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    Clinical Trial Results:
    Gemcitabine in Combination with the Oral Irreversible ErbB Inhibitor Afatinib versus Gemcitabine Alone in Patients with Metastatic Pancreatic Cancer: an Explorative Randomized Phase II Trial

    Summary
    EudraCT number
    2011-004063-77
    Trial protocol
    DE  
    Global end of trial date
    02 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Feb 2019
    First version publication date
    23 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACCEPT
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Klinikum der Universität München-Großhadern
    Sponsor organisation address
    Marchioninistr. 15, München, Germany, 81377
    Public contact
    Study Office, Klinikum der Universität München - Großhadern, +49 89440072208, Matthias.Wolff@med.uni-muenchen.de
    Scientific contact
    Study Office, Klinikum der Universität München - Großhadern, +49 89440072208, Matthias.Wolff@med.uni-muenchen.de
    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
    28 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the combination of afatinib plus gemcitabine is superior to gemcitabine alone in the treatment of metastatic pancreatic cancer.
    Protection of trial subjects
    This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable European and national regulations (including European Directive 2001/20/EC and German Drug Law (AMG)) and with the ethical principles laid down in the Declaration of Helsinki. Participating subjects signed the informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    23 Apr 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 119
    Worldwide total number of subjects
    119
    EEA total number of subjects
    119
    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)
    25
    From 65 to 84 years
    91
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    34 investigational sites in Germany were participating. 119 subjects were screened and enrolled at 25 of these 34 investigational sites. The first patient was enrolled on 23-Apr-2013, the last patient on 31-Jan-2017.

    Pre-assignment
    Screening details
    Patients with histologically (not cytologically) confirmed diagnosis of metastatic pancreatic adenocarcinoma (stage IV according to UICC 2009 classification: each T, each N, M1), who were treatment-naive for locally advanced and metastatic disease. - ECOG 0-1.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    The randomization ratio is set to 2:1 for the experimental arm (with gemcitabine plus afatinib).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Gemcitabine plus Afatinib
    Arm description
    Intravenous administration of 1000 mg/m² BSA gemcitabine on D1, D8, D15 of each 28-day treatment cycle and oral administration of 40 mg afatinib daily. Treatment was continued until disease progression, unacceptable toxicity or other reasons (e.g. patient’s wish, investigator’s decision).
    Arm type
    Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg afatinib flat dose, p.o. once daily.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Powder for solution for infusion, Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration of 1000 mg/m² BSA, 30 min intravenous infusion on Day1, Day8, and D15. Repetition of the cycle every 4 weeks.

    Arm title
    Gemcitabine
    Arm description
    Intravenous administration of 1000 mg/m² BSA gemcitabine on D1, D8, D15 of each 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity or other reasons (e.g. patient’s wish, investigator’s decision).
    Arm type
    Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Powder for solution for infusion, Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Intravenous administration of 1000 mg/m² BSA, 30 min infusion, on Day1, Day 8, Day 15. Repetition of the cycles every four weeks.

    Number of subjects in period 1 [1]
    Gemcitabine plus Afatinib Gemcitabine
    Started
    77
    38
    Completed
    0
    0
    Not completed
    77
    38
         Progression
    33
    20
         Protocol deviation
    4
    2
         Death
    13
    4
         Physician decision
    7
    4
         Lack of compliance
    -
    1
         Adverse event, non-fatal
    8
    3
         Patients' wish
    11
    4
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Four patients had not been treated, two patients in arm "Gemcitabine plus Afatinib" and two patients in arm "Gemcitabine".

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gemcitabine plus Afatinib
    Reporting group description
    Intravenous administration of 1000 mg/m² BSA gemcitabine on D1, D8, D15 of each 28-day treatment cycle and oral administration of 40 mg afatinib daily. Treatment was continued until disease progression, unacceptable toxicity or other reasons (e.g. patient’s wish, investigator’s decision).

