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    Clinical Trial Results:
    Phase IIb/III randomized, double-blind trial of BIBW 2992 plus best supportive care (BSC) versus placebo plus BSC in non-small cell lung cancer patients failing erlotinib or gefitinib

    Summary
    EudraCT number
    		 2007-005983-28
    Trial protocol
    		 ES   GB   BE   NL   DE   FR   IT  
    Global end of trial date
    04 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    16 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1200.23
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00656136
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173 , Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG, 001 800 243 0127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG, 001 800 243 0127, clintriage.rdg@boehringer-ingelheim.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
    04 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of BIBW 2992 plus BSC versus placebo plus BSC in a double-blind randomized trial in non-small cell lung cancer patients with progressive disease after at least one but not more than two lines of chemotherapy and at least 12 weeks of treatment with erlotinib or gefitinib
    Protection of trial subjects
    Only subjects who were considered eligible by investigators based on the protocol-specific inclusion and exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given.Close monitoring of all subjects was adhered to throughout the trial conduct. Symptomatic treatment of tumour associated symptoms were allowed throughout. Dose reduction was allowed in cases of pre-specified, protocol defined adverse events. For patients who experienced CTCAE (version 3.0) grade ≥3 drug-related adverse events (AEs) despite appropriate supportive care, or grade ≥2 AEs, a dose reduction scheme was followed after a treatment pause to allow the AE to decrease to CTCAE grade ≤1 or baseline (within a maximum of 14 days). Further instructions on managing diarrhoea, nausea and vomiting, and rash, respectively were provided in the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 May 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
    Netherlands: 15
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    China: 124
    Country: Number of subjects enrolled
    Taiwan: 156
    Country: Number of subjects enrolled
    Korea, Republic of: 106
    Country: Number of subjects enrolled
    Singapore: 15
    Country: Number of subjects enrolled
    Canada: 56
    Country: Number of subjects enrolled
    Thailand: 26
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    698
    EEA total number of subjects
    174
    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)
    462
    From 65 to 84 years
    234
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All enrolled subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Patients were randomised to receive afatinib plus BSC or matching placebo plus BSC in a double-blind fashion. Patients, investigators and the sponsor’s trial team involved in site monitoring, data management and analysing the results of the study remained blinded to the randomised treatment assignments up to the static snapshot created for primary analysis of overall survival in July 2010.. Additionally, readers for the independent central imaging unit were blinded to treatment assignments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.

    Arm title
    		 Afatinib 50 mg/Day
    Arm description
    		 Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus Best Supportive Care (BSC) or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus Best Supportive Care (BSC) or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).

    Number of subjects in period 1 [1]
    		Placebo Afatinib 50 mg/Day
    Started
    195
    390
    Completed
    0
    0
    Not completed
    195
    390
         Adverse event, serious fatal
    3
    22
         Other reason not defined above
    4
    4
         Patient refused to continue study medication
    7
    10
         Adverse event, non-fatal
    2
    29
         Progressive disease
    177
    322
         Protocol deviation
    2
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.

    Reporting group title
    Afatinib 50 mg/Day
    Reporting group description
    		 Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus Best Supportive Care (BSC) or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).

    Reporting group values
    		 Placebo Afatinib 50 mg/Day Total
    Number of subjects
    		 195 390 585
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 127 275 402
        From 65-84 years
    		 68 114 182
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59 ( 10.4 ) 58 ( 10.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 117 231 348
        Male
    		 78 159 237
    Race/Ethnicity
    Units: Subjects
        Caucasian
    		 72 121 193
        Eastern Asian
    		 110 227 337
        Other Asian
    		 12 38 50
        Other
    		 1 4 5
    Baselinne Eastern Cooperative Oncology Group (ECOG) Performance Score
    ECOG performance score was measured on a 6 point scale where 0="Fully active", 1="Restricted in physically strenuous activity", 2="Ambulatory and capable of all self care but unable to carry out any work activities', 3="Capable of only limited self care, confined to bed or chair 50% or more of waking hours", 4="bedbound", and 5="Death'.
    Units: Subjects
        ECOG score=0
    		 53 92 145
        ECOG score=1
    		 127 268 395
        ECOG score=2
    		 15 30 45

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.

