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    Clinical Trial Results:
    ARCHER 1009: A Randomized Double Blind Phase 3 Efficacy and Safety Study of PF-00299804 (Dacomitinib) vs Erlotinib for the Treatment of Advanced Non-Small Cell Lung Cancer Following Progression After, or Intolerance to, at Least One Prior Chemotherapy

    Summary
    EudraCT number
    2010-022656-22
    Trial protocol
    ES   SE   SK   PL   HU   IE   FI   BE   GB   DE   AT   DK   GR  
    Global end of trial date
    14 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Sep 2016
    First version publication date
    23 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A7471009
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate that dacomitinib treatment was superior to erlotinib treatment with respect to Progression Free Survival (PFS) in either of the co-primary populations (all participants with advanced NSCLC and the participants with KRAS-WT tumors with advanced NSCLC). The secondary objectives were to compare overall survival (OS), objective response rate (ORR), and duration of response (DR) between arms in the co-primary populations as well as patient reported outcomes (PROs), pharmacokinetics (PK) and safety and tolerability in each arm.
    Protection of trial subjects
    The investigator ensured that each study participant, or his/her legally acceptable representative, was fully informed about the nature and objectives of the study and possible risks associated with participation. The investigator, or a person designated by the investigator, obtained written informed consent from each participant or the participant's legally acceptable representative before any study-specific activity was performed. The investigator retained the original of each participant's signed consent form. All parties ensured protection of participant personal data and did not include participant names on any sponsor forms, reports, publications, or in any other disclosures, except where required by laws.
    Background therapy
    -
    Evidence for comparator
    Erlotinib is an orally administered EGFR Tyrosine Kinase Inhibitor that has been licensed as a single agent therapy for use in NSCLC after failure of at least one chemotherapy regimen. Regulatory approval was supported by a Phase 3 trial (BR.21) in 731 participants previously treated for advanced non-small cell lung cancer randomized to best supportive care versus best supportive care plus erlotinib 150 mg daily. Participants treated with erlotinib had superior response rate (8.9 percent versus <1 percent), PFS (10 versus 8 weeks) and OS (6.7 versus 4.7 months) compared to supportive care alone.
    Actual start date of recruitment
    16 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    China: 31
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    Greece: 18
    Country: Number of subjects enrolled
    Hungary: 38
    Country: Number of subjects enrolled
    India: 5
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    Japan: 103
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Poland: 51
    Country: Number of subjects enrolled
    Russian Federation: 66
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 36
    Country: Number of subjects enrolled
    Spain: 104
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Switzerland: 30
    Country: Number of subjects enrolled
    United Kingdom: 40
    Country: Number of subjects enrolled
    United States: 177
    Country: Number of subjects enrolled
    France: 54
    Worldwide total number of subjects
    878
    EEA total number of subjects
    409
    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)
    490
    From 65 to 84 years
    385
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 134 sites with 878 participants randomized in a 1:1 ratio to 1 of 2 treatment arms, of these 872 were treated. Eligible participants who provided written informed consent and met all inclusion and exclusion criteria were assigned a Single Subject Identification number and randomized by the central randomization system.

    Pre-assignment
    Screening details
    There were no significant study milestones following participant enrollment, but prior to group assignment.

    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
    Investigator, Monitor, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A (blinded dacomitinib and blinded erlotinib placebo)
    Arm description
    Participants randomized to Arm A received dacomitinib 45 mg orally once daily and erlotinib 150 mg placebo orally once daily. Participants began treatment within 3 days after randomization and continued treatment without breaks until they experienced unacceptable toxicity, tumor progression, or death.
    Arm type
    Experimental

    Investigational medicinal product name
    Dacomitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg orally once daily

    Arm title
    Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Arm description
    Participants randomized to Arm B received erlotinib 150 mg orally once daily and dacomitinib 45 mg placebo orally once daily. Participants began treatment within 3 days after randomization and continued treatment without breaks until they experienced unacceptable toxicity, tumor progression, or death.
    Arm type
    Active comparator

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg orally once daily

    Number of subjects in period 1
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Started
    439
    439
    Completed
    0
    0
    Not completed
    439
    439
         Randomized but not treated
    3
    3
         Other, not specified
    1
    -
         Adverse event, serious fatal
    359
    371
         Study terminated by sponsor
    49
    37
         Consent withdrawn by subject
    23
    24
         Lost to follow-up
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (blinded dacomitinib and blinded erlotinib placebo)
    Reporting group description
    Participants randomized to Arm A received dacomitinib 45 mg orally once daily and erlotinib 150 mg placebo orally once daily. Participants began treatment within 3 days after randomization and continued treatment without breaks until they experienced unacceptable toxicity, tumor progression, or death.

    Reporting group title
    Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Reporting group description
    Participants randomized to Arm B received erlotinib 150 mg orally once daily and dacomitinib 45 mg placebo orally once daily. Participants began treatment within 3 days after randomization and continued treatment without breaks until they experienced unacceptable toxicity, tumor progression, or death.

    Reporting group values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo) Total
    Number of subjects
    439 439 878
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    226 264 490
        From 65-84 years
    211 174 385
        85 years and over
    2 1 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    63.3 ± 9.57 61.7 ± 9.71 -
    Gender, Male/Female
    Units: participants
        Female
    151 162 313
        Male
    288 277 565

    End points

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    End points reporting groups
    Reporting group title
    Arm A (blinded dacomitinib and blinded erlotinib placebo)
    Reporting group description
    Participants randomized to Arm A received dacomitinib 45 mg orally once daily and erlotinib 150 mg placebo orally once daily. Participants began treatment within 3 days after randomization and continued treatment without breaks until they experienced unacceptable toxicity, tumor progression, or death.

