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    Clinical Trial Results:
    Local Oestrogen Treatment in Postmenopausal Women Undergoing Pelvic Organ Prolapse Surgery (LOTUS) - Feasibility Study

    Summary
    EudraCT number
    2014-000179-18
    Trial protocol
    GB  
    Global end of trial date
    01 Sep 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Aug 2019
    First version publication date
    29 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_13-322
    Additional study identifiers
    ISRCTN number
    ISRCTN46661996
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    MHRA: 21761/0318/001-0001
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Aston Webb Building, Birmingham, United Kingdom, B15 2TT
    Public contact
    Mr Sean Jennings, University of Birmingham, 0121 4158011, researchgovernance@contacts.bham.ac.uk
    Scientific contact
    Dr Pallavi Latthe , Birmingham Women’s Hospital, 0121 627 2672, platthe@nhs.net
    Sponsor organisation name
    Birmingham Women's NHS Foundation Trust
    Sponsor organisation address
    Edgbaston, Birmingham, United Kingdom, B15 2TG
    Public contact
    Kelly Hard, Birmingham Women's NHS Foundation Trust, kellyhard@nhs.net
    Scientific contact
    Dr Pallavi Latthe, Birmingham Women's Hospital, 0121 627 2672, platthe@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
    30 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the feasibility study is to find out if an appropriately powered randomised controlled trial can be realistically undertaken. The feasibility study will also allow the research team to identify any barriers to recruitment and compliance, and fine tune study procedures such as data collection and prescription of the study treatments. The aim of the definitive study would be to test the hypothesis that vaginal oestrogen treatment of postmenopausal women undergoing pelvic floor repair surgery leads to improved patient reported outcomes in relation to urinary, bowel, sexual function and prolapse related quality of life (QoL). Feasibility study specific objectives: 1.To obtain estimates for important aspects of the protocol to allow development of a definitive trial 2.To derive real- time data on the design aspects of the study I.Proportion of eligible women of those screened II.Proportion of eligible women randomised III.Attrition rates IV.Compliance with treatment
    Protection of trial subjects
    We ensure that all staff are GCP trained and will only grant access to allow staff at site to become involved in the trial if their GCP is in date. It is imperative that all investigators and staff at the sites have a thorough understanding of anticipated adverse events and the reporting process of these events as it is their responsibility to notify adverse events and SAE's to the Trial Office and for the Sponsor, or designated delegate, to report to the regulatory authority and ethics committee. For each SAE, the following information will be collected, from the gynaecologist, treating doctor or woman herself. SmPC updates are checked monthly and any changes circulated to sites and pharmacy. The patient Information Sheet contained the details of the Patient Advice and Liaison Service (PALS) for the individual sites.
    Background therapy
    Prolapse may be associated with weakening or atrophy of the genital tract. Oestrogen deficiency secondary to menopause results in weakening of the supporting ligaments of the pelvic organs and the pelvic floor muscles worsening the symptoms of prolapse. The vagina also contains oestrogen receptors and is sensitive to changes in circulating levels of oestrogen. Low oestradiol levels after the menopause lead to reduced vascularity of the tissues, along with a decrease in the glycogen content of epithelial cells. This in turn, leads to a fall in lactobacilli content and an increase in pH, encouraging the growth of certain bacteria, including coliforms. 9This may lead to overcolonization of the vagina, irritation and discharge. A decrease in oestrogen levels also results in atrophy of the vaginal epithelium, with more parabasal cells and fewer superficial cells seen on cytology. Associated symptoms include vaginal dryness, soreness, dyspareunia, dysuria or urinary urgency. Oestrogen treatment can be used to reduce thinning of the vaginal and pelvic tissues. This may help to reduce or prevent the symptoms of prolapse, or may be used to make other prolapse treatments work better. The different preparations of topical hormone replacement therapy (HRT) (creams, pessaries, tablets and the estradiol vaginal ring all appear equally effective for treating vaginal atrophy but the evidence on their effectiveness in reducing symptoms related to prolapse or indeed reducing the risk of recurrence of prolapse postoperatively is non-existent.
    Evidence for comparator
    Participants will be randomised individually into the study in an equal 1:1 ratio. A 'minimisation' procedure using a computer-based algorithm will be used to avoid chance imbalances in important stratification variables. Multicentre feasibility open label trial comparing vaginal low-dose oestrogen with no treatment, in 100 consenting postmenopausal women who are planning to undergo POP surgery. They will be randomly allocated to: Intervention group (Group A): This will comprise of 6 weeks course of oestradiol 10 μg preoperatively per vaginum (once daily for 2 weeks followed by twice weekly for four weeks) and then 10μg oestradiol per vaginum twice weekly from 6-26 weeks postoperatively. Comparison group (Group B) will receive no vaginal oestrogen treatment
    Actual start date of recruitment
    01 Jun 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety, Scientific research
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    42
    From 65 to 84 years
    58
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    100 women were recruited to the trial between July 2015 to August 2016. Women were recruited from six UK centres with equal numbers in both the pessary group and the no treatment group.

