Local Uterine Application of Low Molecular Weight Heparin (LMWH) in Intra-cytoplasmic Sperm Injection (ICSI)

February 17, 2016 updated by: Mona Aboulghar, The Egyptian IVF-ET Center

Local Uterine Application of Low Molecular Weight Heparin (LMWH) in Intra-cytoplasmic Sperm Injection (ICSI) a Randomised Controlled Pilot Study

Heparin also has the ability to bind with and modulate a wide variety of proteins, which can influence a number of physiological processes involved in implantation & trophoblastic development. These processes include adhesion of the blastocyst to the endometrial surface & trophoblastic differentiation & invasion.

A recent Cochrane review hinted towards research to study the possible effects of the local (uterine), & NOT SYSTEMIC application of heparin during Assisted reproductive technology (ART). Based on the above evidence the investigators hypothesize that low molecular weight heparin given intrauterine at mock embryo transfer after oocyte pick up will help improve pregnancy rates in patients undergoing ART.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Following ethical approval of the committee of Egyptian IVF-ET center, a pilot prospective randomized controlled study will include 40 patients, in which the study arm (group A ) will be injected with LMWH intrauterine during mock embryo transfer, just after ovum pickup, while the control arm (group B) will be injected intrauterine with similar volume tissue culture media (G.2 plus ref. 10132, Vitrolife) also after ovum pickup. Admission into either group will be through randomization after inclusion & exclusion criteria have been met and before start of controlled ovarian stimulation protocol.

The standard long gonadotrophin-releasing hormone (GnRH) agonist protocol will be used for patients with predicted normal response based on clinical & hormonal profile ; 1 mg of leuprolide acetate daily s.c injection (Lucrin ®; Abbott, Hoofddorp, The Netherlands) is applied from the mid luteal phase onward till the day of human chorionic gonadotropin (HCG) injection.

Gonadotropins in the form of human menopausal gonadotropin (HMG) (Merional ®, IBSA, Institut Biochimique SA, Lugano, Switzerland) will be given by intramuscular injection (IM) from the 2nd day of menstruation, The starting dose range from 150 to 450 IU depending on the basal follicle stimulating hormone (FSH) level, Antral follicle count (AFC) , Patient's age and body mass index (BMI).

In all protocols, stimulation is monitored by trans vaginal ultrasonography and serial estradiol (E2) measurements starting from day 7 of the cycle and the gonadotropin dose is adjusted individually according to follicular response.

After the development of at least three leading follicles≥18 mm, 10,000 unit of HCG (Choriomon, IBSA, Institut Biochimique SA) is given IM, and a trans-vaginal ultrasound-guided oocyte retrieval is performed 36 hours later.

After scheduled oocyte pick up, a mock embryo transfer will be done using labotec catheter (Labotec, Gottingen Germany), and an injection of Enaoxaprin sodium (LMWH) (Clexane® Sanofi S.A Paris, France) will be given intrauterine in group A patients.

LMWH is safe in pregnancy, category B drug , and given empirically sometimes in luteal phase and in early 1st trimester without reported problems, it has a half life of 4 Hours, and therefore it should not have any negative effects on developing embryos as it will not be present at the time of transfer while already performing it s desired effect on the endometrium.

The dose of LMWH given was calculated comparatively according to the work done by our group Mansour et.al, 2011, where intrauterine administration 500 IU of HCG improved the implantation and pregnancy rates.

Given the fact that this has not been attempted before, the best way to compare two different drugs is through biological activity. So if the investigators want to use 500 IU of LMWH, and knowing that In the in vitro purified system, enoxaparin sodium has a high anti Xa activity (approximately 100 IU/mg), so to get 500 IU of LMWH we need 5mg. Clexane 20mg is packed in a 0.2ml syringe, And therefore the investigators need to inject 0.05ml intrauterine using labotec catheter. (1/4 OF THE ORIGINAL SYRINGES CONTENT..i.e 5mg).

The control arm (group B) will be injected intrauterine with similar volume of tissue culture media (G.2 plus ref. 10132, Vitrolife) Oocytes are then fertilized in vitro using ICSI and after three to five days embryo transfer will be done using labotec catheter (Labotec, Gottingen Germany) with ultrasound guidance.

Progesterone pessaries 400 mg twice daily (Cyclogest 400mg ®Actavis plc. Dublin, Ireland) is given as a luteal support starting from the day of embryo transfer and continued for 16 days after.

Pregnancy is defined as the occurrence of a positive β-HCG >10 IU on day 12 after embryo transfer and a second higher value 2 days later, followed by ultrasonography confirmation of cardiac activity at 6 weeks gestation

A third party not involved in the actual study will moniter progress of the results and record them. Study will be stopped if more than 10 consecutive patients fail to get pregnant in the LMWH group. If the pregnancy rate >25% in the intervention group by the end of 20 cases, then recruitment willl continue till 60 patients are enrolled on each study arm.

Study Type

Interventional

Enrollment (Actual)

120

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
    • Maadi
      • Cairo, Maadi, Egypt, 11431
        • The Egyptian IVF-ET Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 37 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  1. Normal serum prolactin level & thyroid stimulating hormone (TSH)
  2. Unexplained infertility
  3. Tubal factor infertility
  4. BMI <30 kg/m2

Exclusion Criteria:

  1. Reduced ovarian reserve by AFC, Anti-mullerian hormone (AMH)
  2. Presence of non disconnected hydrosalpinges
  3. Frozen embryo transfer cycles
  4. Uterine Anomalies
  5. Submucous fibroids and polyps
  6. Uterine synechia
  7. Contraindication of pregnancy e.g.: Somatic and mental diseases, which are contraindications for carrying of a pregnancy and childbirth, inborn malformations or acquired deformations of uterus cavity which make embryo implantation or carrying of a pregnancy impossible ,ovarian tumors

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group A
After scheduled oocyte pick up, a mock embryo transfer will be done using labotec catheter (Labotec, Gottingen Germany), and an injection of Enaoxaprin sodium (LMWH) (Clexane® Sanofi S.A Paris, France) will be given intrauterine in group A patients, 500 IU of LMWH which is 5mg, in 0.05 ml.
Drug: Enaoxaprin sodium
intrauterine administration after oocyte pickup as the main experimental intervention
Other Names:
  • Clexane
Placebo Comparator: Group B
The control arm (group B) will be injected intrauterine with similar volume of tissue culture media (G.2 plus ref. 10132, Vitrolife)
Drug: tissue culture media
intrauterine administration after oocyte pickup as placebo
Other Names:
  • (G.2 plus ref. 10132, Vitrolife)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
pregnancy rate
Time Frame: 14 days
safety
14 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Early miscarriage rate
Time Frame: 12 weeks
12 weeks
Implanation rate
Time Frame: 3 weeks after ET
3 weeks after ET

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Egyptian IVF-ET Center

Investigators

  • Principal Investigator: Mona M Aboulghar, M.D, IVF consultant

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2015

Primary Completion (Actual)

May 1, 2015

Study Completion (Actual)

December 1, 2015

Study Registration Dates

First Submitted

December 17, 2014

First Submitted That Met QC Criteria

December 21, 2014

First Posted (Estimate)

December 25, 2014

Study Record Updates

Last Update Posted (Estimate)

February 18, 2016

Last Update Submitted That Met QC Criteria

February 17, 2016

Last Verified

February 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 152014

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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