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    Clinical Trial Results:
    Randomised double blind control trial of single dose methotrexate versus expectant management in women with tubal ectopic pregnancy

    Summary
    EudraCT number
    		 2004-003753-56
    Trial protocol
    		 GB  
    Global end of trial date
    25 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2018
    First version publication date
    14 Oct 2018
    Other versions
    Summary report(s)
    		 FINAL STUDY REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    04WH19
    Additional study identifiers
    ISRCTN number
    		 ISRCTN95698259
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College Hospital NHS Foundation Trust
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE5 9RS
    Public contact
    Ms Jackie Ross, King's College Hospital NHS Foundation Trust, 0044 02032993168, jackie.ross1@nhs.net
    Scientific contact
    Ms Jackie Ross, King's College Hospital NHS Foundation Trust, 0044 02032993168, jackie.ross1@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
    Final
    Date of interim/final analysis
    22 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of methotrexate as compared to placebo in the non-surgical management of tubal ectopic pregnancies
    Protection of trial subjects
    Trial subjects will be questioned at each visit regarding symptoms and signs which may be related to the methotrexate, specifically abdominal pain, nausea, diarrhoea, dry eyes, stomatitis. Surgery will be advised if the hCG increases by more than 15% on two consecutive occasions, there is evidence of haematoperitoneum, or if the patient is in severe pain.
    Background therapy
    		 None
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Aug 2005
    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: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    80
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants are women presenting to the early pregnancy units with a definite ultrasound diagnosis of tubal ectopic pregnancy from two centres within the UK between 2005 and 2014.

    Pre-assignment
    Screening details
    		 The study will include women presenting to the early pregnancy units with a definite ultrasound diagnosis of tubal ectopic pregnancy.

    Pre-assignment period milestones
    Number of subjects started
    		 80
    Number of subjects completed
    		 80

    Period 1
    Period 1 title
    Whole Group (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Methotrexate
    Arm description
    		 Participants randomized to receive methotrexate 50mg/m2 administered as an IM injection on one occasion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Methotrexate 50mg/m2 administered as a single dose intramuscular injection,

    Arm title
    		 Placebo
    Arm description
    		 Participants eligible for inclusion randomized to receive placebo administered as a single dose intramuscular injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Normal saline administered as a single dose intramuscular injection

    Number of subjects in period 1
    		Methotrexate Placebo
    Started
    42
    38
    Completed
    36
    35
    Not completed
    6
    3
         Consent withdrawn by subject
    6
    3

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Methotrexate
    Reporting group description
    		 Participants randomized to receive methotrexate 50mg/m2 administered as an IM injection on one occasion.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants eligible for inclusion randomized to receive placebo administered as a single dose intramuscular injection

    Primary: Efficacy of systemic methotrexate as compared to placebo in the non-surgical management of tubal ectopic pregnancies.

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    End point title
    		 Efficacy of systemic methotrexate as compared to placebo in the non-surgical management of tubal ectopic pregnancies. [1]
    End point description
    The primary outcome measure is the number of surgical procedures in each group
    End point type
    Primary
    End point timeframe
    Within the duration of the trial - ie up to day 14 or when weekly Beta HCG level = 20 iU/L or lower.
    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: Please see attached reports and publication for statistical results and analysis.
    End point values
    		 Methotrexate Placebo
    Number of subjects analysed
    36
    35
    Units: whole
    36
    35
    Attachments
    		 Participant flow chart
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    until 3 months post randomization and administration of active or placebo injection.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Methotrexate
    Reporting group description
    		 Active intervention group

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Serious adverse events
    		 Methotrexate Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 35 (11.43%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Ruptured ectopic pregnancy
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy
    Additional description: Pregnancy reported within the 3 months post randomization and administration of IMP
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    Additional description: Participants admitted to hospital overnight with abdominal pain.
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Methotrexate Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 36 (22.22%)
    4 / 35 (11.43%)
    Pregnancy, puerperium and perinatal conditions
    Abdominal pain
         subjects affected / exposed
    8 / 36 (22.22%)
    4 / 35 (11.43%)
         occurrences all number
    8
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2010
    Clarification regarding extension to end of trial date detailed in the protocol.
    17 Aug 2011
    Amendment to allow each Pharmacy to use their own stock and brand of IMP/ placebo rather than have them supplied from a central location. Labels will remain the same except the name of the dispensing pharmacy

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Feb 2008
    Changes in conduct or management of the trial Change or addition of principal investigator(s), co-ordinating investigator y Change/addition of site(s)
    15 May 2008

    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/27731538
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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
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