    Reporting group title
    Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Reporting group description
    Participants randomized to Arm B received erlotinib 150 mg orally once daily and dacomitinib 45 mg placebo orally once daily. Participants began treatment within 3 days after randomization and continued treatment without breaks until they experienced unacceptable toxicity, tumor progression, or death.

    Primary: Progression-Free Survival (PFS) per Independent Radiologic Review.

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    End point title
    Progression-Free Survival (PFS) per Independent Radiologic Review.
    End point description
    PFS was defined as the time from randomization to the date of disease progression as by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 per Independent Radiologic Review or death due to any cause, whichever occurred first.
    End point type
    Primary
    End point timeframe
    Baseline until progression or death
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    439
    439
    Units: Months
        median (confidence interval 95%)
    2.6 (1.9 to 2.8)
    2.5 (1.9 to 2.8)
    Statistical analysis title
    Analysis for PFS per Independent Review
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.195 [1]
    Method
    1-sided stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.933
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.797
         upper limit
    1.093
    Notes
    [1] - One-sided P-value stratified by EGFR status, KRAS status and baseline ECOG.

    Primary: Progression-Free Survival (PFS) per Independent Radiologic Review in KRAS wild-type (WT) participants.

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    End point title
    Progression-Free Survival (PFS) per Independent Radiologic Review in KRAS wild-type (WT) participants.
    End point description
    PFS was defined as the time from randomization to the date of disease progression as by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 per Independent Radiologic Review or death due to any cause, whichever occurred first. Tumor tissue from participants' original diagnostic biopsies or recently obtained biopsies were analyzed to determine KRAS status.
    End point type
    Primary
    End point timeframe
    Baseline until progression or death
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    256
    263
    Units: Months
        median (confidence interval 95%)
    2.6 (1.9 to 2.9)
    2.5 (1.9 to 3)
    Statistical analysis title
    Analysis for PFS per Independent Review (KRAS-WT)
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.643 [2]
    Method
    1-sided stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.037
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.848
         upper limit
    1.268
    Notes
    [2] - One-sided P-value stratified by EGFR status and baseline ECOG.

    Secondary: PFS based on investigator review.

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    End point title
    PFS based on investigator review.
    End point description
    PFS was defined as the time from randomization to the date of disease progression as by RECIST v1.1 per Investigator's Review or death due to any cause, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    Baseline until progression or death.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    439
    439
    Units: Months
        median (confidence interval 95%)
    1.9 (1.9 to 2.6)
    1.9 (1.8 to 2.1)
    Statistical analysis title
    Analysis for PFS per Investigator Review
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.069 [3]
    Method
    1-sided stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.899
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.78
         upper limit
    1.035
    Notes
    [3] - One sided P-value stratified by EGFR status, KRAS status and baseline ECOG.

    Secondary: PFS based on investigator review in KRAS-WT participants.

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    End point title
    PFS based on investigator review in KRAS-WT participants.
    End point description
    PFS was defined as the time from randomization to the date of disease progression as by RECIST v1.1 per Investigator's Review or death due to any cause, whichever occurred first. Tumor tissue from participants' original diagnostic biopsies or recently obtained biopsies were analyzed to determine KRAS status.
    End point type
    Secondary
    End point timeframe
    Baseline until progression or death.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    256
    263
    Units: Months
        median (confidence interval 95%)
    1.9 (1.8 to 2.7)
    1.9 (1.8 to 2.6)
    Statistical analysis title
    Analysis for PFS per Investigator Review (KRAS-WT)
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.728 [4]
    Method
    1-sided stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.057
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.881
         upper limit
    1.267
    Notes
    [4] - One-sided P-value stratified by EGFR status and baseline ECOG.

    Secondary: Overall Survival (OS).

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    End point title
    Overall Survival (OS).
    End point description
    OS was defined as the time from randomization to the date of death for any cause. In the absence of confirmation of death, survival time was censored at the last date the patient was known to be alive (ie, at their last known alive date from long term follow-up).
    End point type
    Secondary
    End point timeframe
    Baseline until death or last date known to be alive.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    439
    439
    Units: Months
        median (confidence interval 95%)
    7.9 (6.8 to 9)
    8.3 (7.4 to 9.7)
    Statistical analysis title
    Analysis for OS
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    878
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.638 [5]
    Method
    1-sided stratified log-rank test.
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.887
         upper limit
    1.188
    Notes
    [5] - One-sided P-value stratified by EGFR status, KRAS status and baseline ECOG.

    Secondary: OS in KRAS-WT participants.

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    End point title
    OS in KRAS-WT participants.
    End point description
    OS was defined as the time from randomization to the date of death for any cause. In the absence of confirmation of death, survival time was censored at the last date the patient was known to be alive (ie, at their last known alive date from long term follow-up). Tumor tissue from participants' original diagnostic biopsies or recently obtained biopsies were analyzed to determine KRAS status.
    End point type
    Secondary
    End point timeframe
    Baseline until death or last date known to be alive.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    256
    263
    Units: Months
        median (confidence interval 95%)
    8.1 (6.7 to 9.4)
    8.5 (7.5 to 10.2)
    Statistical analysis title
    Analysis for OS (KRAS-WT)
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.775 [6]
    Method
    1-sided stratified log-rank test.
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.078
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.886
         upper limit
    1.312
    Notes
    [6] - One-sided P-value stratified by EGFR status and baseline ECOG.