    Reporting group title
    Gemcitabine
    Reporting group description
    Intravenous administration of 1000 mg/m² BSA gemcitabine on D1, D8, D15 of each 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity or other reasons (e.g. patient’s wish, investigator’s decision).

    Reporting group values
    Gemcitabine plus Afatinib Gemcitabine Total
    Number of subjects
    77 38 115
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    17 6 23
        From 65-84 years
    57 32 89
        85 years and over
    3 0 3
    Age continuous
    Note: Age at time of randomisation.
    Units: years
        median (full range (min-max))
    73.0 (37 to 89) 72.5 (55 to 84) -
    Gender categorical
    Units: Subjects
        Female
    33 17 50
        Male
    44 21 65
    ECOG Performance status
    Units: Subjects
        ECOG 0
    46 21 67
        ECOG 1
    31 17 48
    Stratification factor - CA 19-9
    Note: Stratification factor at the time of randomisation. It is possible that in the CRF another value is documented during baseline.
    Units: Subjects
        ≤ 1000 U/mL
    41 18 59
        > 1000 U/mL
    36 20 56
    Stratification factor - Bilirubin
    Note: Stratification factor at the time of randomisation. It is possible that in the CRF another value is documented during baseline.
    Units: Subjects
        Bilirubin normal (≤ 1 x ULN)
    70 33 103
        Bilirubin elevated (1.1 - <2xULN, <5xULN)
    7 5 12
    Combination of the stratification factors
    Note: Stratification factor at time of randomisation. It is possible that in the CRF another value is documented during baseline.
    Units: Subjects
        CA19-9 ≤ 1000 U/mL, Bilirubin ≤ 1 x ULN
    39 17 56
        CA19-9 ≤ 1000 U/mL, Bilirubin 1.1 - <2xULN,<5xULN
    2 1 3
        CA19-9 > 1000 U/mL, Bilirubin ≤ 1 x ULN
    31 16 47
        CA19-9 > 1000 U/mL, Bilirubin 1.1 - <2xULN,<5xULN
    5 4 9
    Subject analysis sets

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients, who have been treated with at least one dose of the study medication (gemcitabine, afatinib).

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Full Analysis Set is a subset of the safety analysis set, which included only patients, who had received at least one dose of study drug in this study and fulfilled the selection criteria of the study. Seven patients were excluded from the statistical analysis because they had not fulfilled the selection criteria and/or their baseline data were not available and it was impossible to verify proper inclusion according to selection criteria. These patients were determined in a blinded review in cooperation between the CRO and the sponsor representative.

    Subject analysis set title
    Per-Protocol set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Patients of the Full Analysis Set, who passed at least two cycles of therapy according to the protocol and reached the first staging (unless their treatment had to be interrupted because of early progression or early death). The Per-Protocol set is a subset of the safety analysis set and the full analysis set.

    Subject analysis sets values
    Safety set Full Analysis Set Per-Protocol set
    Number of subjects
    115
    108
    92
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    23
    21
    19
        From 65-84 years
    89
    84
    71
        85 years and over
    3
    3
    2
    Age continuous
    Note: Age at time of randomisation.
    Units: years
        median (full range (min-max))
    73.0 (37 to 89)
    73.0 (37 to 89)
    73.5 (37 to 89)
    Gender categorical
    Units: Subjects
        Female
    50
    47
    40
        Male
    65
    61
    52
    ECOG Performance status
    Units: Subjects
        ECOG 0
    67
    64
    53
        ECOG 1
    48
    44
    39
    Stratification factor - CA 19-9
    Note: Stratification factor at the time of randomisation. It is possible that in the CRF another value is documented during baseline.
    Units: Subjects
        ≤ 1000 U/mL
    59
    54
    41
        > 1000 U/mL
    56
    54
    51
    Stratification factor - Bilirubin
    Note: Stratification factor at the time of randomisation. It is possible that in the CRF another value is documented during baseline.
    Units: Subjects
        Bilirubin normal (≤ 1 x ULN)
    103
    97
    81
        Bilirubin elevated (1.1 - <2xULN, <5xULN)
    12
    11
    11
    Combination of the stratification factors
    Note: Stratification factor at time of randomisation. It is possible that in the CRF another value is documented during baseline.
    Units: Subjects
        CA19-9 ≤ 1000 U/mL, Bilirubin ≤ 1 x ULN
    56
    52
    39
        CA19-9 ≤ 1000 U/mL, Bilirubin 1.1 - <2xULN,<5xULN
    3
    2
    2
        CA19-9 > 1000 U/mL, Bilirubin ≤ 1 x ULN
    47
    45
    42
        CA19-9 > 1000 U/mL, Bilirubin 1.1 - <2xULN,<5xULN
    9
    9
    9