    Reporting group title
    Afatinib 50 mg/Day
    Reporting group description
    		 Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus Best Supportive Care (BSC) or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was the duration from the date of randomization to the date of death. Patients who were alive were censored at the last contact date prior to the database lock. For the primary analysis 11 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Primary analysis data cut-off date was 08 July 2010. For the final analysis 13 patients were lost to follow-up and were censored at the last contact date when they were known to be still alive. Final analysis data cut-off date was 01 April 2014.
    End point type
    Primary
    End point timeframe
    From randomization until death or the last patient out date (01 April 2014), an average of 12 months
    End point values
    		 Placebo Afatinib 50 mg/Day
    Number of subjects analysed
    195 [1]
    390 [2]
    Units: months
    arithmetic mean (confidence interval 95%)
        Primary analysis (358 deaths)
    11.96 (10.15 to 14.26)
    10.78 (9.95 to 11.99)
        Final analysis (526 deaths)
    11.73 (10.05 to 14.06)
    10.87 (9.95 to 12.25)
    Notes
    [1] - Randomized Set (RS) includes all randomized patients that received one dose of study medication
    [2] - Randomized Set (RS) includes all randomized patients that received one dose of study medication
    Statistical analysis title
    		 Primary analysis comparison of overall survival
    Statistical analysis description
    Primary analysis was performed after 358 deaths were observed among randomized patients. The data cut-off date for the primary analysis was 08 July 2010. The hazard ratio was calculated as Afatinib versus placebo.
    Comparison groups
    Afatinib 50 mg/Day v Placebo
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.7428 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.077
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.862
         upper limit
    		 1.346
    Notes
    [3] - P-value is one-sided (afatinib vs placebo) log rank test stratified by gender and baseline ECOG score (0,1 vs 2)
    [4] - Model stratified by gender and baseline ECOG score (0,1 vs 2)
    Statistical analysis title
    		 Final analysis comparison of overall survival
    Statistical analysis description
    Final analysis was performed after 526 deaths were observed among randomized patients. The data cut-off date for the final analysis was 01 April 2014. The hazard ratio was calculated as Afatinib versus placebo.
    Comparison groups
    Placebo v Afatinib 50 mg/Day
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.3955 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.976
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.814
         upper limit
    		 1.17
    Notes
    [5] - P-value is one-sided (afatinib vs placebo) log rank test stratified by gender and baseline ECOG score (0,1 vs 2)
    [6] - Model stratified by gender and baseline ECOG score (0,1 vs 2)

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS is defined as time from randomisation to disease progression or death whichever occurs first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours version 1.0 (RECIST 1.0).
    End point type
    Secondary
    End point timeframe
    From randomization to disease progression, death or the data cutoff on 07 July 2010, an average of 3.3 months
    End point values
    		 Placebo Afatinib 50 mg/Day
    Number of subjects analysed
    195
    390
    Units: months
        median (confidence interval 95%)
    1.08 (0.95 to 1.68)
    3.29 (2.79 to 4.4)
    Statistical analysis title
    		 Cox regression for Progression Free Survival
    Statistical analysis description
    Cox proportional hazard model, stratified by baseline ECOG performance score (0,1 vs. 2) and gender (male vs. female), was used to estimate the HR (afatinib vs. placebo)
    Comparison groups
    Placebo v Afatinib 50 mg/Day
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.381
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.306
         upper limit
    		 0.475
    Notes
    [7] - P-value is one-sided (afatinib vs placebo) log rank test stratified by gender and baseline ECOG score (0,1 vs 2)

    Secondary: Objective Response Rate (OR)

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    End point title
    		 Objective Response Rate (OR)
    End point description
    OR is defined as complete response (CR) and partial response (PR). Assessed by central independent review according to RECIST 1.0.
    End point type
    Secondary
    End point timeframe
    From randomization to disease progression, death or the data cutoff on 07 July 2010, an average of 3.3 months
    End point values
    		 Placebo Afatinib 50 mg/Day
    Number of subjects analysed
    195
    390
    Units: percentage patients
        number (confidence interval 95%)
    0.5 (0 to 2.8)
    7.4 (5 to 10.5)
    Statistical analysis title
    		 Logistic regression for Objective Response Rate
    Statistical analysis description
    Logistic regression model adjusted for stratification factors, gender and baseline ECOG score (0, 1 vs 2)
    Comparison groups
    Placebo v Afatinib 50 mg/Day
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0071 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    15.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 115
    Notes
    [8] - P-value is derived from logistic regression model adjusted for stratification factors, gender and baseline ECOG score (0, 1 vs 2)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of first drug administration up to 28 days after the last drug administration for on-treatment adverse events or the last patient out dated on 4 October 2013.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Afatinib 50 mg/Day
    Reporting group description
    		 Patients started with a 50 mg/day dose. Dose reductions were permitted by the protocol to 40 mg/day plus BSC or 30 mg /day plus BSC based upon prespecified Adverse Events and Common Terminology Criteria for Adverse Events (CTCAE) grade (Version 3.0).