    Secondary: Best Overall Response (BOR) per Independent Radiologic Review.

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    End point title
    Best Overall Response (BOR) per Independent Radiologic Review.
    End point description
    The BOR was the best response per RECIST (version 1.1) criteria as assessed by independent assessment recorded from randomization until disease progression.
    End point type
    Secondary
    End point timeframe
    Baseline until progression or initiation of new anti-cancer therapy or death.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    439
    439
    Units: Participants
        Complete response
    6
    8
        Partial response
    46
    27
        Stable/No response
    163
    182
        Objective progression
    151
    146
        Indeterminate
    73
    76
    No statistical analyses for this end point

    Secondary: BOR per Investigator review.

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    End point title
    BOR per Investigator review.
    End point description
    The BOR was the best response per RECIST (version 1.1) criteria as assessed by investigator assessment recorded from randomization until disease progression.
    End point type
    Secondary
    End point timeframe
    Baseline until progression or initiation of new anti-cancer therapy or death.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    439
    439
    Units: Participants
        Complete response
    2
    3
        Partial response
    57
    42
        Stable/No response
    136
    136
        Objective progression
    191
    206
        Indeterminate
    53
    52
    No statistical analyses for this end point

    Secondary: Duration of Response (DR) based on Independent Radiologic Review.

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    End point title
    Duration of Response (DR) based on Independent Radiologic Review.
    End point description
    DR was defined as the time from first documentation of response assessed by independent review (CR or PR whichever occurred first) to date of progression or death due to any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Baseline to date of progression or death due to any cause.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    52
    35
    Units: Months
        median (confidence interval 95%)
    9.2 (6.9 to 20.2)
    10.1 (5.6 to 14.8)
    No statistical analyses for this end point

    Secondary: DR based on Investigator review.

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    End point title
    DR based on Investigator review.
    End point description
    DR was defined as the time from first documentation of response assessed by investigator review (CR or PR whichever occurred first) to date of progression or death due to any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Baseline to date of progression or death due to any cause.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    59
    45
    Units: Months
        median (confidence interval 95%)
    10.4 (7.4 to 16.6)
    9.2 (6.2 to 11.3)
    No statistical analyses for this end point

    Secondary: Trough concentrations (Ctrough) of dacomitinib.

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    End point title
    Trough concentrations (Ctrough) of dacomitinib. [7]
    End point description
    Mean Trough Plasma Concentration (Ctrough) values of dacomitinib observed from Cycle 2 through 5, Day 1 for dose compliant participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 5 Day 1
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses was planned for this endpoint
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo)
    Number of subjects analysed
    317
    Units: Ctrough (ng/mL)
    geometric mean (standard deviation)
        Cycle (C) 2 Day (D) 1 (n=317)
    61.0102 ± 43.97236
        C3D1 (n=175)
    46.5229 ± 36.41317
        C4D1 (n=131)
    44.2708 ± 42.80979
        C5D1 (n=95)
    38.0307 ± 25.71773
    No statistical analyses for this end point

    Secondary: Trough concentrations (Ctrough) of PF-05199265.

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    End point title
    Trough concentrations (Ctrough) of PF-05199265. [8]
    End point description
    Mean Ctrough values of PF-05199265 observed from Cycle 2 through 5, Day 1 for dose compliant participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 5 Day 1
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses was planned for this endpoint
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo)
    Number of subjects analysed
    323
    Units: Ctrough (ng/mL)
    geometric mean (standard deviation)
        Cycle (C) 2 Day (D) 1 (n=323)
    6.3695 ± 10.50644
        C3D1 (n=179)
    5.8706 ± 7.27404
        C4D1 (n=136)
    6.438 ± 7.15898
        C5D1 (n=100)
    6.5353 ± 8.45218
    No statistical analyses for this end point

    Secondary: Time to deterioration (TTD) in pain, dyspnea, fatigue or cough patient reported disease symptoms.

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    End point title
    Time to deterioration (TTD) in pain, dyspnea, fatigue or cough patient reported disease symptoms.
    End point description
    TTD defined as the time from first dose (baseline) to the first time a patient's score in pain, dyspnea, fatigue or cough from the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-LC13) increased by ≥10 points. A ≥10 point increase in score had to be maintained for ≥2 consecutive cycles for the symptom to be considered deteriorated. Participants were censored at the last time when they completed an assessment for pain, dyspnea, fatigue or cough if they had not deteriorated. A 10 point or higher change in the score is perceived by participants as clinically significant.
    End point type
    Secondary
    End point timeframe
    From Baseline to deterioration while on study treatment
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    421
    424
    Units: Months
        median (confidence interval 95%)
    1 (1 to 1.9)
    1 (0.9 to 1.4)
    Statistical analysis title
    Analysis for TTD
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    1-sided stratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.902
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.761
         upper limit
    1.069

    Secondary: Mean and difference in mean in Functioning and Global Quality of Life (QOL) as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