    End points

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    End points reporting groups
    Reporting group title
    Gemcitabine plus Afatinib
    Reporting group description
    Intravenous administration of 1000 mg/m² BSA gemcitabine on D1, D8, D15 of each 28-day treatment cycle and oral administration of 40 mg afatinib daily. Treatment was continued until disease progression, unacceptable toxicity or other reasons (e.g. patient’s wish, investigator’s decision).

    Reporting group title
    Gemcitabine
    Reporting group description
    Intravenous administration of 1000 mg/m² BSA gemcitabine on D1, D8, D15 of each 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity or other reasons (e.g. patient’s wish, investigator’s decision).

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients, who have been treated with at least one dose of the study medication (gemcitabine, afatinib).

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Full Analysis Set is a subset of the safety analysis set, which included only patients, who had received at least one dose of study drug in this study and fulfilled the selection criteria of the study. Seven patients were excluded from the statistical analysis because they had not fulfilled the selection criteria and/or their baseline data were not available and it was impossible to verify proper inclusion according to selection criteria. These patients were determined in a blinded review in cooperation between the CRO and the sponsor representative.

    Subject analysis set title
    Per-Protocol set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Patients of the Full Analysis Set, who passed at least two cycles of therapy according to the protocol and reached the first staging (unless their treatment had to be interrupted because of early progression or early death). The Per-Protocol set is a subset of the safety analysis set and the full analysis set.

    Primary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    The overall survival (OS) was defined as the duration from the first administration of gemcitabine/afatinib to death. Patients without events were censored at the date of their last contact.
    End point type
    Primary
    End point timeframe
    Survival status was recorded up to 12 months after the end of treatment.
    End point values
    Gemcitabine plus Afatinib Gemcitabine
    Number of subjects analysed
    71
    37
    Units: months
        median (confidence interval 80%)
    7.3 (6.2 to 8.4)
    7.4 (6.0 to 9.1)
    Statistical analysis title
    null hypothesis test of the primary endpoint (FAS)
    Comparison groups
    Gemcitabine plus Afatinib v Gemcitabine
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.8038 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.058
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.791
         upper limit
    1.414
    Notes
    [1] - HR > 1 favors Gemcitabine/Afatinib.
    [2] - OS was defined as the duration from first the administration of gemcitabine and or afatinib to death. Patients without events were censored at the date of their last contact.

    Secondary: Progression-free survival (PFS)