    Pre-assignment
    Screening details
    The trial approached 325 women with a POP and wanting surgery and were screened for eligibility, with 157 found to be eligible . Of these screened 100 women were randomised over a 13-month period (July 2015 to August 2016). Of the 100 randomised women, 85 ultimately had surgery. Of the other 15, 6 could not have surgery due to health issues.

    Pre-assignment period milestones
    Number of subjects started
    100
    Number of subjects completed
    100

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Oestradiol 10 μg
    Arm description
    Intervention group (Group A): This will comprise of 6 weeks course of oestradiol 10 μg preoperatively per vaginum (once daily for 2 weeks followed by twice weekly for four weeks) and then 10μg oestradiol per vaginum twice weekly from 6-26 weeks postoperatively.
    Arm type
    Experimental

    Investigational medicinal product name
    Vagifem
    Investigational medicinal product code
    PL 04668/0237
    Other name
    Pharmaceutical forms
    Vaginal tablet
    Routes of administration
    Vaginal use
    Dosage and administration details
    6 weeks course of oestradiol 10 μg preoperatively per vaginum (once daily for 2 weeks followed by twice weekly for four weeks) and then 10μg oestradiol per vaginum twice weekly from 6-26 weeks postoperatively.

    Arm title
    Placebo
    Arm description
    Matched placebo Intervention group (Group B): : This will comprise of 6 weeks course of pessary preoperatively per vaginum (once daily for 2 weeks followed by twice weekly for four weeks) and then twice weekly from 6-26 weeks postoperatively.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Vaginal tablet
    Routes of administration
    Vaginal use
    Dosage and administration details
    10 mg

    Number of subjects in period 1
    Oestradiol 10 μg Placebo
    Started
    50
    50
    Completed
    50
    50

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oestradiol 10 μg
    Reporting group description
    Intervention group (Group A): This will comprise of 6 weeks course of oestradiol 10 μg preoperatively per vaginum (once daily for 2 weeks followed by twice weekly for four weeks) and then 10μg oestradiol per vaginum twice weekly from 6-26 weeks postoperatively.

    Reporting group title
    Placebo
    Reporting group description
    Matched placebo Intervention group (Group B): : This will comprise of 6 weeks course of pessary preoperatively per vaginum (once daily for 2 weeks followed by twice weekly for four weeks) and then twice weekly from 6-26 weeks postoperatively.

    Reporting group values
    Oestradiol 10 μg Placebo Total
    Number of subjects
    50 50 100
    Age categorical
    Age category for the trial is 16-99 years of age.
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    21 21 42
        From 65-84 years
    29 29 58
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.7 ± 8.2 65.9 ± 8.4 -
    Gender categorical
    All female participants
    Units: Subjects
        Female
    50 50 100
    Ethnicity
    Units: Subjects
        White
    45 43 88
        Asian
    2 3 5
        Black
    3 1 4
        Mixed
    0 2 2
        Chinese
    0 0 0
        Other ethnic group
    0 1 1
        Not stated
    0 0 0
    Parity
    Units: Subjects
        <=2
    27 26 53
        >2
    23 24 47
    Maximum stage of prolapse
    Units: Subjects
        One
    7 7 14
        Two
    23 23 46
        Three/Four
    20 20 40
    Hysterectomy
    Units: Subjects
        Yes
    12 8 20
        No
    38 42 80
    Treatment for over active bladder
    Units: Subjects
        Yes
    0 0 0
        No
    50 50 100
    Vaginal pessary/ring currently in place
    Units: Subjects
        Yes
    5 8 13
        No
    45 42 87
    Concomitant continence surgery
    Units: Subjects
        Yes
    2 3 5
        No
    48 47 95
    Physiotherapy treatment for prolapse/Urinary incontinence in last 12 months
    Units: Subjects
        Yes
    8 10 18
        No
    42 40 82
    Previous operation for prolapse
    Units: Subjects
        Yes
    4 4 8
        No
    46 46 92
    Drug treatment for urinary incontinence
    Units: Subjects
        Yes
    0 4 4
        No
    50 46 96
    BMI
    Units: mg/k2
        arithmetic mean (standard deviation)
    28.1 ± 5.1 28.2 ± 7 -
    Spontaneous vaginal delivery
    Units: subjects
        median (inter-quartile range (Q1-Q3))
    2 (2 to 3) 2 (2 to 4) -
    Caesareans
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0) 0 (0 to 0) -
    Anterior
    Units: Number of repairs
        median (inter-quartile range (Q1-Q3))
    1 (1 to 1) 1 (1 to 1) -
    Posterior
    Units: Number of repairs
        median (inter-quartile range (Q1-Q3))
    1 (1 to 1) 1 (1 to 1) -
    Subject analysis sets