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    End point title
    Mean and difference in mean in Functioning and Global Quality of Life (QOL) as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)
    End point description
    EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 to the end of treatment or withdrawal.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    421
    424
    Units: Units on a scale.
    arithmetic mean (confidence interval 95%)
        QLQ-C30 Global QoL
    56.4068 (54.631 to 58.183)
    58.3425 (56.554 to 60.131)
        QLQ-C30 Cognitive Functioning
    83.898 (82.275 to 85.521)
    83.0913 (81.461 to 84.722)
        QLQ-C30 Emotional Functioning
    79.1982 (77.39 to 81.007)
    78.4682 (76.658 to 80.279)
        QLQ-C30 Physical Functioning
    75.2138 (73.25 to 77.21)
    73.6849 (71.719 to 75.651)
        QLQ-C30 Role Functioning
    69.3252 (66.771 to 71.879)
    68.1033 (65.553 to 70.653)
        QLQ-C30 Social Functioning
    74.7868 (72.371 to 77.203)
    76.2839 (73.864 to 78.703)
    Statistical analysis title
    Mixed Model Analysis for Global QoL
    Statistical analysis description
    Analysis presented for QLQ-C30 Global QoL. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -1.9357
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.278
         upper limit
    0.407
    Statistical analysis title
    Mixed Model Analysis for Cognitive Functioning
    Statistical analysis description
    Analysis presented for QLQ-C30 cognitive functioning. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    0.8067
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.312
         upper limit
    2.926
    Statistical analysis title
    Mixed Model Analysis for Emotional Functioning
    Statistical analysis description
    Analysis presented for QLQ-C30 emotional functioning. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.575
         upper limit
    3.035
    Statistical analysis title
    Mixed Model Analysis for Physical Functioning
    Statistical analysis description
    Analysis presented for QLQ-C30 physical functioning. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    1.5289
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.756
         upper limit
    3.814
    Statistical analysis title
    Mixed Model Analysis for Role Functioning
    Statistical analysis description
    Analysis presented for QLQ-C30 role functioning. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    1.2219
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.975
         upper limit
    4.419
    Statistical analysis title
    Mixed Model Analysis for Social Functioning
    Statistical analysis description
    Analysis presented for QLQ-C30 social functioning. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -1.497
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.575
         upper limit
    1.581

    Secondary: Mean and difference in mean in QLQ-C30 Symptoms as Assessed by the EORTC-QLQ-C30.

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    End point title
    Mean and difference in mean in QLQ-C30 Symptoms as Assessed by the EORTC-QLQ-C30.
    End point description
    EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 to the end of treatment or withdrawal.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    421
    424
    Units: Units on a scale.
    arithmetic mean (confidence interval 95%)
        QLQ-C30 Appetite loss
    28.596 (25.841 to 31.351)
    27.3109 (24.532 to 30.09)
        QLQ-C30 Constipation
    8.2496 (6.392 to 10.108)
    14.1726 (12.299 to 16.046)
        QLQ-C30 Diarrhea
    38.8641 (36.303 to 41.425)
    18.6077 (16.017 to 21.198)
        QLQ-C30 Dysponea
    28.3313 (25.736 to 30.927)
    32.8812 (30.282 to 35.48)
        QLQ-C30 Fatigue
    35.0885 (32.848 to 37.329)
    36.7469 (34.494 to 38.999)
        QLQ-C30 Financial Difficulties
    20.0597 (17.76 to 22.36)
    20.0597 (17.76 to 22.36)
        QLQ-C30 Insomnia
    19.7903 (17.413 to 22.168)
    24.6615 (22.276 to 27.046)
        QLQ-C30 Nausea and Vomiting
    9.1438 (7.759 to 10.528)
    9.6362 (8.208 to 11.065)
        QLQ-C30 Pain
    25.185 (22.867 to 27.503)
    24.8754 (22.551 to 27.2)
    Statistical analysis title
    Mixed Model Analysis for Appetite loss
    Statistical analysis description
    Analysis presented for QLQ-C30 Appetite loss. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    1.2851
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.416
         upper limit
    4.986
    Statistical analysis title
    Mixed Model Analysis for Constipation
    Statistical analysis description
    Analysis presented for QLQ-C30 Constipation. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -5.923
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.432
         upper limit
    -3.414
    Statistical analysis title
    Mixed Model Analysis for Diarrhea
    Statistical analysis description
    Analysis presented for QLQ-C30 Diarrhea. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    20.2564
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.874
         upper limit
    23.639
    Statistical analysis title
    Mixed Model Analysis for Dysponea
    Statistical analysis description
    Analysis presented for QLQ-C30 Dysponea. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -4.5499
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.719
         upper limit
    -1.381
    Statistical analysis title
    Mixed Model Analysis for Fatigue
    Statistical analysis description
    Analysis presented for QLQ-C30 Fatigue. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -1.6584
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.442
         upper limit
    1.125
    Statistical analysis title
    Mixed Model Analysis for Financial Difficulties
    Statistical analysis description
    Analysis presented for QLQ-C30 Financial Difficulties. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -0.1469
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.056
         upper limit
    2.762
    Statistical analysis title
    Mixed Model Analysis for Insomnia
    Statistical analysis description
    Analysis presented for QLQ-C30 Insomnia. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -4.8711
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.998
         upper limit
    -1.745
    Statistical analysis title
    Mixed Model Analysis for Nausea and Vomiting
    Statistical analysis description
    Analysis presented for QLQ-C30 Nausea and Vomiting. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -0.4924
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.485
         upper limit
    1.5
    Statistical analysis title
    Mixed Model Analysis for Pain
    Statistical analysis description
    Analysis presented for QLQ-C30 Pain. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    0.3096
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.646
         upper limit
    3.265

    Secondary: Mean and difference in mean in Lung Cancer Symptom Scores as Assessed by the EORTC QLQ- LC13.