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    End point title
    Progression-free survival (PFS)
    End point description
    Survival status of each participating patient was recorded up to 12 months after the end of treatment. Additional statistical analyses: 2-sided log-rank test with 95% CI for HR, stratified by the baseline values of CA 19-9. Of note, HR > 1 favours "≤ 1000 U/mL. Comparison of the groups after stratification by CA 19-9 value ≤ 1000 U/ml and > 1000 U/ml within each treatment arm: Within the experimental arm in the FAS (N=71): median(≤1000 U/ml )=4.7, median(>1000U/ml)= 3.0; p= 0.0042, HR= 2.057 (CI: 1.240 to 3.413). Within the control arm in the FAS (N=37): median(≤1000 U/ml)= 5.3, median (>1000U/ml)= 3.8; p= 0.0836, HR= 1.825 (CI: 0.910 to 3.663). Comparison of the groups after stratification by CA 19-9 value ≤ 1000 U/ml and > 1000 U/ml within the FAS (N=108): median(≤1000 U/ml)= 5.2, median (>1000U/ml)= 3.4; p= 0.0009, HR= 1.952 (CI: 1.301 to 2.929).
    End point type
    Secondary
    End point timeframe
    PFS was defined as the duration from the date of first administration of Gemcitabine/Afatinib to first progression (acc. to RECIST 1.1) or death, whichever occurred first. Patients without an event were censored at the last tumour staging by imaging.
    End point values
    Gemcitabine plus Afatinib Gemcitabine
    Number of subjects analysed
    71
    37
    Units: months
        median (confidence interval 95%)
    3.9 (3.2 to 5.2)
    3.9 (2.0 to 5.8)
    Statistical analysis title
    Kaplan-Meier analysis of PFS
    Comparison groups
    Gemcitabine plus Afatinib v Gemcitabine
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [3]
    P-value
    = 0.4282 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.846
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.558
         upper limit
    1.283
    Notes
    [3] - exploratory only
    [4] - log-rank test (2-sided, alpha=0.05)

    Secondary: One-year overall survival rate

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    End point title
    One-year overall survival rate
    End point description
    One-year overall survival rate was calculated as the percentage of patients who were alive one year after the first administration of gemcitabine and or afatinib.
    End point type
    Secondary
    End point timeframe
    The timeframe of the One-year overall survival rate was defined as the time from the first administration to one year after the first administration of afatinib and/or gemcitabine.
    End point values
    Gemcitabine plus Afatinib Gemcitabine
    Number of subjects analysed
    71
    37
    Units: Number of subjects analysed
        25.4% for the exp. arm
    18
    0
        21.6% for the contr. arm
    0
    8
    Statistical analysis title
    One-year overall survival rate
    Comparison groups
    Gemcitabine plus Afatinib v Gemcitabine
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [5]
    P-value
    = 0.8135
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.231
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.477
         upper limit
    3.177
    Notes
    [5] - exploratory analysis only

    Secondary: CA 19-9 tumor marker response - OS

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    End point title
    CA 19-9 tumor marker response - OS
    End point description
    Stratification factor at the time of randomisation, an analysis of its prognostic influence on the overall survival. Additional statistical analyses: 2-sided log-rank test with 95% CI for HR, stratified by the baseline values of CA 19-9. Of note, HR > 1 favours ≤ 1000 U/mL Comparison of the groups after stratification by CA 19-9 value ≤ 1000 U/ml and > 1000 U/ml within each treatment arm: Within the experimental arm in the FAS (N=71): median(≤1000 U/ml )=8.2, median(>1000U/ml)= 5.6; p= 0.0893, HR= 1.564 (CI: 0.929 to 2.632). Within the control arm in the FAS (N=37): median(≤1000 U/ml)= 8.4, median (>1000U/ml)= 5.0; p= 0.0531, HR= 2.033 (CI: 0.977 to 4.230). Comparison of the groups after stratification by CA 19-9 value ≤ 1000 U/ml and > 1000 U/ml within the FAS (N=108): median(≤1000 U/ml)= 8.4, median (>1000U/ml)= 5.6; p= 0.0531, HR= 2.033 (CI: 0.977 to 4.230).
    End point type
    Secondary
    End point timeframe
    OS was defined as the duration from first administration of the gemcitabine and/or afatinib to death. Patients without events were censored at the date of their last contact.
    End point values
    Gemcitabine plus Afatinib Gemcitabine Full Analysis Set Per-Protocol set
    Number of subjects analysed
    71
    37
    108
    92
    Units: months
    median (confidence interval 95%)
        ≤ 1000 U/ml
    8.2 (6.2 to 12.7)
    8.4 (6.0 to 13.9)
    8.4 (6.7 to 11.3)
    9.9 (7.0 to 12.7)
        > 1000 U/ml
    5.6 (3.9 to 8.6)
    5.0 (3.4 to 9.3)
    5.6 (3.9 to 7.5)
    6.2 (4.3 to 8.6)
    No statistical analyses for this end point

