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    Clinical Trial Results:
    GEM for Ectopic Pregnancies II: Combination gefitinib and methotrexate to treat ectopic pregnancies

    Summary
    EudraCT number
    		 2011-001747-69
    Trial protocol
    		 GB  
    Global end of trial date
    01 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jun 2019
    First version publication date
    12 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ACTRN: 12610000684022
    Sponsors
    Sponsor organisation name
    University of Edinburgh
    Sponsor organisation address
    QMRI, 51 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Ann Doust, University of Edinburgh, +44 1312429492, ann.doust@ed.ac.uk
    Scientific contact
    Andrew Horne, University of Edinburgh, +44 1312429492, andrew.horne@ed.ac.uk
    Sponsor organisation name
    NHS Lothian
    Sponsor organisation address
    QMRI, 51 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Ann Doust, University of Edinburgh, +44 1312429492, ann.doust@ed.ac.uk
    Scientific contact
    Prof Andrew Horne, University of Edinburgh, +44 1312429492, andrew.horne@ed.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
    18 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of a single intramuscular injection of MTX (50mg/m2) and seven days of oral gefitinib 250mg in regressing stable ectopic pregnancies with a serum human chorionic gonadotrophin level at presentation (reflects ectopic pregnancy size) of between 1000-10,000 IU/L. It was a single arm trial that aimed to recruit 50 participants who met the inclusion criteria. It was powered to show the drug is at least 70% effective in successfully resolving ectopic pregnancies without need for surgery. This trial also set out to further collect information on safety and tolerability of the drug.
    Protection of trial subjects
    For protection of subjects 1) The trial was overseen by a Trial Steering Committee who had a member assessing safety sitting on the committee. In addition, this committee comprised of members from The University of Melbourne (2 Professors) and an independent Professor of Reproductive Biology at the University of Edinburgh. 2) The protocols had full REC approval and all participants provided written, informed consent 3) All adverse / serious adverse outcomes were formally reported to REC committees. 4) All trial subjects were aware of what to do in an event of any emergency: contact details for the hospital as well as a phone number where they could contact study investigators.
    Background therapy
    		 All participants had the standard intramuscular methotrexate dose that is widely used to medically treat ectopic pregnancies. Thus, all were given a single intramuscular injection of methotrexate (50mg/m2), but they also then were given seven tablets of 250 mg of gefitinib (the trial medication).
    Evidence for comparator
    		 This was a single arm trial and there was no comparator arm. The thought when designing this small trial was that it was premature to embark of a formal randomised trial therefore the next step was this small single arm phase II study.
    Actual start date of recruitment
    01 Mar 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: 19
    Country: Number of subjects enrolled
    Australia: 11
    Worldwide total number of subjects
    30
    EEA total number of subjects
    19
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 We recruited participants between March 2012 and April 2014. Participants were recruited from 3 Australian Centres and 1 in Edinburgh. Recruitment was done in the early pregnancy units where investigators were alerted by staff of potential participants who were diagnosed with an ectopic pregnancy that may fit the criteria as per our protocol.

    Pre-assignment
    Screening details
    		 Patients we referred by their direct clinical care team to members of the research team.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Active arm (single arm study)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gefitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250mg, once daily for 7 days

    Number of subjects in period 1
    		Active arm (single arm study)
    Started
    30
    Completed
    28
    Not completed
    2
         Consent withdrawn by subject
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 30 30
    Age categorical
    Study inclusion criterion stipulated an age range of 18-45 years.
    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)
    		 30 30
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        Age
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (inter-quartile range (Q1-Q3))
    		 30.5 (23.5 to 33.8) -
    Gender categorical
    This study investigates a treatment for women with ectopic pregnancies - all subjects are female
    Units: Subjects
        Female
    		 30 30
    Age categorical
    Study inclusion criterion stipulated an age range of 18-45 years
    Units: Subjects
        18-45 years
    		 30 30
    Maternal serum hCG concentration
    Units: iu/l
        median (full range (min-max))
    		 2108 (1031 to 8575) -
    Subject analysis sets

    Subject analysis set title
    Analysis of ectopic pregnancy outcomes
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Outcomes analysed from 28 subjects (19 from the UK) who completed the study medication regime as per the protocol (single stat dose of 50mg/m² intramuscular methotrexate, plus 250mg oral gefitinib daily for seven days) for the treatment of tubal ectopic pregnancy.

    Subject analysis sets values
    		 Analysis of ectopic pregnancy outcomes
    Number of subjects
    28
    Age categorical
    Study inclusion criterion stipulated an age range of 18-45 years.
    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)
    28
        From 65-84 years
    0
        85 years and over
    0
        Age
    0
    Age continuous
    Units: years
        arithmetic mean (inter-quartile range (Q1-Q3))
    30.5 (23.5 to 33.8)
    Gender categorical
    This study investigates a treatment for women with ectopic pregnancies - all subjects are female
    Units: Subjects
        Female
    28
    Age categorical
    Study inclusion criterion stipulated an age range of 18-45 years
    Units: Subjects
        18-45 years
    28
    Maternal serum hCG concentration
    Units: iu/l
        median (full range (min-max))

    End points

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    End points reporting groups
    Reporting group title
    Active arm (single arm study)
    Reporting group description
    		 -

    Subject analysis set title
    Analysis of ectopic pregnancy outcomes
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Outcomes analysed from 28 subjects (19 from the UK) who completed the study medication regime as per the protocol (single stat dose of 50mg/m² intramuscular methotrexate, plus 250mg oral gefitinib daily for seven days) for the treatment of tubal ectopic pregnancy.

    Primary: Resolution of ectopic pregnancy without need for surgical intervention

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    End point title
    		 Resolution of ectopic pregnancy without need for surgical intervention [1]
    End point description
    Resolution of ectopic pregnancy without need for surgical intervention
    End point type
    Primary
    End point timeframe
    Serial blood tests to track serum hCG concentration levels collected and analysed pre-treatment (day 1), on days 4, 7 and 11, then weekly until either (i) surgical intervention was warranted or (ii) serum hCG concentration fell to non-pregnant levels.
    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: No statistical analyses for this end point
    End point values
    		 Active arm (single arm study)
    Number of subjects analysed
    28
    Units: Number of participants without surgery
    28
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of consent to discharge following hCG <15 or surgical management of EP
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Serious adverse events
    		 Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 30 (73.33%)
    Investigations
    All investigations
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences all number
    7
    Nervous system disorders
    All nervous system disorders
         subjects affected / exposed
    8 / 30 (26.67%)
         occurrences all number
    8
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    All General disorders and administration site conditions
         subjects affected / exposed
    10 / 30 (33.33%)
         occurrences all number
    12
    Gastrointestinal disorders
    All Gastrointestinal disorders
         subjects affected / exposed
    17 / 30 (56.67%)
         occurrences all number
    34
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    16 / 30 (53.33%)
         occurrences all number
    23
    Respiratory, thoracic and mediastinal disorders
    All respiratory, thoracic and mediastinel disorders
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Pain of skin
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    17 / 30 (56.67%)
         occurrences all number
    17
    Pruritus
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    5
    Infections and infestations
    All infections and infestations
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24812320
    http://www.ncbi.nlm.nih.gov/pubmed/23872290
    http://www.ncbi.nlm.nih.gov/pubmed/29941341
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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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