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received matching placebo for 50 mg, 40 mg or 30 mg afatinib tablets starting with 50 mg/day. Dose reductions were managed in the same way as for the afatinib arm.

    Serious adverse events
    		 Afatinib 50 mg/Day Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    136 / 390 (34.87%)
    36 / 195 (18.46%)
         number of deaths (all causes)
    49
    15
         number of deaths resulting from adverse events
    3
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    16 / 390 (4.10%)
    7 / 195 (3.59%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 7
         deaths causally related to treatment / all
    0 / 14
    0 / 7
    Malignant pleural effusion
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    11 / 390 (2.82%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Metastases to liver
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    5 / 390 (1.28%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 390 (0.00%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (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
    3 / 390 (0.77%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Extravasation
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 390 (0.77%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 390 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 390 (1.79%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         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
    Cough
         subjects affected / exposed
    0 / 390 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 390 (2.05%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Dyspnoea at rest
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 390 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydropneumothorax
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    14 / 390 (3.59%)
    7 / 195 (3.59%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 390 (1.28%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    9 / 390 (2.31%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 6
    0 / 2
    Wheezing
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    4 / 390 (1.03%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood culture positive
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium increased
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (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
    Fall
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 390 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 390 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain mass
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    3 / 390 (0.77%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    1 / 390 (0.26%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye movement disorder
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    18 / 390 (4.62%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    18 / 21
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 390 (0.00%)
    3 / 195 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (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
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 390 (1.03%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    4 / 390 (1.03%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    3 / 390 (0.77%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 390 (1.28%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (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
    Acute prerenal failure
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (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
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    7 / 390 (1.79%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 390 (0.26%)
    2 / 195 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 390 (0.51%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (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
    3 / 390 (0.77%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (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 / 390 (0.26%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (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
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 390 (1.03%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 390 (2.56%)
    4 / 195 (2.05%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    5 / 390 (1.28%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (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
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 390 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 390 (0.77%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    8 / 390 (2.05%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    5 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    2 / 390 (0.51%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    5 / 390 (1.28%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 390 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Afatinib 50 mg/Day Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    383 / 390 (98.21%)
    167 / 195 (85.64%)
    Investigations
    Weight decreased
         subjects affected / exposed
    37 / 390 (9.49%)
    2 / 195 (1.03%)
         occurrences all number
    41
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    20 / 390 (5.13%)
    6 / 195 (3.08%)
         occurrences all number
    23
    8
    Headache
         subjects affected / exposed
    21 / 390 (5.38%)
    9 / 195 (4.62%)
         occurrences all number
    23
    12
    Dysgeusia
         subjects affected / exposed
    22 / 390 (5.64%)
    1 / 195 (0.51%)
         occurrences all number
    22
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 390 (5.90%)
    3 / 195 (1.54%)
         occurrences all number
    29
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    36 / 390 (9.23%)
    16 / 195 (8.21%)
         occurrences all number
    41
    17
    Chest pain
         subjects affected / exposed
    27 / 390 (6.92%)
    11 / 195 (5.64%)
         occurrences all number
    30
    12
    Fatigue
         subjects affected / exposed
