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    Clinical Trial Results:
    A Phase II Multicentre Randomised, Parallel Group, Double-Blind, Placebo Controlled Study of ZD1839 (Iressa™) (250mg Tablet) Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Chemotherapy Naïve Patients with Advanced (Stage IIIB or IV) Non-Small Cell Lung Cancer (NSCLC) and Poor Performance Status INSTEP (Iressa NSCLC Trial Evaluating Poor Performance Patients)

    Summary
    EudraCT number
    2004-004206-25
    Trial protocol
    IE   CZ  
    Global end of trial date
    24 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Mar 2017
    First version publication date
    15 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D7913C00711
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00259064
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    One Medimmune Way, 101 ORD, 2233C, Gaithersburg, United States, MD 20878
    Public contact
    Yuri Rukazenkov, AstraZeneca, +44 01625 231825, yuri.rukazenkov@astrazeneca.com
    Scientific contact
    Yuri Rukazenkov, AstraZeneca, +44 01625 231825, yuri.rukazenkov@astrazeneca.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
    22 Feb 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Feb 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare gefitinib (IRESSA™, ZD1839) + best supportive care (BSC) versus placebo + BSC in terms of progression-free survival (PFS).
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Sep 2004
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 26
    Country: Number of subjects enrolled
    Canada: 114
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    United Kingdom: 40
    Worldwide total number of subjects
    201
    EEA total number of subjects
    61
    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)
    36
    From 65 to 84 years
    147
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Patients were screened prior to entry into study & were required to fulfil all inclusion/exclusion criteria which included: a diagnosis of NSCLC, locally advanced or metastatic disease, not amenable to curative surgery, radiotherapy or chemotherapy; Measurable disease according to RECIST; No prior chemotherapy, biological or immunological therapy.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor
    Blinding implementation details
    Patients were randomised in a ratio of 1:1 to receive either gefitinib 250 mg or matching placebo tablets in combination with BSC. Study treatment wasdispensed to patients in a double blind manner on Day 1 and every 12 weeks thereafter until the patient discontinued.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Gefitinib
    Arm description
    Gefitinib 250 mg plus Best Supportive Care
    Arm type
    Experimental

    Investigational medicinal product name
    Gefitinib
    Investigational medicinal product code
    Other name
    Iressa
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250 mg daily

    Arm title
    Placebo
    Arm description
    Matched Placebo plus Best Supportive Care
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet daily

    Number of subjects in period 1
    Gefitinib Placebo
    Started
    100
    101
    Completed
    100
    101
    Period 2
    Period 2 title
    Overall Trial
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor
    Blinding implementation details
    Patients were randomised in a ratio of 1:1 to receive either gefitinib 250 mg or matching placebo tablets in combination with BSC. Study treatment wasdispensed to patients in a double blind manner on Day 1 and every 12 weeks thereafter until the patient discontinued.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Gefitinib
    Arm description
    Gefitinib 250 mg plus Best Supportive Care
    Arm type
    Experimental

    Investigational medicinal product name
    Gefitinib
    Investigational medicinal product code
    Other name
    Iressa
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250 mg daily

    Arm title
    Placebo
    Arm description
    Matched Placebo plus Best Supportive Care
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet daily

    Number of subjects in period 2
    Gefitinib Placebo
    Started
    100
    101
    Completed
    99
    99
    Not completed
    1
    2
         Consent withdrawn by subject
             1
             2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gefitinib
    Reporting group description
    Gefitinib 250 mg plus Best Supportive Care

    Reporting group title
    Placebo
    Reporting group description
    Matched Placebo plus Best Supportive Care

    Reporting group values
    Gefitinib Placebo Total
    Number of subjects
    100 101 201
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    19 17 36
        From 65-84 years
    73 74 147
        85 years and over
    8 10 18
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    72.3 ± 9.5 73.9 ± 9 -
    Gender Categorical
    Units: Subjects
        Female
    39 40 79
        Male
    61 61 122
    Race
    Units: Subjects
        Caucasian
    96 97 193
        Oriental
    4 3 7
        other
    0 1 1
    Smoking history
    Units: Subjects
        Habitual
    19 19 38
        Occasional
    0 2 2
        Ex Smoker
    71 71 142
        Non Smoker
    10 9 19
    WHO Performance Status
    World Health Organisation (WHO) performance status is a scale from 0 (fully active) to 5 (dead), indicating patients ability to perform certain activities of daily life. All patients in this study have PS of 2 or 3.
    Units: Subjects
        2: in bed <= 50% of time
    55 63 118
        3: in bed > 50% of time
    45 38 83