    Secondary: CA 19-9 tumor marker -PFS

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    End point title
    CA 19-9 tumor marker -PFS
    End point description
    Stratification factor at the time of randomisation, an analysis of its prognostic influence on the progression-free survival. Additional statistical analyses: 2-sided log-rank test with 95% CI for HR, stratified by the baseline values of CA 19-9. Of note, HR > 1 favours ≤ 1000 U/mL Comparison of the groups after stratification by CA 19-9 value ≤ 1000 U/ml and > 1000 U/ml within each treatment arm: Within the experimental arm in the FAS (N=71): median(≤1000 U/ml )=4.7, median(>1000U/ml)= 3.0; p= 0.0042, HR= 2.057 (95% CI: 1.240 to 3.413). Within the control arm in the FAS (N=37): median(≤1000 U/ml)= 5.3, median (>1000U/ml)= 3.8; p= 0.0836, HR= 1.825 (95% CI: 0.910 to 3.663). Comparison of the groups after stratification by CA 19-9 value ≤ 1000 U/ml and > 1000 U/ml within the FAS (N=108): median(≤1000 U/ml)= 5.2, median (>1000U/ml)= 3.4; p= 0.0009, HR= 1.952 (CI: 1.301 to 2.929).
    End point type
    Secondary
    End point timeframe
    PFS was defined as the duration from the first administration of gemcitabine and or afatinib to first progression (acc. to RECIST 1.1) or death, whichever occurred first.
    End point values
    Gemcitabine plus Afatinib Gemcitabine Full Analysis Set Per-Protocol set
    Number of subjects analysed
    71
    37
    108
    92
    Units: months
    median (confidence interval 95%)
        ≤ 1000 U/ml
    4.7 (3.6 to 6.6)
    5.3 (2.1 to 7.2)
    5.2 (3.7 to 6.2)
    5.4 (3.8 to 6.7)
        > 1000 U/ml
    3.0 (1.6 to 4.5)
    3.8 (1.6 to 5.6)
    3.4 (1.7 to 4.5)
    3.4 (1.7 to 4.5)
    No statistical analyses for this end point

    Secondary: CA 19-9 tumor marker -1-year overall survival rate

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    End point title
    CA 19-9 tumor marker -1-year overall survival rate
    End point description
    Stratification factor at the time of randomisation, an analysis of its prognostic influence on one-year overall survival rate. Additional statistical analyses: 2-sided fisher's exact test with 95% CI for OR, stratified by the baseline values of CA 19-9. Comparison of the groups after stratification by CA 19-9 value ≤ 1000 U/ml and > 1000 U/ml within each treatment arm: Within the experimental arm in the FAS (N=71): For ≤1000 U/ml=32.4% (N=12/37), For >1000U/ml= 17.6% (N=6/34); p= 0.1808, OR= 2.240 (CI: 0.732 to 6.856). Within the control arm in the FAS (N=37): For ≤1000 U/ml= 35.3% (N=6/17), For >1000U/ml= 10.0% (N=2/20); p= 0.1090, OR= 4.909 (CI: 0.838 to 28.745). Comparison of the groups after stratification by CA 19-9 value ≤ 1000 U/ml and > 1000 U/ml within the FAS (N=108): For ≤1000 U/ml= 33.3% (N=18/54), For >1000U/ml= 14.8% (N=8/54); p= 0.0416, OR= 2.875 (CI: 1.123 to 7.361).
    End point type
    Secondary
    End point timeframe
    Stratification factor at the time of randomisation.
    End point values
    Gemcitabine plus Afatinib Gemcitabine
    Number of subjects analysed
    71
    37
    Units: Subjects
        32.4% for ≤1000 U/ml (exp. arm)
    12
    0
        17.6% for >1000U/ml (exp. arm)
    6
    0
        35.3% for ≤1000 U/ml (contr. arm)
    0
    6
        10.0% for >1000U/ml (contr. arm)
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the informed consent onwards through the observational phase and within 28 days after the last drug administration of the study medication.
    Adverse event reporting additional description
    Information on all adverse events, with particular emphasis on potential dose-limiting toxicities. Missing data were imputed.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Gemcitabine plus Afatinib
    Reporting group description
    Intravenous administration of 1000 mg/m² gemcitabine on D1, D8, D15 of each 28-day treatment cycle and oral administration of 40 mg afatinib daily. Treatment was continued until disease progression, unacceptable toxicity or other reasons (patient’s wish, investigator’s decision).

