Clinical Trial Results:
Local Oestrogen Treatment in Postmenopausal Women Undergoing Pelvic Organ Prolapse Surgery (LOTUS) - Feasibility Study
Summary
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EudraCT number |
2014-000179-18 |
Trial protocol |
GB |
Global end of trial date |
01 Sep 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Aug 2019
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First version publication date |
29 Aug 2019
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RG_13-322
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Additional study identifiers
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ISRCTN number |
ISRCTN46661996 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
MHRA: 21761/0318/001-0001 | ||
Sponsors
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Sponsor organisation name |
University of Birmingham
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Sponsor organisation address |
Aston Webb Building, Birmingham, United Kingdom, B15 2TT
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Public contact |
Mr Sean Jennings, University of Birmingham, 0121 4158011, researchgovernance@contacts.bham.ac.uk
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Scientific contact |
Dr Pallavi Latthe , Birmingham Women’s Hospital, 0121 627 2672, platthe@nhs.net
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Sponsor organisation name |
Birmingham Women's NHS Foundation Trust
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Sponsor organisation address |
Edgbaston, Birmingham, United Kingdom, B15 2TG
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Public contact |
Kelly Hard, Birmingham Women's NHS Foundation Trust, kellyhard@nhs.net
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Scientific contact |
Dr Pallavi Latthe, Birmingham Women's Hospital, 0121 627 2672, platthe@nhs.net
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Oct 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Aug 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Sep 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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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
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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.
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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
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Safety, Scientific research | ||
Long term follow-up duration |
12 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 100
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Worldwide total number of subjects |
100
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EEA total number of subjects |
100
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
42
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From 65 to 84 years |
58
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85 years and over |
0
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Recruitment
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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
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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
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Number of subjects started |
100 | |||||||||
Number of subjects completed |
100 | |||||||||
Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
PL 04668/0237
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Other name |
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Pharmaceutical forms |
Vaginal tablet
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Routes of administration |
Vaginal use
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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.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Vaginal tablet
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Routes of administration |
Vaginal use
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Dosage and administration details |
10 mg
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Baseline characteristics reporting groups
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Reporting group title |
Oestradiol 10 μg
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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
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Period 1
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Baseline set
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End points reporting groups
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Reporting group title |
Oestradiol 10 μg
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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
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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
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Baseline set
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End point title |
Primary PFDI-SF20 at 6 months | |||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
From Randomisation to completion of PFDI-SF20 at 6 months
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Statistical analysis title |
linear regression model | |||||||||||||||
Comparison groups |
Placebo v Oestradiol 10 μg
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Number of subjects included in analysis |
79
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
Method |
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Parameter type |
Mean difference (final values) | |||||||||||||||
Point estimate |
0.6
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-18.4 | |||||||||||||||
upper limit |
17.2 |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Randomisation to completion of follow up
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14
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Reporting groups
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Reporting group title |
Oestrogen Group
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Reporting group description |
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Reporting group title |
Placebo
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Reporting group description |
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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. |
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
N/A |