    Subject analysis set title
    Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Baseline set

    Subject analysis sets values
    Period 1
    Number of subjects
    100
    Age categorical
    Age category for the trial is 16-99 years of age.
    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)
    42
        From 65-84 years
    58
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.8 ± 8.3
    Gender categorical
    All female participants
    Units: Subjects
        Female
    100
    Ethnicity
    Units: Subjects
        White
    88
        Asian
    5
        Black
    4
        Mixed
    2
        Chinese
    0
        Other ethnic group
    1
        Not stated
    0
    Parity
    Units: Subjects
        <=2
    53
        >2
    47
    Maximum stage of prolapse
    Units: Subjects
        One
    14
        Two
    64
        Three/Four
    40
    Hysterectomy
    Units: Subjects
        Yes
    20
        No
    80
    Treatment for over active bladder
    Units: Subjects
        Yes
    0
        No
    100
    Vaginal pessary/ring currently in place
    Units: Subjects
        Yes
    13
        No
    87
    Concomitant continence surgery
    Units: Subjects
        Yes
    5
        No
    95
    Physiotherapy treatment for prolapse/Urinary incontinence in last 12 months
    Units: Subjects
        Yes
    18
        No
    82
    Previous operation for prolapse
    Units: Subjects
        Yes
    8
        No
    92
    Drug treatment for urinary incontinence
    Units: Subjects
        Yes
    4
        No
    96
    BMI
    Units: mg/k2
        arithmetic mean (standard deviation)
    28.2 ± 5.5
    Spontaneous vaginal delivery
    Units: subjects
        median (inter-quartile range (Q1-Q3))
    2 (2 to 3)
    Caesareans
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    Anterior
    Units: Number of repairs
        median (inter-quartile range (Q1-Q3))
    1 (1 to 1)
    Posterior
    Units: Number of repairs
        median (inter-quartile range (Q1-Q3))
    1 (1 to 1)

    End points

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    End points reporting groups
    Reporting group title
    Oestradiol 10 μg
    Reporting group description
    Intervention group (Group A): This will comprise of 6 weeks course of oestradiol 10 μg preoperatively per vaginum (once daily for 2 weeks followed by twice weekly for four weeks) and then 10μg oestradiol per vaginum twice weekly from 6-26 weeks postoperatively.

    Reporting group title
    Placebo
    Reporting group description
    Matched placebo Intervention group (Group B): : This will comprise of 6 weeks course of pessary preoperatively per vaginum (once daily for 2 weeks followed by twice weekly for four weeks) and then twice weekly from 6-26 weeks postoperatively.

    Subject analysis set title
    Period 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Baseline set

    Primary: Primary PFDI-SF20 at 6 months

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    End point title
    Primary PFDI-SF20 at 6 months
    End point description
    End point type
    Primary
    End point timeframe
    From Randomisation to completion of PFDI-SF20 at 6 months
    End point values
    Oestradiol 10 μg Placebo
    Number of subjects analysed
    38
    41
    Units: Subjects
    arithmetic mean (standard deviation)
        Numbers
    45.4 ± 43.8
    45.0 ± 37.1
    Statistical analysis title
    linear regression model
    Comparison groups
    Placebo v Oestradiol 10 μg
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.4
         upper limit
    17.2

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Randomisation to completion of follow up
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14
    Reporting groups
    Reporting group title
    Oestrogen Group
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no adverse events. Just 4 serious adverse events.
    Serious adverse events
    Oestrogen Group Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 50 (4.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Leukaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bleeding time abnormal
    Additional description: Patient bleeding heavily and admitted to hospital for antibiotics.
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    High Temperature
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         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
    Oestrogen Group Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)

    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.
    N/A
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