Condition category
Pregnancy and Childbirth
Date applied
11/09/2012
Date assigned
16/10/2012
Last edited
25/09/2013
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Every year in England and Wales there are 700,000 births and thus hundreds of thousands of delighted parents. However, many couples are not so fortunate; in the same period of time: 15% of couples experience sub-fertility; 25% (500,000) of conceptions fail to implant; 15% (300,000) of pregnancies end in early miscarriage; 2% of couples suffer recurrent miscarriages (three or more losses). We have shown that failure of the lining of the womb (endometrium) to prepare adequately for pregnancy a process known as decidualisation is an underlying factor in these clinical problems.
During decidualisation, the endometrial lining becomes transformed into a secretory lining in preparation for accepting the embryo. Decidualisation is a characteristic of the endometrium of the pregnant uterus. Decidualisation is a process that occurs in early pregnancy. It is an adaption of the uterus to enable implantation of the embryo.
The blood thinning agent, Heparin, has been used in an attempt to improve reproductive success. However, heparin has always been given by daily sub-cutaneous injections causing bruising, pain and occasionally bleeding. These injections are given for weeks. Heparin also has the ability to increase activity of growth factors in the endometrium thereby improving decidualisation and increase successful implantation of the pregnancy.
We would like administer Heparin as a single dose by flushing it directly into the womb prior to pregnancy, during the window of implantation (5-7 days after ovulation). We wish to study whether this new method of administration enhances decidualisation and minimises the adverse effects of heparin.

Who can participate?
Women 18 years or older but younger than 45 years who are able to give informed consent and had previous unsuccessful in vitro fertility (IVF) treatment (no live birth after transfer of two good quality embryos) or had recurrent miscarriages (3 or more miscarriages) in the past.

What does the study involve?
Patient will be recruited with informed written consent. The patient will have a minimum of 24 hours to review the patient information sheet and consent form. If the patient consents, she will be asked to use barrier contraception for the month in which the study occurs.
These patients will be asked to attend 5 to 7 days after ovulation (as assessed by a home ovulation kit) and they will be randomized (after a negative pregnancy test) to either receive locally administered low molecular weight heparin (intervention group) OR locally administered saline (control group). After administration, they will mobilize and after four hours, bloods for Anti-Xa (assessing systemic heparin activity) will be taken. The patient will then go home with a side effect diary. 24 hours later the patient will re-attend and an endometrial biopsy (sampling of lining of the womb) will be taken together with a full blood count and liver function tests. All of these procedures will performed in outpatient and you will go home afterwards
A telephone consultation will follow 14 days later to ask about period heaviness and duration. Participant questionnaire and side effects diaries will be sent by pre-paid envelope back to principal investigator.

What are the possible benefits and risks of participating?
There is no immediate medical benefit to you from taking part, however, the information that we gain from this study may help us to treat women in the future. We do not expect any commercially significant results to be gained from this research. It is possible that the action of taking an endometrial biopsy may help the endometrium to respond correctly to an implanting embryo, however, the medical evidence for this is currently limited and there is no guarantee that the biopsy may help. You will be informed of the results by letter and you will be invited to a patient information evenings at the end of study
Women who are pregnant cannot take part in this study and who could possibly be pregnant. Sampling the lining of the womb (endometrial biopsy) may be uncomfortable or slightly painful, but leaves no long term effects because your womb lining regenerates every month.
There is a very small risk of bleeding with the use of heparin which is a blood thinning agent. For this reason, we will take a blood test 4 and 24 hours after administration. If you have any bruises which appear suddenly, please call us immediately as this might indicate a problem with bleeding. We have an antidote against the blood thinning agent which will reverse its effect. There is a very small risk of infection but we will perform pelvic swabs prior to any intervention in the study if not done recently.

Where is the study run from?
The study will be conducted at University of Warwick. The patients will be seen in outpatients at Centre of Reproductive Medicine at University Hospitals Coventry and Warwickshire NHS Trust.

When is study starting and how long is it expected to run for?
The proposed date of starting the study is 1st January 2013. However, this depends upon ethical and MHRA approval. Duration of the study will be 12 months from the ethics approval to collect samples from patients. A further 12 months will be required to analyse the data.