    Reporting group title
    Gemcitabine
    Reporting group description
    Treatment with 1000 mg/m² gemcitabine on D1, D8, D15 of each 28-day treatment cycle. Treatment was continued until disease progression, unacceptable toxicity or other reasons (patient’s wish, investigator’s decision).

    Serious adverse events
    Gemcitabine plus Afatinib Gemcitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    53 / 77 (68.83%)
    22 / 38 (57.89%)
         number of deaths (all causes)
    15
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Thrombosis
    Additional description: In the analysis listing, the term 'thromboembolic event' is used as a preprinted term. It comprises the PTs 'thrombosis' and 'pulmonary embolism'. Here, the events of pulmonary embolism are subtracted.
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Stent placement
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm
         subjects affected / exposed
    6 / 77 (7.79%)
    4 / 38 (10.53%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 6
    0 / 4
    Metastases to peritoneum
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    7 / 77 (9.09%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 77 (6.49%)
    4 / 38 (10.53%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac death
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Death
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oedema
    Additional description: In the analysis listing, the term 'Oedema (lower leg)' is used as a preprinted term.
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Bilirubin conjugated increased
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 77 (5.19%)
    3 / 38 (7.89%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
    Additional description: In the analysis listing, the term 'thromboembolic event' is used as a preprinted term. It comprises the PTs 'thrombosis' and 'pulmonary embolism'. Here, the events of thrombosis are subtracted.
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Interstitial lung disease
    Additional description: Substitute for the preprinted term: "ILD-like syndrome (pneumonitis, pulmonary infiltrates)".
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    6 / 77 (7.79%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    6 / 77 (7.79%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    5 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 77 (5.19%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (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
    1 / 77 (1.30%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ileus
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
    Additional description: According to MedDRA 21.0 is "acute kidney injury" the new PT for the outdated MedDRA 16.1 PT "renal failure acute".
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 38 (10.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hypersensitivity vasculitis
    Additional description: According to MedDRA 21.0 is "hypersensitivity vasculitis" the new PT for the outdated MedDRA 16.1 PT "Leukocytoclastic vasculitis".
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (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
    Pathological fracture
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (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
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    19 / 77 (24.68%)
    8 / 38 (21.05%)
         occurrences causally related to treatment / all
    9 / 24
    3 / 13
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Gemcitabine plus Afatinib Gemcitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 77 (100.00%)
    37 / 38 (97.37%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 38 (2.63%)
         occurrences all number
    6
    3
    Thrombosis
    Additional description: In the analysis listing, the term 'thromboembolic event' is used as a preprinted term. It comprises the PTs 'thrombosis' and 'pulmonary embolism'. Events of pulmonary embolism were substrated and occurred in less than 5% of the patients.
         subjects affected / exposed
    7 / 77 (9.09%)
    1 / 38 (2.63%)
         occurrences all number
    7
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 38 (2.63%)
         occurrences all number
    3
    1
    Chills
         subjects affected / exposed
    4 / 77 (5.19%)
    3 / 38 (7.89%)
         occurrences all number