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    End point title
    Mean and difference in mean in Lung Cancer Symptom Scores as Assessed by the EORTC QLQ- LC13.
    End point description
    The QLQ-LC13 includes questions specific to the disease associated symptoms (dyspnea, cough, haemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy, and alopecia), and analgesic use of lung cancer patients.
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 to the end of treatment or withdrawal.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    421
    424
    Units: Units on a scale.
    arithmetic mean (confidence interval 95%)
        QLQ-LC13 Trouble Swallowing
    10.1934 (8.36 to 12.027)
    7.5553 (5.711 to 9.4)
        QLQ-LC13 Coughing
    28.379 (26.037 to 30.721)
    32.6294 (30.272 to 34.986)
        QLQ-LC13 Haemoptysis
    3.4751 (2.118 to 4.832)
    4.5515 (2.615 to 6.488)
        QLQ-LC13 Sore Mouth
    20.4054 (18.115 to 22.696)
    11.0509 (8.731 to 13.371)
        QLQ-LC13 Shortness of Breath
    27.1651 (25.161 to 29.169)
    28.3413 (26.346 to 30.337)
        QLQ-LC13 Peripheral Neuropathy
    19.4905 (17.222 to 21.759)
    20.1284 (17.85 to 22.407)
        QLQ-LC13 Alopecia
    14.8327 (11.848 to 17.818)
    16.1963 (13.22 to 19.173)
        QLQ-LC13 Pain in Chest
    16.4268 (14.335 to 18.518)
    17.643 (15.541 to 19.745)
        QLQ-LC13 Pain in Arm or Shoulder
    15.984 (13.864 to 18.104)
    17.1315 (14.989 to 19.274)
        QLQ-LC13 Pain in other Parts
    21.5437 (19.02 to 24.067)
    22.6124 (20.06 to 25.165)
        QLQ-LC13 Any Med for Pain
    61.8437 (58.169 to 65.519)
    61.8115 (58.038 to 65.585)
    Statistical analysis title
    Mixed Model Analysis for Trouble Swallowing
    Statistical analysis description
    Analysis presented for Trouble Swallowing as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    2.6381
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.172
         upper limit
    5.104
    Statistical analysis title
    Mixed Model Analysis for Coughing
    Statistical analysis description
    Analysis presented for Coughing as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -4.2504
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.178
         upper limit
    -1.322
    Statistical analysis title
    Mixed Model Analysis for Haemoptysis
    Statistical analysis description
    Analysis presented for Haemoptysis as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -1.0764
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.997
         upper limit
    1.845
    Statistical analysis title
    Mixed Model Analysis for Sore Mouth
    Statistical analysis description
    Analysis presented for Sore Mouth as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    9.3545
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.211
         upper limit
    12.497
    Statistical analysis title
    Mixed Model Analysis for Shortness of Breath
    Statistical analysis description
    Analysis presented for Shortness of Breath as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -1.1762
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.56
         upper limit
    1.208
    Statistical analysis title
    Mixed Model Analysis for Peripheral Neuropathy
    Statistical analysis description
    Analysis presented for Peripheral Neuropathy as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -0.6378
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.684
         upper limit
    2.408
    Statistical analysis title
    Mixed Model Analysis for Alopecia
    Statistical analysis description
    Analysis presented for Alopecia as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -1.3637
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.546
         upper limit
    1.819
    Statistical analysis title
    Mixed Model Analysis for Pain in Chest
    Statistical analysis description
    Analysis presented for Pain in Chest as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -1.2163
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.885
         upper limit
    1.452
    Statistical analysis title
    Mixed Model Analysis for Pain in Arm or Shoulder
    Statistical analysis description
    Analysis presented for Pain in Arm or Shoulder as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -1.1475
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.902
         upper limit
    1.607
    Statistical analysis title
    Mixed Model Analysis for Pain in other Parts
    Statistical analysis description
    Analysis presented for Pain Other Parts as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -1.0687
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.488
         upper limit
    2.351
    Statistical analysis title
    Mixed Model Analysis for Any Med for Pain
    Statistical analysis description
    Analysis presented for Any Med for Pain as Assessed by the EORTC-QLQ-LC13. Estimated change from baseline was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    0.0322
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.847
         upper limit
    4.911

    Secondary: Mean and difference in mean of the EuroQoL-5 Dimensions (EQ-5D) Visual Analogue Scale (VAS) Score

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    End point title
    Mean and difference in mean of the EuroQoL-5 Dimensions (EQ-5D) Visual Analogue Scale (VAS) Score
    End point description
    The EQ-5D is a validated and reliable self-report preference-based measure developed by the EuroQoL Group to assess health-related quality of life. It consists of the EQ-5D descriptive system and a visual analogue scale-the EQ VAS. The EQ-5D descriptive system measures a participants' health state on 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting “no health problems,” “moderate health problems,” and “extreme health problems.” The EQ VAS records the respondent’s self-rated health on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 to the end of treatment or withdrawal.
    End point values
    Arm A (blinded dacomitinib and blinded erlotinib placebo) Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects analysed
    421
    424
    Units: Units on a scale.
        arithmetic mean (confidence interval 95%)
    65.1908 (63.519 to 66.863)
    65.5794 (63.908 to 67.25)
    Statistical analysis title
    Mixed Model Analysis for EQ-5D VAS
    Statistical analysis description
    Analysis presented for EQ-5D VAS. Mean difference was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects). Confidence intervals provided were not adjusted for multiplicity.
    Comparison groups
    Arm A (blinded dacomitinib and blinded erlotinib placebo) v Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Number of subjects included in analysis
    845
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Repeated measures mixed-effects model.
    Parameter type
    Mean difference
    Point estimate
    -0.3886
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.413
         upper limit
    1.636

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE reporting period is from 1st dose of study drug through 28 days after last dose of study drug. SAE reporting period is from informed consent through 28 days after last dose of study drug.
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Arm B (blinded erlotinib and blinded dacomitinib placebo)
    Reporting group description
    Participants randomized to Arm B received erlotinib 150 mg orally once daily and dacomitinib 45 mg placebo orally once daily. Participants began treatment within 3 days after randomization and continued treatment without breaks until they experienced unacceptable toxicity, tumor progression, or death.