    End points

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    End points reporting groups
    Reporting group title
    Gefitinib
    Reporting group description
    Gefitinib 250 mg plus Best Supportive Care

    Reporting group title
    Placebo
    Reporting group description
    Matched Placebo plus Best Supportive Care
    Reporting group title
    Gefitinib
    Reporting group description
    Gefitinib 250 mg plus Best Supportive Care

    Reporting group title
    Placebo
    Reporting group description
    Matched Placebo plus Best Supportive Care

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    Progression Free Survival (PFS) is defined as the interval between the date of randomisation and the earliest date of objective disease progression according to The Response Evaluation Criteria in Solid Tumours [RECIST] or death due to any cause in the absence of progression
    End point type
    Primary
    End point timeframe
    Overall Study - Assessed every 6 weeks from randomisation
    End point values
    Gefitinib Placebo
    Number of subjects analysed
    100
    101
    Units: days
        median (confidence interval 95%)
    43 (39 to 55)
    41 (37 to 43)
    Statistical analysis title
    Primary Analysis: Hazard Ratio
    Statistical analysis description
    Hazard Ratio(HR) calculated from Cox Proportional hazards model including factors (gender, WHO performance status, histology, smoking history, lung stage classification). The primary analysis does not include progression events, or deaths in the absence of progression, which occur more than 12 weeks after the last evaluable RECIST assessment.
    Comparison groups
    Gefitinib v Placebo
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.2165
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.821
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.123
    Notes
    [1] - Although medians are presented these estimates of PFS are not reliable in this setting: scans were every 6 wks whilst the population progressed rapidly, over half the patients progressing before their first scan. Therefore medians will be more representative of scan timings, rather than actual progression times which may have occurred before the scan takes place. The HR is a much more accurate reflection of the treatment difference, taking into account all information over the study period.

    Secondary: Objective Response Rate

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    End point title
    Objective Response Rate
    End point description
    Objective Response Rate is the number of patients who have either a complete response (CR) or partial reponse (PR) as defined by Response Evaluation Criteria In Solid Tumour (RECIST) during the study.
    End point type
    Secondary
    End point timeframe
    Overall Study - Response is assesed every 6 weeks from randomisation
    End point values
    Gefitinib Placebo
    Number of subjects analysed
    100
    101
    Units: Patients
    6
    1
    Statistical analysis title
    Comparison of Objective Response Rate
    Statistical analysis description
    The objective tumour response rate was compared between gefitinib and placebo using a logistic regression model which included terms for Randomised Treatment, Gender, WHO Performance Status, Histology, Smoking History and Lung Stage Classification. The odds ratio (gefitinib:placebo) was estimated from the model along with its associated 95% CI.
    Comparison groups
    Gefitinib v Placebo
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    6.556
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.741
         upper limit
    58.173

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival (time to death) is defined as the interval between the date of randomisation and the date of patient death, due to any cause, or to the last date the patient was known to be alive. Those patients who are known to be alive at study closure will be regarded as censored in the calculation of the median overall survival time for each treatment group.
    End point type
    Secondary
    End point timeframe
    Assessed every 6 weeks from randomisation until study data cut off (DCO) or death
    End point values
    Gefitinib Placebo
    Number of subjects analysed
    100
    101
    Units: months
        median (confidence interval 95%)
    3.7 (2.6 to 4.4)
    2.8 (2.3 to 3.6)
    Statistical analysis title
    Comparison of Overall Survival
    Statistical analysis description
    Overall survival (time to death) was analysed using a proportional hazards model. The model included terms for Randomised Treatment, Gender, WHO Performance Status, Histology, Smoking History and Lung Stage Classification. The hazard ratio (gefitinib:placebo) was estimated together with its associated 95% confidence interval and p-value.
    Comparison groups
    Gefitinib v Placebo
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2722
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.615
         upper limit
    1.147