    4
    3
    Fatigue
         subjects affected / exposed
    3 / 77 (3.90%)
    2 / 38 (5.26%)
         occurrences all number
    3
    2
    General physical health deterioration
         subjects affected / exposed
    5 / 77 (6.49%)
    0 / 38 (0.00%)
         occurrences all number
    6
    0
    Oedema
    Additional description: (lower leg)
         subjects affected / exposed
    23 / 77 (29.87%)
    12 / 38 (31.58%)
         occurrences all number
    28
    13
    Pain
         subjects affected / exposed
    36 / 77 (46.75%)
    21 / 38 (55.26%)
         occurrences all number
    50
    34
    Swelling
    Additional description: In the analysis listing the preferred term is "local swelling".
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    Pyrexia
         subjects affected / exposed
    13 / 77 (16.88%)
    11 / 38 (28.95%)
         occurrences all number
    20
    16
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    4 / 77 (5.19%)
    2 / 38 (5.26%)
         occurrences all number
    4
    2
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    23 / 77 (29.87%)
    9 / 38 (23.68%)
         occurrences all number
    26
    9
    Lymphocyte count decreased
         subjects affected / exposed
    6 / 77 (7.79%)
    2 / 38 (5.26%)
         occurrences all number
    7
    3
    Blood alkaline phosphatase decreased
         subjects affected / exposed
    5 / 77 (6.49%)
    2 / 38 (5.26%)
         occurrences all number
    5
    2
    Bilirubin conjugated increased
         subjects affected / exposed
    8 / 77 (10.39%)
    5 / 38 (13.16%)
         occurrences all number
    9
    6
    C-reactive protein increased
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 38 (2.63%)
         occurrences all number
    3
    1
    Alanine aminotransferase increased
    Additional description: In the analysis listing, the term 'Liver value ALT' is used as a preprinted term.
         subjects affected / exposed
    34 / 77 (44.16%)
    20 / 38 (52.63%)
         occurrences all number
    58
    28
    Aspartate aminotransferase increased
    Additional description: In the analysis listing, the term 'Liver value increased AST' is used as a preprinted term.
         subjects affected / exposed
    31 / 77 (40.26%)
    16 / 38 (42.11%)
         occurrences all number
    47
    36
    Weight decreased
         subjects affected / exposed
    26 / 77 (33.77%)
    6 / 38 (15.79%)
         occurrences all number
    27
    6
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 38 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    57 / 77 (74.03%)
    23 / 38 (60.53%)
         occurrences all number
    66
    24
    Leukopenia
         subjects affected / exposed
    12 / 77 (15.58%)
    11 / 38 (28.95%)
         occurrences all number
    17
    20
    Lymphopenia
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 38 (5.26%)
         occurrences all number
    3
    2
    Neutropenia
         subjects affected / exposed
    26 / 77 (33.77%)
    20 / 38 (52.63%)
         occurrences all number
    65
    46
    Thrombocytopenia
         subjects affected / exposed
    42 / 77 (54.55%)
    19 / 38 (50.00%)
         occurrences all number
    84
    43
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 77 (6.49%)
    1 / 38 (2.63%)
         occurrences all number
    5
    3
    Dyspnoea
         subjects affected / exposed
    7 / 77 (9.09%)
    1 / 38 (2.63%)
         occurrences all number
    7
    1
    Dyspnoea exertional
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 38 (2.63%)
         occurrences all number
    7
    1
    Epistaxis
         subjects affected / exposed
    7 / 77 (9.09%)
    0 / 38 (0.00%)
         occurrences all number
    31
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 77 (7.79%)
    2 / 38 (5.26%)
         occurrences all number
    6
    2
    Dysgeusia
         subjects affected / exposed
    6 / 77 (7.79%)
    1 / 38 (2.63%)
         occurrences all number
    6
    1
    Somnolence
         subjects affected / exposed
    40 / 77 (51.95%)
    22 / 38 (57.89%)
         occurrences all number
    49
    26
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    5 / 77 (6.49%)
    1 / 38 (2.63%)
         occurrences all number
    6
    1
    Dry eye
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 38 (2.63%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Cheilitis