    Reporting group title
    Arm A (blinded dacomitinib and blinded erlotinib placebo)
    Reporting group description
    Participants randomized to Arm A received dacomitinib 45 mg orally once daily and erlotinib 150 mg placebo orally once daily. Participants began treatment within 3 days after randomization and continued treatment without breaks until they experienced unacceptable toxicity, tumor progression, or death.

    Serious adverse events
    Arm B (blinded erlotinib and blinded dacomitinib placebo) Arm A (blinded dacomitinib and blinded erlotinib placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    169 / 436 (38.76%)
    178 / 436 (40.83%)
         number of deaths (all causes)
    69
    80
         number of deaths resulting from adverse events
    1
    5
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Phlebitis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Internal fixation of fracture
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung cancer metastatic
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung squamous cell carcinoma metastatic
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (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
    1 / 436 (0.23%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 54
    0 / 57
    Tumour associated fever
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 436 (0.69%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Axillary pain
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site pain
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 436 (0.69%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 436 (0.23%)
    5 / 436 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    1 / 1
    3 / 3
    Disease progression
         subjects affected / exposed
    48 / 436 (11.01%)
    53 / 436 (12.16%)
         occurrences causally related to treatment / all
    0 / 48
    0 / 53
         deaths causally related to treatment / all
    0 / 55
    0 / 59
    Drug interaction
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    10 / 436 (2.29%)
    4 / 436 (0.92%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 436 (0.92%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 436 (0.00%)
    3 / 436 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 436 (0.46%)
    5 / 436 (1.15%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 436 (0.00%)
    3 / 436 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation oesophagitis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration bronchial
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood calcium decreased
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 436 (0.69%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 436 (0.69%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 436 (0.23%)
    3 / 436 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Bronchitis chronic
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 436 (1.83%)
    8 / 436 (1.83%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Haemoptysis
         subjects affected / exposed
    1 / 436 (0.23%)
    5 / 436 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 436 (0.69%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pleural effusion
         subjects affected / exposed
    2 / 436 (0.46%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 436 (0.46%)
    3 / 436 (0.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 436 (0.69%)
    4 / 436 (0.92%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 436 (1.15%)
    4 / 436 (0.92%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 436 (1.83%)
    3 / 436 (0.69%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (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 / 436 (0.46%)
    4 / 436 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    2 / 436 (0.46%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         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
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery embolism
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (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 pain
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 436 (1.61%)
    20 / 436 (4.59%)
         occurrences causally related to treatment / all
    6 / 7
    19 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 436 (0.92%)
    4 / 436 (0.92%)
         occurrences causally related to treatment / all
    4 / 5
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatitis acute
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 436 (0.69%)
    5 / 436 (1.15%)
         occurrences causally related to treatment / all
    2 / 4
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 436 (0.46%)
    4 / 436 (0.92%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 436 (0.46%)
    4 / 436 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exfoliative rash
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 436 (0.46%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (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
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (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
    2 / 436 (0.46%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (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
    Cachexia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    4 / 436 (0.92%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    6 / 436 (1.38%)
    13 / 436 (2.98%)
         occurrences causally related to treatment / all
    3 / 7
    11 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acne pustular
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 436 (0.69%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 436 (0.23%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 436 (0.00%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (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
    3 / 436 (0.69%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (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
    15 / 436 (3.44%)
    12 / 436 (2.75%)
         occurrences causally related to treatment / all
    0 / 17
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pyelonephritis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rash pustular
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 436 (0.69%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rhinitis
