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    Clinical Trial Results:
    A pragmatic group sequential placebo controlled randomised trial to determine the effectiveness of Glyceryl trinitrate for retained placenta (GOT-IT Trial)

    Summary
    EudraCT number
    2013-003810-42
    Trial protocol
    GB  
    Global end of trial date
    03 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Mar 2019
    First version publication date
    30 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Version8.0; 27/04/2016
    Additional study identifiers
    ISRCTN number
    ISRCTN88609453
    US NCT number
    NCT02085213
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    NHS Lothian and University of Edinburgh
    Sponsor organisation address
    47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Fiach O'Mahony, ACCORD , 44 1312429418, researchgovernance@ed.ac.uk
    Scientific contact
    Fiach O'Mahony, ACCORD, 44 1312429418, researchgovernance@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
    22 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary research objectives of the internal pilot RCT are: 1) To demonstrate trial processes for approaching women, gaining consent, randomising, treating and assessing outcomes are optimal, and to implement improvements as required; 2) To determine achievable recruitment rates; 3) To determine the likely effect size, to inform a calculation on whether the planned sample size can be reduced whilst maintaining study power; 4) To pilot and modify if required the post-partum questionnaires (assessment of patient satisfaction and collection of health service use outcomes). The primary research objectives of the substantive GOT-IT RCT are: 1) To determine the clinical effectiveness of sublingual GTN in treating RP and avoiding MROP in women with vaginal delivery following failure of current management (defined as a third stage of labour lasting more than 30 mins after active management or 60 mins after physiological followed by active management respectively) (clinical domain);
    Protection of trial subjects
    All potential eligible subjects were screened before they were entered into the trial. They had the following safety assessments performed. 1. Medical history was obtained. 2. Concomitant medications were checked. 3. Blood pressure, heart rate and temperature were recorded at baseline, 5 and 15 minutes post-administration of study medication. 4. Blood loss was captured from the time the study medication was administered until the woman was moved to the post natal area. 5. Adverse events were reported.
    Background therapy
    Study participants had management of the third stage of labour as per current clinical practice which would normally include oxytocin and/or syntometrine.
    Evidence for comparator
    Small studies have suggested that nitric oxide donors such as glyceryl trinitrate (GTN) may be an effective treatment for RP. Six studies report that administration of GTN intravenously or via a sublingual tablet was effective in relaxing the uterus to facilitate insertion of the examining hand for MROP or in facilitating delivery of the placenta by controlled cord traction.
    Actual start date of recruitment
    13 Oct 2014
    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: 1104
    Worldwide total number of subjects
    1104
    EEA total number of subjects
    1104
    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)
    1104
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    October 2014 through July 2017, 29 UK maternity units.

    Pre-assignment
    Screening details
    Women with retained placenta who fulfil the inclusion criteria and do not meet exclusion criteria will be eligible for study entry following informed consent. 1671 screened, 1107 randomised, 3 post-randomisation exclusions, ITT 1104.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All members of the team were blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Intervention
    Arm description
    Sublingual GTN spray
    Arm type
    Experimental

    Investigational medicinal product name
    GTN
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual spray
    Routes of administration
    Sublingual use
    Dosage and administration details
    800mcg;2 puffs sublingual

    Arm title
    Comparator
    Arm description
    Comparator
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual spray
    Routes of administration
    Sublingual use
    Dosage and administration details
    2 puffs sublingual comparator spray

    Number of subjects in period 1
    Intervention Comparator
    Started
    541
    563
    Completed
    535
    556
    Not completed
    6
    7
         Protocol deviation
    1
    -
         Physician decision
    5
    7

    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
    1104 1104
    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)
    1104 1104
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    all female
    Units: Subjects
        Female
    1104 1104
        Male
    0 0
    Subject analysis sets

    Subject analysis set title
    Full data
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat

    Subject analysis sets values
    Full data
    Number of subjects
    1104
    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)
    1104
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    Gender categorical
    all female
    Units: Subjects
        Female
    1104
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    Sublingual GTN spray

    Reporting group title
    Comparator
    Reporting group description
    Comparator

    Subject analysis set title
    Full data
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention to treat

