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    Clinical Trial Results:
    Does the DPP4 Inhibitor (Sitagliptin) Increase Endometrial Mesenchymal Stem Cells in Women with Recurrent Miscarriage?

    Summary
    EudraCT number
    2016-001120-54
    Trial protocol
    GB  
    Global end of trial date
    12 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Feb 2020
    First version publication date
    27 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SQ167015
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University Hospitals Coventry and Warwickshire NHS Trust
    Sponsor organisation address
    Clifford Bridge Road, Coventry, United Kingdom, CV2 2DX
    Public contact
    Mrs Ceri Jones, University Hospitals Coventry and Warwickshire NHS Trust, +44 2476965031, Ceri.Jones@uhcw.nhs.uk
    Scientific contact
    Professor Siobhan Quenby and Dr Shreeya Tewary, University Hospitals Coventry and Warwickshire NHS Trust, +44 2476967528, Siobhan.Quenby@uhcw.nhs.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
    23 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine the effect of Sitagliptin on endometrial mesenchymal stem cell count. This will be assessed by the number of colonies per thousand endometrial stromal cells after 3 months of Sitagliptin (100mg) vs. 3 months of placebo, determined by a clonogenic assay. The pre-specified primary outcome measure was the CFU count per 1000EnSC seeded after 3 cycles of sitagliptin or placebo. However, to mitigate against potential loss of data in case of infection, a total of 1500cells were seeded in 3 wells of a 6-well plate per sample. As there were no obvious criteria to exclude the colony count from a given well, the results are presented as CFU count per 1500EnSC.
    Protection of trial subjects
    Patients were reviewed every 4 weeks to assess for any side effects, with an independent advisor overseeing the trial who was very familiar with using sitagliptin. The endometrial biopsies were taken using a simple manual suction device commonly used in gynaecology clinics. The sampler is inserted through the cervix into the uterus to take the endometrial biopsy. The patients were warned beforehand that the sampler can cause some pelvic pain and cramps due to uterine contractions. They were advised that 400mg of Ibuprofen and 1g of Paracetamol can be taken prior to their visit and Entonox is available to use when the biopsy is being taken. They were also told to bring a sanitary pad as they may experience some spotting after the procedure. It was explained to patients that they must not try for a pregnancy while in the trial, as agreed on the consent form. They were asked to do a pregnancy test at home every 2 weeks, each time a patient attended for a face-face consultation, and before each endometrial biopsy. In the event of a positive pregnancy test patients were asked to stop the medication immediately.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Sep 2016
    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: 38
    Worldwide total number of subjects
    38
    EEA total number of subjects
    38
    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)
    38
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The date of enrolment of the first participant was 15th September 2016. Single centre: University Hospitals Coventry and Warwickshire (UHCW) National Health Service (NHS) Trust.

    Pre-assignment
    Screening details
    Screened 73, Excluded (n=35) Not meeting inclusion criteria (n=7) Declined to participate (n=24) Other reasons (n= 4)

    Pre-assignment period milestones
    Number of subjects started
    38
    Number of subjects completed
    33

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Reason: Number of subjects
    Pregnancy: 2
    Reason: Number of subjects
    Physician decision: 1
    Reason: Number of subjects
    Loss to follow up: 1
    Period 1
    Period 1 title
    Completed 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
    Participants, investigators, research midwives and nurses remained blinded to the IMP allocation throughout the duration of the trial. The IMP was be supplied as blinded packs of Sitagliptin/placebo 100mg capsules.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sitagliptin
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Encapsulated tablet containing 100mg of active Sitagliptin.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Encapsulated tablet containing 100mg of placebo

    Number of subjects in period 1 [1]
    Sitagliptin Placebo
    Started
    16
    17
    Completed
    16
    17
    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: Baseline characteristics have been reported for those that have completed the trial (n=33).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Sitagliptin Placebo Total
    Number of subjects
    16 17 33
    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
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    34.5 ( 4.20 ) 31.3 ( 3.69 ) -
    Gender categorical
    Units: Subjects
        Female
    16 17 33
        Male
    0 0 0
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    26.9 ( 4.67 ) 26.3 ( 4.59 ) -
    Number of previous miscarriages
    Units: miscarriages
        arithmetic mean (standard deviation)
    6.6 ( 3.2 ) 7.6 ( 3.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: The number of colonies per 1500 endometrial stromal cells after 3 months of Sitagliptin (100mg) vs. 3 months of placebo, determined by a clonogenic assay

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    End point title
    The number of colonies per 1500 endometrial stromal cells after 3 months of Sitagliptin (100mg) vs. 3 months of placebo, determined by a clonogenic assay
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and 3 months
    End point values
    Sitagliptin Placebo
    Number of subjects analysed
    16 [1]
    17 [2]
    Units: per 1500 endometrial stromal cells
    arithmetic mean (standard deviation)
        Baseline eMSC count per 1500 cells seeded
    16.1 ( 19.6 )
    24.2 ( 25.6 )
        Final visit eMSC count per 1500 cells seeded
    27.7 ( 35.8 )
    25.1 ( 27.3 )
    Notes
    [1] - Observation for one woman missing for Final visit eMSC count per 1500 cells seeded.
    [2] - Observation for one woman missing for Baseline eMSC count per 1500 cells seeded.
    Statistical analysis title
    Primary analysis
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.15
    Method
    Poisson regression model
    Parameter type
    Rate ratio
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.96
         upper limit
    1.26

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    14/09/2016 - 12/02/2018
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Sitagliptin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Hospitalisation - Participant was admitted to A&E with abdominal pain. Pregnancy test performed whilst at hospital was positive. Participant was discharged from A&E the same day.
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         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: 0%
    Non-serious adverse events
    Sitagliptin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 17 (29.41%)
    12 / 19 (63.16%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 17 (11.76%)
    7 / 19 (36.84%)
         occurrences all number
    2
    7
    Dizziness
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Migraine
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Thirst
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Eye disorders
    Extraocular muscle paresis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Dry throat
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Epistaxis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Androgenetic alopecia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Nervousness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Nov 2016
    A temporary halt of the trial, after 4 patients had been randomised. As some patient’s had their blood tests repeated and recruited using the second eligible test results. Allow time to prepare the protocol amendment with clearer guidance to recruitment and eligibility criteria.
    06 Dec 2016
    Amendment to request the restart of the trial following temporary halt. Amendment to the trial protocol, participant flow in line with current practice, eligibility criteria regarding renal and hepatic function. Patients identified from the implantation clinic will be referred to the recurrent miscarriage clinic to have routine blood tests to ensure there is no cause for their miscarriages before being recruited to SIMPLANT. Consent will be taken at a time that suits the patient after they have had sufficient time to read the patient information leaflet and eligibility has been confirmed. Pharmacovigilence and Safety monitoring has been edited to reflect correct reporting procedures to the Sponsor and regulatory authorities. Unblinding procedure update, as originally, Sharpe Clinical Services were going to make the master unblinding list and provide the code break envelopes however this was done by an independent statistician.
    02 May 2017
    Amendment to the protocol to allow randomisation of up to 40 participants, rather than 34 participants as previously planned, and an extension of the recruitment period.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Nov 2016
    A temporary halt of the trial.
    06 Dec 2016

    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/31928963
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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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