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 436 (0.69%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 436 (0.23%)
    0 / 436 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Viral infection
         subjects affected / exposed
    0 / 436 (0.00%)
    1 / 436 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 436 (0.23%)
    2 / 436 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Arm B (blinded erlotinib and blinded dacomitinib placebo) Arm A (blinded dacomitinib and blinded erlotinib placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    417 / 436 (95.64%)
    424 / 436 (97.25%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    59 / 436 (13.53%)
    65 / 436 (14.91%)
         occurrences all number
    91
    84
    Chest pain
         subjects affected / exposed
    36 / 436 (8.26%)
    21 / 436 (4.82%)
         occurrences all number
    39
    23
    Fatigue
         subjects affected / exposed
    92 / 436 (21.10%)
    78 / 436 (17.89%)
         occurrences all number
    146
    118
    General physical health deterioration
         subjects affected / exposed
    11 / 436 (2.52%)
    9 / 436 (2.06%)
         occurrences all number
    12
    12
    Malaise
         subjects affected / exposed
    7 / 436 (1.61%)
    9 / 436 (2.06%)
         occurrences all number
    14
    18
    Mucosal inflammation
         subjects affected / exposed
    28 / 436 (6.42%)
    67 / 436 (15.37%)
         occurrences all number
    34
    101
    Oedema peripheral
         subjects affected / exposed
    29 / 436 (6.65%)
    17 / 436 (3.90%)
         occurrences all number
    31
    25
    Pain
         subjects affected / exposed
    21 / 436 (4.82%)
    12 / 436 (2.75%)
         occurrences all number
    24
    12
    Pyrexia
         subjects affected / exposed
    36 / 436 (8.26%)
    41 / 436 (9.40%)
         occurrences all number
    44
    56
    Xerosis
         subjects affected / exposed
    7 / 436 (1.61%)
    14 / 436 (3.21%)
         occurrences all number
    8
    19
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    19 / 436 (4.36%)
    16 / 436 (3.67%)
         occurrences all number
    20
    17
    Depression
         subjects affected / exposed
    9 / 436 (2.06%)
    7 / 436 (1.61%)
         occurrences all number
    10
    8
    Insomnia
         subjects affected / exposed
    25 / 436 (5.73%)
    14 / 436 (3.21%)
         occurrences all number
    25
    15
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    10 / 436 (2.29%)
    8 / 436 (1.83%)
         occurrences all number
    11
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    22 / 436 (5.05%)
    8 / 436 (1.83%)
         occurrences all number
    40
    10
    Aspartate aminotransferase increased
         subjects affected / exposed
    21 / 436 (4.82%)
    10 / 436 (2.29%)
         occurrences all number
    37
    12
    Blood bilirubin increased
         subjects affected / exposed
    11 / 436 (2.52%)
    0 / 436 (0.00%)
         occurrences all number
    25
    0
    Blood creatinine increased
         subjects affected / exposed
    13 / 436 (2.98%)
    17 / 436 (3.90%)
         occurrences all number
    17
    26
    Weight decreased
         subjects affected / exposed
    38 / 436 (8.72%)
    64 / 436 (14.68%)
         occurrences all number
    46
    77
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    10 / 436 (2.29%)
    5 / 436 (1.15%)
         occurrences all number
    12
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    43 / 436 (9.86%)
    35 / 436 (8.03%)
         occurrences all number
    57
    64
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    73 / 436 (16.74%)
    54 / 436 (12.39%)
         occurrences all number
    85
    63
    Dysphonia
         subjects affected / exposed
    9 / 436 (2.06%)
    8 / 436 (1.83%)
         occurrences all number
    9
    9
    Dyspnoea
         subjects affected / exposed
    81 / 436 (18.58%)
    76 / 436 (17.43%)
         occurrences all number
    102
    99
    Dyspnoea exertional
         subjects affected / exposed
    9 / 436 (2.06%)
    10 / 436 (2.29%)
         occurrences all number
    9
    12
    Epistaxis
         subjects affected / exposed
    23 / 436 (5.28%)
    37 / 436 (8.49%)
         occurrences all number
    26
    42
    Haemoptysis
         subjects affected / exposed
    37 / 436 (8.49%)
    23 / 436 (5.28%)
         occurrences all number
    42
    25
    Nasal inflammation
         subjects affected / exposed
    0 / 436 (0.00%)
    9 / 436 (2.06%)
         occurrences all number
    0
    11
    Oropharyngeal pain
         subjects affected / exposed
    8 / 436 (1.83%)
    9 / 436 (2.06%)
         occurrences all number
    8
    11
    Pleural effusion
         subjects affected / exposed
    5 / 436 (1.15%)
    11 / 436 (2.52%)
         occurrences all number
    5
    14
    Productive cough
         subjects affected / exposed
    12 / 436 (2.75%)
    13 / 436 (2.98%)
         occurrences all number
    14
    13
    Rhinorrhoea
         subjects affected / exposed
    7 / 436 (1.61%)
    9 / 436 (2.06%)
         occurrences all number
    8
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    25 / 436 (5.73%)
    17 / 436 (3.90%)
         occurrences all number
    26
    19
    Dysgeusia
         subjects affected / exposed
    22 / 436 (5.05%)
    34 / 436 (7.80%)
         occurrences all number
    23
    42
    Headache
         subjects affected / exposed
    20 / 436 (4.59%)
    18 / 436 (4.13%)
         occurrences all number
    28
    37
    Eye disorders
    Dry eye
         subjects affected / exposed
    5 / 436 (1.15%)
    16 / 436 (3.67%)
         occurrences all number
    5
    19
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    19 / 436 (4.36%)
    21 / 436 (4.82%)
         occurrences all number
    22
    29
    Abdominal pain upper
         subjects affected / exposed
    20 / 436 (4.59%)
    21 / 436 (4.82%)
         occurrences all number
    28
    22
    Cheilitis
         subjects affected / exposed
    8 / 436 (1.83%)
    13 / 436 (2.98%)
         occurrences all number
    9
    18
    Constipation
         subjects affected / exposed
    59 / 436 (13.53%)
    43 / 436 (9.86%)
         occurrences all number
    72
    50
    Diarrhoea
         subjects affected / exposed
    217 / 436 (49.77%)
    322 / 436 (73.85%)
         occurrences all number
    371
    692
    Dry mouth
         subjects affected / exposed