    Secondary: Pulmonary symptom improvement

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    End point title
    Pulmonary symptom improvement
    End point description
    Pulmonary symptom improvement is calculated from the responses to the Pulmonary items on the Functional Assessment of Cancer Therapy (Lung) (FACT-L) questionnaire which are: shortness of breath; ease of breathing; tightness in chest and cough A Pulmonary Symptom improvement is defined as an improvement from baseline in at least 1 moderate (score 1) or severe (score 0) pulmonary item of at least 2 points that is maintained for at least 28 days, ie, symptom improvement from moderate (score 1) to minimal (score 3) or none (score 4); or improvement from severe (score 0) to mild (score 2) or minimal (score 3) or none (score 4).
    End point type
    Secondary
    End point timeframe
    Collected three-weekly via a patient diary for all patients for the 1st 18 weeks, then every 6 weeks at each clinic visit up to and including 6 weeks post disease progression.
    End point values
    Gefitinib Placebo
    Number of subjects analysed
    53 [2]
    46 [3]
    Units: Patients
        number (not applicable)
    15
    13
    Notes
    [2] - Patients analysed are those in the Evaluable-for-pulmonary-symptom-improvement population.
    [3] - Patients analysed are those in the Evaluable-for-pulmonary-symptom-improvement population.
    Statistical analysis title
    Comparison of pulmonary sysmptom improvement
    Statistical analysis description
    The pulmonary symptom improvement rate was compared between gefitinib and placebousing a logistic regression model including terms for Randomised Treatment, Gender, WHO Performance Status, Histology, Smoking History and Lung Stage Classification. The odds ratio (gefitinib:placebo) will be estimated from the model along with its associated 95% CI.
    Comparison groups
    Gefitinib v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.986
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.395
         upper limit
    2.46
    Notes
    [4] - Patients analysed are those in the Evaluable-for-pulmonary-symptom-improvement population which included all patients who had at least one LCS pulmonaryitem (shortness of breath, ease of breathing, tightness in chest, or cough) with a baseline score of 0 or 1 (scores ranged from 0 to 4, with a higher score indicating better pulmonary symptoms) and who also had at least 1 evaluable post baseline assessment.

    Secondary: Improvement in Quality of Life as measured by the Trial Outcome Index (TOI)

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    End point title
    Improvement in Quality of Life as measured by the Trial Outcome Index (TOI)
    End point description
    Improvement in patient-reported functionality as measured by TOI (trial outcome index), which is comprised of thephysical and functional well being sectionsand LCS of FACT-L. An improvemetnt is defined to be an increase from baseline score of 6 or more points.
    End point type
    Secondary
    End point timeframe
    Collected three-weekly via a patient diary for all patients for the 1st 18 weeks, then every 6 weeks at each clinic visit up to and including 6 weeks post disease progression.
    End point values
    Gefitinib Placebo
    Number of subjects analysed
    76 [5]
    65 [6]
    Units: patients
    12
    9
    Notes
    [5] - Patients analysed are those in the Evaluable for Quality of Life population, a subset of the ITT.
    [6] - Patients analysed are those in the Evaluable for Quality of Life population, a subset of the ITT.
    Statistical analysis title
    Comparison of QoL improvement measured by the TOI
    Statistical analysis description
    The QoL (Quality of Life) improvement rate as measured by TOI (Trial outcome Index) was compared between gefitinib and placebo using a logistic regression model that includes terms for Randomised Treatment, Gender,WHO Performance Status, Histology, Smoking History and Lung Stage Classification. The odds ratio(gefitinib:placebo) was estimated from the model along with its associated 95% CI.
    Comparison groups
    Gefitinib v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.381
         upper limit
    2.8
    Notes
    [7] - Patients analysed are those in the Evaluable for Quality of Life population, including those with a baseline Quality of Life (QoL) assessment and at least one non-missing post-baseline QoL assessment. A subset of the ITT.

    Secondary: Improvement in Quality of Life as measured by the total score of the FACT-L questionnaire

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    End point title
    Improvement in Quality of Life as measured by the total score of the FACT-L questionnaire
    End point description
    Improvement in patient-reported functionality as measured by the total score of the FACT-L. An improvement is defined to be an increase from baseline score of 6 or more points.
    End point type
    Secondary
    End point timeframe
    Collected three-weekly via a patient diary for all patients for the 1st 18 weeks, then every 6 weeks at each clinic visit up to and including 6 weeks post disease progression.
    End point values
    Gefitinib Placebo
    Number of subjects analysed
    76 [8]
    65 [9]
    Units: patients
    16
    13
    Notes
    [8] - Patients analysed are those in the Evaluable for Quality of Life population, a subset of the ITT.
    [9] - Patients analysed are those in the Evaluable for Quality of Life population, a subset of the ITT.
    Statistical analysis title
    Comparison of QoL improvement measured by FACT-L
    Statistical analysis description
    The QoL(Quality of Life) improvement rate measured by the total score of the FACT-L will be compared between gefitinib and placebo using a logistic regression model that includes terms for Randomised Treatment, Gender,WHO Performance Status, Histology, Smoking History and Lung Stage Classification. The odds ratio(gefitinib:placebo) will be estimated from the model along with its associated 95% CI.
    Comparison groups
    Gefitinib v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.421
         upper limit
    2.408
    Notes
    [10] - Patients analysed are those in the Evaluable for Quality of Life population, including those with a baseline Quality of Life (QoL) assessment and at least one non-missing post-baseline QoL assessment. A subset of the ITT.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs are collected every 21 days for 1st 18 wks, then every 42 days until discontinuation of study drug. At discontinuation, patients are followed up for all existing & new AEs for 30 days; all AEs, toxicities & SAEs should be followed until resolution.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matched Placebo plus Best Supportive Care

    Reporting group title
    Gefitinib
    Reporting group description
    Gefitinib 250 mg plus Best Supportive Care