Who is funding the study?
Biomedical Research Unit, University Hospitals Coventry and Warwickshire NHS Trust

Who is the main contact?
Professor Siobhan Quenby
s.quenby@warwick.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Siobhan Quenby

ORCID ID

Contact details

Clinical Sciences Research Laboratory
Warwick Medical School
University of Warwick
University Hospitals Coventry and Warwickshire NHs Trust
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom
+44 (0)24 7696 8657
s.quenby@warwick.ac.uk

Additional identifiers

EudraCT number

2012-003682-18

ClinicalTrials.gov number

Protocol/serial number

HEP001QUEN

Study information

Scientific title

Endometrial flushing of low molecular weight heparin improves decidualisation - a prospective randomised control pilot study

Acronym

Study hypothesis

To assess the effects of local low molecular weight heparin administration on endometrial decidualisation in a non-conception menstrual cycle.

Added 25/09/2013: study participation was completed in July 2013. All 40 participants were recruited and the study is not recruiting any more participants.

Ethics approval

NRES Committee West Midlands - Edgbaston, 05/11/2012, ref: 12/WM/0347

Study design

Prospective randomized pilot study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Previous at least one unsuccessful IVF treatment, Recurrent Miscarriages

Intervention

Patient will be recruited with informed written consent. The patient will have a minimum of 24 hours to review the patient information sheet and consent form. If the patient consents, she will be asked to use barrier contraception for the month in which the study occurs.These patients will be asked to attend 5 to 7 days after ovulation (as assessed by a home ovulation kit) and they will be randomized (after a negative pregnancy test) to either receive locally administered low molecular weight heparin (intervention group) OR locally administered saline (control group). After administration, they will mobilize and after four hours, bloods for Anti-Xa (assessing systemic heparin activity) will be taken. The patient will
then go home with a side effect diary. 24 hours later the patient will re-attend and an endometrial biopsy will be taken together with a full blood count and liver function tests.

A telephone consultation will follow 14 days later to ask about period heaviness and duration. Participant questionnaire and side effects diaries will be sent by pre-paid envelope back to principal investigator.

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measures

Measurement of effective decidualisation will include the density of uterine natural killer cell by immunohistochemistry

Secondary outcome measures

1. To assess the effect of locally administered heparin on other markers of decidualisation including endometrial stromal cell culture, genome wide expression profile, induction of other decidualisation protein markers including prolactin, Prokinectin, IGFBPs (insulin Like Growth Factor Binding Proteins), HBEGF (Heparin Binding Epidermal Growth Factor)
2. To identify any potential side effects of local endometrial administration of heparin
3. To assess patient acceptability of this method of administration

Overall trial start date

01/01/2013

Overall trial end date

31/12/2013

Reason abandoned

Eligibility

Participant inclusion criteria

1. Women attending the Centre for Reproductive Medicine, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry who had previous one unsuccessful IVF treatment (defined as failure to achieve live birth after transfer of two good quality embryos)
2. Women with recurrent miscarriages (defined as 3 or more unexplained miscarriages)
3. Women 18 years of age or older but younger than 45 years old
4. Able and willing to give informed consent

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

40

Participant exclusion criteria

1. Women who had unprotected sexual intercourse during the month when endometrial flushing is planned
2. Women having a vaginal infection, these women will be eligible for inclusion once treatment of the infection has been completed
3. Pregnancy
4. Breast feeding
5. Women with weight of < 45 kg (due to higher risk of bleeding)
6. Women with bleeding disorders
7. Women with severe hypertension
8. Women with Known Renal or Liver Diseases
9. Women who had recent stroke
10. Women taking Warfarin for any medical condition
11. Women taking systemic steroids, systemic salicylates, acetylsalicylic acid, NSAIDS including Ketorolac, dextran and clopidogrel or any immunosuppressant medications
12. Women with Diabetes Mellitus (due to potential risk of hyperkalaemia)
13. Women with hypersensitivity to Heparin, Pork, Beef or other Animal products
14. Women with Peptic Ulcers
15. Women undergoing Tubal Patency testing, Hysteroscopy or Laparoscopy at the time when endometrial flushing is planned

Recruitment start date

01/01/2013

Recruitment end date

31/12/2013

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Clinical Sciences Research Laboratory
Coventry
CV2 2DX
United Kingdom

Sponsor information

Organisation

University of Warwick (UK)

Sponsor details

c/o Dr Peter Hedges
Research Support Services
University House
Kirby Corner Road
Coventry
Cv4 8UW
United Kingdom

Sponsor type

University/education

Website

http://www2.warwick.ac.uk/

Funders

Funder type

Hospital/treatment centre

Funder name

University Hospitals Coventry and Warwickshire NHS Trust - Biomedical Research Unit (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes