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    Clinical Trial Results:
    Tyrosine kinase Inhibitors in DysplAsia of Lung epithelium Study 1

    Summary
    EudraCT number
    		 2010-023355-29
    Trial protocol
    		 GB  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Mar 2019
    First version publication date
    21 Mar 2019
    Other versions
    Summary report(s)
    		 summary results

    Trial information

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    Trial identification
    Sponsor protocol code
    PO1425
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01405846
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Royal Papworth Hospital NHS Foundation Trust
    Sponsor organisation address
    Ermine Street, Papworth Everard, United Kingdom, CB23 3RE
    Public contact
    Vikki Hughes, Royal Papworth Hospital NHS Foundation Trust, 01480 830541, victoria.hughes1@nhs.net
    Scientific contact
    Dr Robert Rintoul, Royal Papworth Hospital NHS Foundation Trust, 01480 830541, robert.rintoul@nhs.net
    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
    Interim
    Date of interim/final analysis
    11 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to identify a group of patients who have a high incidence of abnormal, pre-cancerous areas in the lining of their airways which put them at high risk of developing lung cancer.
    Protection of trial subjects
    Independent Chair of the Trial Steering Committee
    Background therapy
    		 No background therapy, these patients are standardly clinically managed by routine follow-up to assess if there has been disease progression
    Evidence for comparator
    		 The study also aimed to provide an early indication as to whether the EGFR inhibitor gefitinib can resolve the dysplastic process.. The development of dysplasia is characterised by EGFR overexpression (Merrick et al., Clin Cancer Res 2006;12(7)). Gefitinib (ZD1839, Gefitinib, AstraZeneca Pharmaceuticals, Wilmington, Del.) is an oral inhibitor of EGFR tyrosine kinases. There are extensive in vitro and in vivo data demonstrating that Gefitinib blocks proliferation in cell culture induced by activation of EGFR and causes regression of human tumour xenografts with EGFR over-expression. If such a signal was demonstrated then future randomized trials of EGFR inhibition in this setting would be warranted.
    Actual start date of recruitment
    02 Jan 2012
    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
    United Kingdom: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    7
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was from 01/01/2012 to 12/11/2015 at Royal Papworth Hospital NHS Foundation Trust

    Pre-assignment
    Screening details
    		 Patients underwent a contrast-enhanced staging CT of chest and abdomen and if this did not show any evidence of new or recurrent malignant disease or interstitial lung disease, a flexible bronchoscopy with autofluorescence was performed. Patients found at bronchoscopy to have areas of high-grade dysplasia were consented to the treatment arm

    Pre-assignment period milestones
    Number of subjects started
    		 32
    Number of subjects completed
    		 2

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 no high grade dysplasia: 21
    Reason: Number of subjects
    		 study terminated: 2
    Reason: Number of subjects
    		 Physician decision: 7
    Period 1
    Period 1 title
    Stage 2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    all pts eligible for stage 2 to receive study drug

    Arms
    Arm title
    		 Treatment
    Arm description
    		 Gefitinib 250mg daily for 26 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    gefitinib
    Investigational medicinal product code
    zd1839
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250mg od

    Number of subjects in period 1 [1]
    		Treatment
    Started
    2
    Completed
    2
    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: Patients were enrolled for screening and only those with high grade dysplasia were eligible for the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Stage 2
    Reporting group description
    		 Patients receive 250mg dailing gefitinib for 26 weeks

    Reporting group values
    		 Stage 2 Total
    Number of subjects
    		 2 2
    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)
    		 0 0
        From 65-84 years
    		 2 2
        85 years and over
    		 0 0
    Age continuous
    age range
    Units: years
        median (full range (min-max))
    		 70 (67 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 1 1
    Subject analysis sets

    Subject analysis set title
    response to treatment
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Response to treatment

    Subject analysis sets values
    		 response to treatment
    Number of subjects
    2
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    2
        85 years and over
    0
    Age continuous
    age range
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 Gefitinib 250mg daily for 26 weeks

    Subject analysis set title
    response to treatment
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Response to treatment

    Primary: Response to treatment

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    End point title
    		 Response to treatment
    End point description
    1 = no high grade dyplasia on biopsy and 0 = presence of high grade dysplasia
    End point type
    Primary
    End point timeframe
    Post treatment and 6 months post treatment
    End point values
    		 Treatment response to treatment
    Number of subjects analysed
    2
    2
    Units: biopsy
        number (not applicable)
    0.5
    0.5
    Attachments
    		 consort diagram
    Statistical analysis title
    		 TIDAL study
    Statistical analysis description
    The primary aim of this study was to estimate the proportion of patients in the risk population who are diagnosed as having high-grade dysplasia of the bronchial epithelium on autofluorescence bronchoscopy. There was little information on the true value of this proportion and the aim of this study was to reduce this uncertainty.
    Comparison groups
    Treatment v response to treatment
    Number of subjects included in analysis
    4
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 ≤ 0.05 [2]
    Method
    		 Bayesian Posterior Probability
    Confidence interval
    Notes
    [1] - The statistical analysis is a likelihood-based Bayesian approach to estimation of the proportion using a Beta-Binomial conjugate analysis with a minimally informative Beta(1,1) prior. The analysis will estimate a posterior probability distribution with 80% and 95% credible intervals and estimate the probability that the true proportion is less than 10% which is the level at which further research of this condition in this population would be deemed infeasible.
    [2] - The Bayesian posterior probability distribution for the true incidence rate of high dysplasia had mean of 12% and median of 11%. Credible intervals showed that there is a 95% chance that the true incidence rate falls between 2.7% to 27.0%

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12/01/2012 - 09/08/2016
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Treatment Group
    Reporting group description
    		 -

    Serious adverse events
    		 Treatment Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 2 (50.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory deterioration post-bronchoscopy
    Additional description: Acute respiratory deterioration post-bronchoscopy
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    Investigations
    nodule detected on CT
    Additional description: new benign nodule detected on CT
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Eye disorders
    sore eyes
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    4
    dry cough
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Hepatobiliary disorders
    increase in liver enzymes
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    5
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    increase in creatinine
    Additional description: increase to above ULN
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Infections and infestations
    chest infection
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Nov 2011
    Addition of another site
    19 Jul 2012
    Change from low dose to contract enhanced CT scan in the screening phase

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Feb 2015
    In November 2014 a temporary halt was made to the study to allow for futility analysis. The study was restarted in May 2015 but with clear target for recruiting eligible patients. The Trial Management Group (TMG) was held on the 9th February 2016 and no further eligible patients have been identified despite the very best efforts of the research team. The Independent Chair of the requested that the study be stopped due to futility and this was accepted by the study team. The proposed management of patients receiving treatment at time of the halt: No patients are currently receiving treatment. There were 2 patients who had been given patient information sheets to read, these will be told of the closure of the study. Early termination will not have any consequences on the overall risk benefit assessment of the IMP as the study was primarily designed to assess the rate of high grade dysplasia, which was significantly lower than expected.
    14 May 2015

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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