    Serious adverse events
    Placebo Gefitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 101 (24.75%)
    25 / 100 (25.00%)
         number of deaths (all causes)
    85
    84
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         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
    Death
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Impaired self-care
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 100 (2.00%)
         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
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         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
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular tachycardia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (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
    0 / 101 (0.00%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 101 (0.99%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral disorder
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain stem infarction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Somnolence
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastritis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (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 / 101 (0.99%)
    0 / 100 (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
    2 / 101 (1.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer haemorrhage
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess intestinal
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Corneal abscess
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis viral
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (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
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 101 (2.97%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mycobacterium avium complex infection
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Gefitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    92 / 101 (91.09%)
    89 / 100 (89.00%)
    Investigations
    Weight decrease
         subjects affected / exposed
    3 / 101 (2.97%)
    6 / 100 (6.00%)
         occurrences all number
    3
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 101 (10.89%)
    6 / 100 (6.00%)
         occurrences all number
    13
    6
    Dyspnoea
         subjects affected / exposed
    13 / 101 (12.87%)
    17 / 100 (17.00%)
         occurrences all number
    13
    17
    Epistaxis
         subjects affected / exposed
    2 / 101 (1.98%)
    6 / 100 (6.00%)
         occurrences all number
    2
    9
    Haemoptysis
         subjects affected / exposed
    5 / 101 (4.95%)
    4 / 100 (4.00%)
         occurrences all number
    5
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 101 (0.99%)
    6 / 100 (6.00%)
         occurrences all number
    1
    6
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 101 (0.99%)
    5 / 100 (5.00%)
         occurrences all number
    1
    5
    Dizzines
         subjects affected / exposed
    7 / 101 (6.93%)
    4 / 100 (4.00%)
         occurrences all number
    8
    4
    Headache
         subjects affected / exposed
    4 / 101 (3.96%)
    5 / 100 (5.00%)
         occurrences all number
    6
    7
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 101 (0.00%)
    5 / 100 (5.00%)
         occurrences all number
    0
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    22 / 101 (21.78%)
    14 / 100 (14.00%)
         occurrences all number
    22
    14
    Oedema peripheral
         subjects affected / exposed
    13 / 101 (12.87%)
    13 / 100 (13.00%)
         occurrences all number
    14
    17
    Asthenia
         subjects affected / exposed
    7 / 101 (6.93%)
    9 / 100 (9.00%)
         occurrences all number
    7
    10
    Pyrexia
         subjects affected / exposed
    4 / 101 (3.96%)
    6 / 100 (6.00%)
         occurrences all number
    4
    6
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 101 (4.95%)
    9 / 100 (9.00%)
         occurrences all number
    5
    9
    Confusional state
         subjects affected / exposed
    9 / 101 (8.91%)
    6 / 100 (6.00%)
         occurrences all number
    9
    6
    Insomnia
         subjects affected / exposed
    4 / 101 (3.96%)
    11 / 100 (11.00%)
         occurrences all number
    4
    12
    Depression
         subjects affected / exposed
    5 / 101 (4.95%)
    2 / 100 (2.00%)
         occurrences all number
    6
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    19 / 101 (18.81%)
    17 / 100 (17.00%)
         occurrences all number
    22
    19
    Abdominal pain
         subjects affected / exposed
    9 / 101 (8.91%)
    11 / 100 (11.00%)
         occurrences all number
    9
    11
    Diarrhoea
         subjects affected / exposed
    20 / 101 (19.80%)
    50 / 100 (50.00%)
         occurrences all number
    24
    65
    Dyspepsia
         subjects affected / exposed
    3 / 101 (2.97%)
    6 / 100 (6.00%)
         occurrences all number
    3
    6
    Nausea
         subjects affected / exposed
    31 / 101 (30.69%)
    30 / 100 (30.00%)
         occurrences all number
    35
    37
    Dysphagia
         subjects affected / exposed
    4 / 101 (3.96%)
    5 / 100 (5.00%)
         occurrences all number
    4
    5
    Vomiting
         subjects affected / exposed
    14 / 101 (13.86%)
    21 / 100 (21.00%)
         occurrences all number
    15
    24
    Stomatitis
         subjects affected / exposed
    5 / 101 (4.95%)
    9 / 100 (9.00%)
         occurrences all number
    5
    9
    Skin and subcutaneous tissue disorders
    Decubitis ulcer
         subjects affected / exposed
    1 / 101 (0.99%)
    5 / 100 (5.00%)
         occurrences all number
    1
    5
    Dermatitis acneiform
         subjects affected / exposed
    2 / 101 (1.98%)
    6 / 100 (6.00%)
         occurrences all number
    2
    6
    Dry skin
         subjects affected / exposed
    1 / 101 (0.99%)
    19 / 100 (19.00%)
         occurrences all number
    1
    23
    Rash
         subjects affected / exposed
    10 / 101 (9.90%)
    34 / 100 (34.00%)
         occurrences all number
    14
    41
    Pruritis
         subjects affected / exposed
    2 / 101 (1.98%)
    9 / 100 (9.00%)
         occurrences all number
    3
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 101 (7.92%)
    7 / 100 (7.00%)
         occurrences all number
    9
    7
    Muscular weakness
         subjects affected / exposed
    5 / 101 (4.95%)
    7 / 100 (7.00%)
         occurrences all number
    5
    7
    Musculoskeletal pain
         subjects affected / exposed
    5 / 101 (4.95%)
    7 / 100 (7.00%)
         occurrences all number
    5
    7
    pain in extremity
         subjects affected / exposed
    5 / 101 (4.95%)
    4 / 100 (4.00%)
         occurrences all number
    8
    4
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    5 / 101 (4.95%)
    5 / 100 (5.00%)
         occurrences all number
    5
    6
    Anorexia
         subjects affected / exposed
    17 / 101 (16.83%)
    20 / 100 (20.00%)
         occurrences all number
    19
    21
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    7 / 101 (6.93%)
    11 / 100 (11.00%)
         occurrences all number
    7
    13
    Oral candidiasis
         subjects affected / exposed
    5 / 101 (4.95%)
    3 / 100 (3.00%)
         occurrences all number
    5
    3
    Urinary tract infection
         subjects affected / exposed
    8 / 101 (7.92%)
    8 / 100 (8.00%)
         occurrences all number
    8
    8

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Oct 2005
    Amendment included: Extension of recruitment period due to slow recruitment from 11 months to 27 months; Clarification of exploratory objectives, planned biomarker analyses and confirmation of the biomarkers to be investigated; Change to allow patients to continue receiving study medication following disease progression, if the patient is deriving clinical benefit; Updated information regarding ZD1839 exposure, including ISEL clinical study data and rodent carcinogenicity data; Clarification of timings for visit 1 and visit 2; Clarification of Exclusion Criteria, Item 2 (radiotherapy, to allow discrimination between wide field and local irradiation.); Confirmation that proteomics no longer applicable to this protocol; Clarification of the reporting requirements for overdose; confirmation that no germline genetic analysis will be performed on any tumour tissue from this study; correction of volume of blood sampling to be taken at baseline.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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