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    Clinical Trial Results:
    Trial of afatinib (BIBW 2992) in suspected or confirmed mutant EGFR lung cancer patients unfit for chemotherapy

    Summary
    EudraCT number
    2011-003608-19
    Trial protocol
    GB  
    Global end of trial date
    30 Nov 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL/09/0426
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01415011
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    TIMELY Trial Co-ordinator, CR UK & UCL Cancer Trials Centre, +44 02076799284, ctc.timely@ucl.ac.uk
    Scientific contact
    TIMELY Trial Co-ordinator, University College London, +44 02076799284, ctc.timely@ucl.ac.uk
    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
    15 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To examine the efficacy and safety of afatinib (BIBW 2992) in non-small cell lung cancer patients who had either suspected or confirmed EGFR mutation and were considered unfit for chemotherapy. The primary outcome measure is progression free survival at 6 months.
    Protection of trial subjects
    Regular Trial Management Group meetings and Independent Data Monitoring Committee meetings were held throughout the trial to monitor overall safety in the patient group. Pharmacovigilance requirements and safety compliance rules were detailed in the trial protocol with overall risk assessment, on-site monitoring and central monitoring conducted by the trial teams. Patient data is stored in a secure manner and the trial is registered in accordance with the Data Protection Act.
    Background therapy
    In the TIMELY trial, loperamide was a named NIMP. At the time of initiation of treatment with afatinib (BIBW 2992), patients were given a supply of loperamide to keep with them at all times, and were counselled on the appropriate use. Loperamide was administered to the patients for management of diarrhoea adverse events associated with afatinib.
    Evidence for comparator
    No comparators where applicable in the trial design.
    Actual start date of recruitment
    01 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 39
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    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)
    9
    From 65 to 84 years
    27
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 39 eligible patients were recruited to the study between 12th March 2013 and 13th August 2015. Patients were recruited from 13 different UK NHS hospital sites.

    Pre-assignment
    Screening details
    Patient enrolled were non-small cell lung cancer patients with comorbidities precluding chemotherapy, with either (i) EGFR-mutation, PS 0-3, or (ii) suspected EGFR-mutation (tissue unavailable/failed genotyping), never/former-light smoker, adenocarcinoma, and performance status 0-2.

    Period 1
    Period 1 title
    Overall trial
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable.

    Arms
    Arm title
    Single arm - 40mg daily oral afatinib
    Arm description
    All patients were given daily oral afatinib (BIBW 2992) (40mg) until disease progression, toxicity, or physician/patient decision. Afatinib (BIBW 2992) was provided to all patients in cycles of 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    BIBW 2992
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each patient started afatinib at a dose of 40mg, once daily, orally, in the form of tablet. Each cycle of afatinib was administered every 28 days. Daily dosing continued until progression, unacceptable adverse events or other reason necessitating withdrawal. 30mg and 20mg doses were provided for patients who required protocol dose modifications due to adverse events.

    Number of subjects in period 1
    Single arm - 40mg daily oral afatinib
    Started
    39
    Completed
    39
    Period 2
    Period 2 title
    1 month
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    Single arm - 40mg daily oral afatinib
    Arm description
    All patients were given daily oral afatinib (BIBW 2992) (40mg) until disease progression, toxicity, or physician/patient decision. Afatinib (BIBW 2992) was provided to all patients in cycles of 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    BIBW 2992
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each patient started afatinib at a dose of 40mg, once daily, orally, in the form of tablet. Each cycle of afatinib was administered every 28 days. Daily dosing continued until progression, unacceptable adverse events or other reason necessitating withdrawal. 30mg and 20mg doses were provided for patients who required protocol dose modifications due to adverse events.

    Number of subjects in period 2
    Single arm - 40mg daily oral afatinib
    Started
    39
    Completed
    39

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    Patients had any stage non-small cell lung cancer with either suspected or confirmed EGFR status and were unable to receive chemotherapy due to co-morbidity. At trial entry, patients were age 18 or over, were required to have adequate organ function and have no existing conditions that would exclude them from treatment with afatinib, such as interstitial lung disease, and cardiac abnormalities. Patients assessments were fortnightly for the first two cycles, then monthly for twelve months and two-monthly thereafter. After discontinuing afatinib (BIBW 2992), all patients were followed-up two-monthly during the first twelve months. Tumour response was evaluated by CT scan of the chest and abdomen (4 calendar weeks after the start date for treatment and then every 8 calendar weeks until disease progression). If after 1 year the patient was still on afatinib (BIBW 2992) CT scans were planned every 12 calendar weeks.