    72 / 390 (18.46%)
    23 / 195 (11.79%)
         occurrences all number
    82
    23
    Mucosal inflammation
         subjects affected / exposed
    95 / 390 (24.36%)
    2 / 195 (1.03%)
         occurrences all number
    118
    3
    Pyrexia
         subjects affected / exposed
    36 / 390 (9.23%)
    7 / 195 (3.59%)
         occurrences all number
    48
    9
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    25 / 390 (6.41%)
    8 / 195 (4.10%)
         occurrences all number
    28
    8
    Constipation
         subjects affected / exposed
    43 / 390 (11.03%)
    24 / 195 (12.31%)
         occurrences all number
    48
    26
    Diarrhoea
         subjects affected / exposed
    334 / 390 (85.64%)
    18 / 195 (9.23%)
         occurrences all number
    552
    22
    Mouth ulceration
         subjects affected / exposed
    51 / 390 (13.08%)
    0 / 195 (0.00%)
         occurrences all number
    67
    0
    Nausea
         subjects affected / exposed
    90 / 390 (23.08%)
    39 / 195 (20.00%)
         occurrences all number
    105
    43
    Stomatitis
         subjects affected / exposed
    82 / 390 (21.03%)
    2 / 195 (1.03%)
         occurrences all number
    98
    2
    Vomiting
         subjects affected / exposed
    75 / 390 (19.23%)
    25 / 195 (12.82%)
         occurrences all number
    103
    35
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    54 / 390 (13.85%)
    36 / 195 (18.46%)
         occurrences all number
    65
    38
    Dyspnoea
         subjects affected / exposed
    54 / 390 (13.85%)
    22 / 195 (11.28%)
         occurrences all number
    58
    24
    Epistaxis
         subjects affected / exposed
    73 / 390 (18.72%)
    1 / 195 (0.51%)
         occurrences all number
    93
    1
    Productive cough
         subjects affected / exposed
    9 / 390 (2.31%)
    13 / 195 (6.67%)
         occurrences all number
    9
    14
    Rhinorrhoea
         subjects affected / exposed
    42 / 390 (10.77%)
    2 / 195 (1.03%)
         occurrences all number
    45
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    27 / 390 (6.92%)
    0 / 195 (0.00%)
         occurrences all number
    34
    0
    Dermatitis acneiform
         subjects affected / exposed
    28 / 390 (7.18%)
    1 / 195 (0.51%)
         occurrences all number
    36
    1
    Dry skin
         subjects affected / exposed
    62 / 390 (15.90%)
    14 / 195 (7.18%)
         occurrences all number
    64
    14
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    30 / 390 (7.69%)
    0 / 195 (0.00%)
         occurrences all number
    31
    0
    Pruritus
         subjects affected / exposed
    73 / 390 (18.72%)
    11 / 195 (5.64%)
         occurrences all number
    90
    12
    Rash
         subjects affected / exposed
    248 / 390 (63.59%)
    23 / 195 (11.79%)
         occurrences all number
    344
    25
    Skin fissures
         subjects affected / exposed
    32 / 390 (8.21%)
    0 / 195 (0.00%)
         occurrences all number
    34
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    17 / 390 (4.36%)
    10 / 195 (5.13%)
         occurrences all number
    18
    10
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    29 / 390 (7.44%)
    22 / 195 (11.28%)
         occurrences all number
    33
    23
    Pain in extremity
         subjects affected / exposed
    27 / 390 (6.92%)
    4 / 195 (2.05%)
         occurrences all number
    30
    4
    Muscle spasms
         subjects affected / exposed
    20 / 390 (5.13%)
    3 / 195 (1.54%)
         occurrences all number
    24
    3
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    25 / 390 (6.41%)
    0 / 195 (0.00%)
         occurrences all number
    27
    0
    Paronychia
         subjects affected / exposed
    131 / 390 (33.59%)
    1 / 195 (0.51%)
         occurrences all number
    145
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    118 / 390 (30.26%)
    22 / 195 (11.28%)
         occurrences all number
    130
    23
    Hypokalaemia
         subjects affected / exposed
    29 / 390 (7.44%)
    4 / 195 (2.05%)
         occurrences all number
    34
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Apr 2009
    • An increase in sample size. Recruitment rate for the study after initiation was higher than initially projected, but the death rate appeared lower than expected. In order to increase expected power for the trial to 90% (initially 85%) Amendment 1 to the CTP increased the randomisation from 400 to 560 patients. The increase in number of deaths to 359 (initially 309) required for analysis provided 90% power. • A pharmacogenetic analysis substudy was added to the protocol; however, this substudy was not conducted. Patient enrolment accrued more quickly than expected; patients were accrued before having the logistics of the amendment implemented entirely. • An additional exclusion criterion. Patients with known interstitial lung disease were to be excluded from the trial. • Clarification of safety monitoring and reporting. A flow chart was added to the CTP which outlined the process for reporting AEs occurring in patients discontinued from the trial. • Removal of the pelvic scan requirement as this scan was not clinically indicated or standard of care for the NSCLC patient population targeted for the trial.
    26 Jul 2010
    The key change to the CTP provided by Global Amendment 2, dated 26 July 2010 was the restricted use of potent P-gp inhibitors and inducers concomitantly with study medication during the trial. The results of a Phase I trial indicated increased exposure to afatinib when taken in combination with ritonavir. The amendment provided guidance regarding the exclusion of P-gp inhibitors and inducers as well as management of patients who were already receiving P-gp inhibitors and inducers.

    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.
    Age of two subjects is missing, as the platform does not provide the option of "missing" category, the two subjects were included to age range Adults (18-64 years): N=460 + N=2 (missing age)
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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