         subjects affected / exposed
    5 / 77 (6.49%)
    0 / 38 (0.00%)
         occurrences all number
    5
    0
    Constipation
         subjects affected / exposed
    14 / 77 (18.18%)
    12 / 38 (31.58%)
         occurrences all number
    14
    13
    Diarrhoea
         subjects affected / exposed
    55 / 77 (71.43%)
    5 / 38 (13.16%)
         occurrences all number
    79
    8
    Dry mouth
         subjects affected / exposed
    9 / 77 (11.69%)
    2 / 38 (5.26%)
         occurrences all number
    9
    2
    Flatulence
         subjects affected / exposed
    4 / 77 (5.19%)
    0 / 38 (0.00%)
         occurrences all number
    5
    0
    Nausea
         subjects affected / exposed
    38 / 77 (49.35%)
    17 / 38 (44.74%)
         occurrences all number
    58
    23
    Stomatitis
    Additional description: Also PT Stomatitis of the SOC General disorders and administration site conditions
         subjects affected / exposed
    30 / 77 (38.96%)
    3 / 38 (7.89%)
         occurrences all number
    38
    4
    Vomiting
         subjects affected / exposed
    23 / 77 (29.87%)
    9 / 38 (23.68%)
         occurrences all number
    30
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    7 / 77 (9.09%)
    1 / 38 (2.63%)
         occurrences all number
    8
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    4 / 77 (5.19%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    18 / 77 (23.38%)
    4 / 38 (10.53%)
         occurrences all number
    23
    5
    Pruritus
         subjects affected / exposed
    11 / 77 (14.29%)
    1 / 38 (2.63%)
         occurrences all number
    12
    1
    Dermatitis acneiform
    Additional description: In the analysis listing the PT is "Acneiform exanthema (rash).
         subjects affected / exposed
    50 / 77 (64.94%)
    2 / 38 (5.26%)
         occurrences all number
    68
    2
    Nail disorder
    Additional description: In the analysis listings the PT is "Other nail changes (e.g. grooved nails, panaritium)".
         subjects affected / exposed
    14 / 77 (18.18%)
    0 / 38 (0.00%)
         occurrences all number
    15
    0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    24 / 77 (31.17%)
    7 / 38 (18.42%)
         occurrences all number
    26
    7
    Dehydration
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 38 (2.63%)
         occurrences all number
    2
    2
    Hyperkalaemia
         subjects affected / exposed
    10 / 77 (12.99%)
    1 / 38 (2.63%)
         occurrences all number
    11
    2
    Hyponatraemia
         subjects affected / exposed
    4 / 77 (5.19%)
    4 / 38 (10.53%)
         occurrences all number
    4
    4
    Infections and infestations
    Paronychia
         subjects affected / exposed
    9 / 77 (11.69%)
    0 / 38 (0.00%)
         occurrences all number
    11
    0
    Infection
         subjects affected / exposed
    35 / 77 (45.45%)
    16 / 38 (42.11%)
         occurrences all number
    35
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2013
    Adaption of the section “listed adverse events for afatinib” according to the Investigator´s Brochure (IB) V. 14 of afatinib Implementation of recommendations on wound healing disorders during afatinib treatment and application of afatinib via a gastric tube Changes regarding laboratory test required before starting treatment. Laboratory tests do not need to be repeated on Cycle 1 day 1 if performed within 72 hours before treatment start
    14 Sep 2015
    Due to several updates of the IB for afatinib, V.16.0, the section listing “adverse events” were removed from the protocol. Instead, a referral to the most recent IB which was available at all centres The section listing “adverse events” for gemcitabine was removed from the trial protocol. Instead, it is referred to the most recent version of the German “Fachinformation” (Summary of Product Characteristics – SPC) which was available at all centres Adaptions concerning number of study centres, study period, publications, requirements for starting a new cycle with gemcitabine

    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.
    The endpoint "duration of response" could not be analysed statistically, because the number of patients achieving CR and/or PR was too low for the calculation of the median and related confidence interval (due to the indication mPDAC).
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