    Reporting group values
    Overall trial Total
    Number of subjects
    39 39
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    9 9
        From 65-84 years
    27 27
        85 years and over
    3 3
    Age continuous
    Units: years
        median (full range (min-max))
    72 (36 to 90) -
    Gender categorical
    Units: Subjects
        Female
    30 30
        Male
    9 9
    WHO performance status
    Units: Subjects
        PS 0 - Fully Active
    6 6
        PS 1 - Ambulatory (work able)
    21 21
        PS 2 - Ambulatory (not work able)
    11 11
        PS 3 - Limited Selfcare
    1 1
    EGFR mutation
    Units: Subjects
        Confirmed EGFR
    21 21
        Suspected EGFR
    18 18
    Non-Small Cell Lung Cancer (NSCLC) Stage
    Units: Subjects
        Stage 1 NSCLC
    1 1
        Stage II NSCLC
    0 0
        Stage III NSCLC
    8 8
        Stage IV NSCLC
    30 30

    End points

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    End points reporting groups
    Reporting group title
    Single arm - 40mg daily oral afatinib
    Reporting group description
    All patients were given daily oral afatinib (BIBW 2992) (40mg) until disease progression, toxicity, or physician/patient decision. Afatinib (BIBW 2992) was provided to all patients in cycles of 28 days.
    Reporting group title
    Single arm - 40mg daily oral afatinib
    Reporting group description
    All patients were given daily oral afatinib (BIBW 2992) (40mg) until disease progression, toxicity, or physician/patient decision. Afatinib (BIBW 2992) was provided to all patients in cycles of 28 days.

    Primary: Progression-free survival at 6 months

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    End point title
    Progression-free survival at 6 months [1]
    End point description
    The end point value reported is the proportion of patients alive and progression free at 6 months with corresponding exact binomial 80% confidence interval.
    End point type
    Primary
    End point timeframe
    Progression-free survival at 6 months; calculated as the time between the date of registration and date of first progression or death (from any cause), whichever occured first. Patients who have not died or progressed were censored at the date last seen.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: TIMELY was a single arm study; the system is unable to accommodate the details required for statistical analysis for a single arm trial, therefore the analysis details have not been added.
    End point values
    Single arm - 40mg daily oral afatinib
    Number of subjects analysed
    39
    Units: Proportion alive and progression free
        number (confidence interval 80%)
    0.590 (0.474 to 0.698)
    No statistical analyses for this end point

    Secondary: Overall Response

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    End point title
    Overall Response
    End point description
    End point type
    Secondary
    End point timeframe
    Best response from initial response assessment for the whole duration of the trial.
    End point values
    Single arm - 40mg daily oral afatinib
    Number of subjects analysed
    39
    Units: Number of responders
        Partial Response
    21
        Stable Disease
    13
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall survival is defined as the time from start of treatment to death from any cause. The median follow up time censoring for deaths was 42 months (range for survivors 32 to 65).
    End point values
    Single arm - 40mg daily oral afatinib
    Number of subjects analysed
    39
    Units: Months
        median (confidence interval 95%)
    15.5 (10.0 to 27.5)
    Attachments
    OS all patients
    No statistical analyses for this end point

    Secondary: Progression free survival in patients aged 70 and over

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    End point title
    Progression free survival in patients aged 70 and over
    End point description
    End point type
    Secondary
    End point timeframe
    Defined as the time from start of treatment to progression or death from any cause in patient aged 70 and over.
    End point values
    Single arm - 40mg daily oral afatinib
    Number of subjects analysed
    39
    Units: Months
    median (confidence interval 95%)
        Aged 70 or over
    6.7 (3.0 to 10.2)
        Under 70 years old
    8.2 (4.6 to 27.5)
    Attachments
    PFS by age
    No statistical analyses for this end point

    Secondary: Treatment Compliance

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    End point title
    Treatment Compliance
    End point description
    End point type
    Secondary
    End point timeframe
    Calculated from date of first dose to date of last known dose. Patients who were still on treatment at the time of analysis were censored at the date last seen.
    End point values
    Single arm - 40mg daily oral afatinib
    Number of subjects analysed
    39
    Units: Months
        median (confidence interval 95%)
    4.4 (3.0 to 10.2)
    Attachments
    Time on treatment
    No statistical analyses for this end point

    Secondary: Change in performance status at 1 month

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    End point title
    Change in performance status at 1 month
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline assessment at registration and one month after registration (+/- 1 week).
    End point values
    Single arm - 40mg daily oral afatinib Single arm - 40mg daily oral afatinib
    Number of subjects analysed
    39
    39
    Units: Number of patients
        Fully Active - WHO PS 0
    6
    3
        Ambulatory (work able) - WHO PS 1
    21
    24
        Ambulatory (not work able) - WHO PS 2
    11
    5
        Limited Selfcare - WHO PS 3
    1
    0
        Dead - WHO PS 5
    0
    2
        Unknown
    0
    5
    Statistical analysis title
    Wilcoxon signed-rank test
    Comparison groups
    Single arm - 40mg daily oral afatinib v Single arm - 40mg daily oral afatinib
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    = 0.5
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Wilcoxon signed-rank test to determine whether there is evidence of a change in performance status from registration to 1 month.

