for bevacizumab were revised; dosing information for both Tarceva and bevacizumab were revised; the frequency of survival follow-up increased to every 6 weeks; number of study centers increased; medical monitor changed; informed consent form was revised.
    31 Oct 2005
    Participants with squamous cell carcinoma and participants with treated brain metastases were included; eligibility criteria was revised; secondary objective regarding the association of survival, progression-free survival, and treatment effect with markers of epidermal growth factor receptor (EGFR) expression has been modified to include EGFR gene copy number measured by fluorescence in situ hybridization (FISH); exclusion criteria was changed to allow non-small cell lung cancer (NSCLC) participants with certain profiles to enroll; the aspirin requirment was revised to a daily dose not exceeding 325 miligrams (mg); the approach for statistical testing of the primary and secondary endpoints was clarified.
    03 Mar 2006
    The medical monitor and alternate contact changed; eligibility criteria was revised; secondary objective regarding the association of survival, progression-free survival, and treatment effect with markers of epidermal growth factor receptor (EGFR) expression has been modified to include EGFR gene copy number measured by fluorescence in situ hybridization (FISH); exclusion criteria was changed to allow non-small cell lung cancer (NSCLC) participants with certain profiles to enroll; dose modification was revised to state that if Tarceva is permanently discontinued; the participant should be discontinued from the treatment phase of the study and should enter survival follow-up; the aspirin requirment was revised to a daily dose not exceeding 325 miligrams (mg); antiplatelet drugs given at standard doses were permitted; the approach for statistical testing of the primary and secondary endpoints was clarified; safety monitoring plan was described.
    30 Nov 2006
    Revisions to the statistical methods introducing interim efficacy analysis; updated background information on bevacizumab and erlotinib was provided; dose modification criteria was modified; information was uodated for the guidelines on the mangement of certain study treatment-related toxicities.
    12 Mar 2009
    AE data collection was limited to collection of SAEs for the remainder of the study.
    11 Oct 2012
    No further patient data was to be collected except for SAEs reporting via MedWatch FDA 3500 forms and no AEs were collected in the clinical database any longer; Participants began receiving study drugs directly from Astellas Pharma US, Inc. labeled as “erlotinib” at their current dosage; no dose adjustments were permitted

    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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