    13 / 436 (2.98%)
    14 / 436 (3.21%)
         occurrences all number
    14
    14
    Dyspepsia
         subjects affected / exposed
    16 / 436 (3.67%)
    20 / 436 (4.59%)
         occurrences all number
    17
    21
    Dysphagia
         subjects affected / exposed
    16 / 436 (3.67%)
    16 / 436 (3.67%)
         occurrences all number
    21
    16
    Gastrooesophageal reflux disease
         subjects affected / exposed
    11 / 436 (2.52%)
    9 / 436 (2.06%)
         occurrences all number
    11
    9
    Nausea
         subjects affected / exposed
    81 / 436 (18.58%)
    90 / 436 (20.64%)
         occurrences all number
    105
    113
    Stomatitis
         subjects affected / exposed
    52 / 436 (11.93%)
    81 / 436 (18.58%)
         occurrences all number
    60
    133
    Vomiting
         subjects affected / exposed
    70 / 436 (16.06%)
    71 / 436 (16.28%)
         occurrences all number
    103
    94
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    19 / 436 (4.36%)
    23 / 436 (5.28%)
         occurrences all number
    30
    52
    Alopecia
         subjects affected / exposed
    18 / 436 (4.13%)
    14 / 436 (3.21%)
         occurrences all number
    19
    14
    Dermatitis acneiform
         subjects affected / exposed
    88 / 436 (20.18%)
    81 / 436 (18.58%)
         occurrences all number
    160
    171
    Dry skin
         subjects affected / exposed
    84 / 436 (19.27%)
    86 / 436 (19.72%)
         occurrences all number
    103
    127
    Erythema
         subjects affected / exposed
    21 / 436 (4.82%)
    18 / 436 (4.13%)
         occurrences all number
    29
    21
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    7 / 436 (1.61%)
    16 / 436 (3.67%)
         occurrences all number
    7
    21
    Pruritus
         subjects affected / exposed
    54 / 436 (12.39%)
    49 / 436 (11.24%)
         occurrences all number
    77
    89
    Rash
         subjects affected / exposed
    203 / 436 (46.56%)
    218 / 436 (50.00%)
         occurrences all number
    379
    387
    Rash maculo-papular
         subjects affected / exposed
    12 / 436 (2.75%)
    18 / 436 (4.13%)
         occurrences all number
    22
    49
    Skin exfoliation
         subjects affected / exposed
    10 / 436 (2.29%)
    15 / 436 (3.44%)
         occurrences all number
    12
    17
    Skin fissures
         subjects affected / exposed
    19 / 436 (4.36%)
    24 / 436 (5.50%)
         occurrences all number
    25
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 436 (2.29%)
    15 / 436 (3.44%)
         occurrences all number
    13
    16
    Back pain
         subjects affected / exposed
    30 / 436 (6.88%)
    35 / 436 (8.03%)
         occurrences all number
    33
    40
    Muscle spasms
         subjects affected / exposed
    11 / 436 (2.52%)
    15 / 436 (3.44%)
         occurrences all number
    14
    18
    Muscular weakness
         subjects affected / exposed
    9 / 436 (2.06%)
    2 / 436 (0.46%)
         occurrences all number
    11
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    8 / 436 (1.83%)
    13 / 436 (2.98%)
         occurrences all number
    8
    14
    Musculoskeletal pain
         subjects affected / exposed
    19 / 436 (4.36%)
    20 / 436 (4.59%)
         occurrences all number
    24
    21
    Myalgia
         subjects affected / exposed
    9 / 436 (2.06%)
    2 / 436 (0.46%)
         occurrences all number
    9
    2
    Pain in extremity
         subjects affected / exposed
    26 / 436 (5.96%)
    26 / 436 (5.96%)
         occurrences all number
    26
    28
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    119 / 436 (27.29%)
    138 / 436 (31.65%)
         occurrences all number
    161
    208
    Dehydration
         subjects affected / exposed
    14 / 436 (3.21%)
    26 / 436 (5.96%)
         occurrences all number
    15
    30
    Hypoalbuminaemia
         subjects affected / exposed
    16 / 436 (3.67%)
    8 / 436 (1.83%)
         occurrences all number
    21
    10
    Hypokalaemia
         subjects affected / exposed
    21 / 436 (4.82%)
    28 / 436 (6.42%)
         occurrences all number
    26
    35
    Hypomagnesaemia
         subjects affected / exposed
    19 / 436 (4.36%)
    22 / 436 (5.05%)
         occurrences all number
    25
    25
    Hyponatraemia
         subjects affected / exposed
    13 / 436 (2.98%)
    13 / 436 (2.98%)
         occurrences all number
    21
    14
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    14 / 436 (3.21%)
    29 / 436 (6.65%)
         occurrences all number
    16
    34
    Cystitis
         subjects affected / exposed
    5 / 436 (1.15%)
    9 / 436 (2.06%)
         occurrences all number
    6
    10
    Lower respiratory tract infection
         subjects affected / exposed
    9 / 436 (2.06%)
    5 / 436 (1.15%)
         occurrences all number
    13
    5
    Nasopharyngitis
         subjects affected / exposed
    20 / 436 (4.59%)
    19 / 436 (4.36%)
         occurrences all number
    22
    27
    Paronychia
         subjects affected / exposed
    44 / 436 (10.09%)
    94 / 436 (21.56%)
         occurrences all number
    70
    211
    Rash pustular
         subjects affected / exposed
    9 / 436 (2.06%)
    9 / 436 (2.06%)
         occurrences all number
    12
    10
    Respiratory tract infection
         subjects affected / exposed
    5 / 436 (1.15%)
    10 / 436 (2.29%)
         occurrences all number
    6
    11
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 436 (2.75%)
    13 / 436 (2.98%)
         occurrences all number
    15
    14
    Urinary tract infection
         subjects affected / exposed
    19 / 436 (4.36%)
    18 / 436 (4.13%)
         occurrences all number
    26
    32

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2012
    This amendment clarified wording/guidance for pulmonary toxicity and on-study LVEF evaluation. Also updated information and guidance on drugs dependent on CYP2D6 for metabolism, established the IOBU-SDMC with the scope to enhance safety data monitoring.
    22 Apr 2013
    Amended references to the summary of product characteristics as the single reference safety document for the comparator erlotinib, updated dacomitinib concomitant medication guide and included guidance on the use of acid-reducing agents.

    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.
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