    Secondary: Progression-free survival

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    End point title
    Progression-free survival
    End point description
    End point type
    Secondary
    End point timeframe
    Progression-free survival is defined as the time from registration to the date of first progression or death (from any cause), whichever occurs first. Patients who have not died or progressed were censored at the date last seen.
    End point values
    Single arm - 40mg daily oral afatinib
    Number of subjects analysed
    39
    Units: Months
        median (confidence interval 95%)
    7.9 (4.6 to 10.5)
    Attachments
    PFS all patients
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occured between informed consent and 30 days post last administration of afatinib.
    Adverse event reporting additional description
    Adverse events were collected from patients through clinical assessment and review of self-reported patient diaries. For each type of adverse event, the maximum toxicity grade was obtained for each patient. Focus is on those with a grade 3 or 4 event. The proportion of patients with any grade 3 or 4 event are examined.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    All trial subjects
    Reporting group description
    For each type of adverse event, the maximum toxicity grade was obtained for each patient.

    Serious adverse events
    All trial subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 39 (51.28%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    2
    Injury, poisoning and procedural complications
    Food poisoning
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Creatinine increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    2 / 2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Mucositis oral
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest wall pain
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyponatremia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia coli infection
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Nail infection
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Norovirus
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    All trial subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 39 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Surgical and medical procedures
    Toe nail surgery
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Toe nail surgery
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Nail infection
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Food poisoning
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Investigations
    Creatinine increased
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Cardiac disorders
    Left ventricular failure
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Pneumonitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 39 (30.77%)
         occurrences all number
    12
    Nausea
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Mouth ulceration
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Left loin pain
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Dehydration
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Hypercalcemia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Hypokalemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Hypomagnesemia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Hyponatremia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Lung infection
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Escherichia Coli
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Norovirus
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Paronychia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Sepsis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2013
    Protocol version 2.0 dated 15th March 2013: 1. Updated Investigator's Brochure (IB)for afatinib implemented - version 13, dated 11th July 2012. 2. The IMP name BIBW 2992 was amended to afatinib (BIBW 2992) on all trial documents following generic name approval. 3. Participant Information sheet and Protocol updated to include new safety information described in the updated IB. 4. Reference Safety Information updated; all serious adverse reactions were evaluated, in order to determine whether they are suspected unexpected serious adverse reactions, using information contained in the current investigator brochure for Afatinib (BIBW 2992).
    05 Nov 2013
    Protocol version 3 dated 12th November 2013: 1. Updated Afatinib Investigator's Brochure implemented - version 14 dated 4th July 2013. 2. Reference Safety Information; all serious adverse reactions were evaluated, in order to determine whether they are suspected unexpected serious adverse reactions, using information contained in the updated investigator brochure for afatinib (BIBW 2992) version 14 dated 04/07/2013 using the list of expected AEs under section 7. 3. The main change was to include patients with a known EGFR mutation. As a result the trial title has been amended on all trial documents to reflect the inclusion of this group of patients. 4. The Participant Information Sheet was updated to include an additional side effect referenced in the updated safety information. 5. Protocol updated to include confirmed EGFR patients and the safety profile of afatinib was updated with information from ongoing phase I and II trials.
    02 Jul 2014
    Protocol version 4.0 dated 24th June 2014: Clarification regarding eligibility of patients with WHO performance status (PS) 3 added. Patients with a confirmed activating EGFR mutation and WHO PS 0-3 were eligible, whereas patients who had suspected EGFR mutation were only eligible if WHO PS was 0-2.
    12 Dec 2016
    Protocol version 5 dated 9th August 2016: 1. End of trial definition updated. 2. Inclusion of central review of progression.

    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.
    1. SAEs and non-serious grade 3+ AEs are listed under non-serious AE section. 2. Under non-serious AEs, only the highest grade experienced by patients was collected and therefore the 'subjects affected' number has been entered for 'occurrences'.
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