    Primary: Need for manual removal of placenta by 15 minutes

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    End point title
    Need for manual removal of placenta by 15 minutes
    End point description
    Need for MROP of placenta
    End point type
    Primary
    End point timeframe
    Within 15 minutes of intervention
    End point values
    Intervention Comparator Full data
    Number of subjects analysed
    535
    556
    1104
    Units: Numbers
    535
    556
    1104
    Attachments
    Untitled (Filename: Screen Shot 2019-03-12 at 17.42.29.png)
    Statistical analysis title
    Statistical analysis
    Statistical analysis description
    Analysis of primary outcome
    Comparison groups
    Intervention v Comparator
    Number of subjects included in analysis
    1091
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    t-test, 2-sided
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.04

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and serious adverse events were recorded form the time a participant signs the consent form until the 6 week postnatal outcome assessment point.
    Adverse event reporting additional description
    Adverse events are assessed for the following: 1. Seriousness 2. Causality 3. Expectedness 4. Severity
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Active(GTN)
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Active(GTN) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 541 (4.99%)
    25 / 563 (4.44%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Procedural headache
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hysterectomy
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
    Additional description: Anaphylaxis due to Suxamethonium
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Postpartum haemorrhage
         subjects affected / exposed
    23 / 541 (4.25%)
    16 / 563 (2.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retained products of conception
         subjects affected / exposed
    1 / 541 (0.18%)
    3 / 563 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 563 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Endometritis
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 563 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 563 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
    Additional description: Escheria coli and clostridium difficile infection
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Active(GTN) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    166 / 541 (30.68%)
    185 / 563 (32.86%)
    Vascular disorders
    Deep vein thrombosis
    Additional description: Potential deep vein thrombosis
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 563 (0.00%)
         occurrences all number
    0
    0
    Injury, poisoning and procedural complications
    Perineal injury
         subjects affected / exposed
    1 / 541 (0.18%)
    1 / 563 (0.18%)
         occurrences all number
    0
    0
    Investigations
    Blood pressure decreased
         subjects affected / exposed
    6 / 541 (1.11%)
    21 / 563 (3.73%)
         occurrences all number
    0
    0
    Tachycardia
         subjects affected / exposed
    5 / 541 (0.92%)
    6 / 563 (1.07%)
         occurrences all number
    0
    0
    Blood pressure increased
         subjects affected / exposed
    4 / 541 (0.74%)
    0 / 563 (0.00%)
         occurrences all number
    0
    0
    Full blood count
    Additional description: Uncoagulated full blood count sample
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 563 (0.00%)
         occurrences all number
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 541 (0.00%)
    4 / 563 (0.71%)
         occurrences all number
    0
    0
    Syncope
         subjects affected / exposed
    0 / 541 (0.00%)
    3 / 563 (0.53%)
         occurrences all number
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 563 (0.00%)
         occurrences all number
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Postpartum haemorrhage
         subjects affected / exposed
    166 / 541 (30.68%)
    175 / 563 (31.08%)
         occurrences all number
    0
    0
    Placenta accreta
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences all number
    0
    0
    Retained products of conception
    Additional description: Postnatal readmission for retained products
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences all number
    0
    0
    Gastrointestinal disorders
    Oral discomfort
         subjects affected / exposed
    2 / 541 (0.37%)
    0 / 563 (0.00%)
         occurrences all number
    0
    0
    Constipation
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 563 (0.00%)
         occurrences all number
    0
    0
    Nausea
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences all number
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences all number
    0
    0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 541 (0.00%)
    1 / 563 (0.18%)
         occurrences all number
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Facial rash
         subjects affected / exposed
    1 / 541 (0.18%)
    0 / 563 (0.00%)
         occurrences all number
    0
    0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    7 / 541 (1.29%)
    10 / 563 (1.78%)
         occurrences all number
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2014
    Protocol V3.0 Substantial Amendment 2 Change of exclusion criteria from women having an instrumental delivery to women having an instrumental delivery in theatre.
    27 Apr 2016
    Protocol V8.0 Substantial Amendment 11 1. The original definition of haemodynamically stable was systolic blood pressure more than 100mmHG and pulse less than 110 beats per minute. This definition was changed to satisfy all there defintions: Haemodynamically stable Heart rate ≤ 119bpm Systolic blood pressure >100mmHg 2. Change in exclusion criteria to allow co-enrolment to exist for CTIMP trials, providing there was a CTIMP-CTIMP agreement between the Sponsors and investigators of each trial.

    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/28928192
    http://www.ncbi.nlm.nih.gov/pubmed/28539111
    http://www.ncbi.nlm.nih.gov/pubmed/27245155
    http://www.ncbi.nlm.nih.gov/pubmed/27066777
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