Low Molecular Weight Heparin to Improve Pregnancy Outcome in Patients With Recurrent Implantation Failure (BRIF)

Effect of Low Molecular Weight Heparin (Bemiparin) on Implantation Rate in Patients With Recurrent Implantation Failure Undergoing IVF/ICSI - A Prospective Randomized Clinical Trial

The objective of this study is to determine the effect of Bemiparin, a low molecular weight heparin, on implantation rate in women with unexplained recurrent implantation failure undergoing IVF/ICSI treatment.

Study Overview

• Status: Completed
• Conditions: Sterility
• Intervention / Treatment: Drug: Bemiparin sodium

Detailed Description

Recurrent implantation failure (RIF), defined as failure of conception following three or more consecutive In Vitro Fertilization (IVF) cycles despite the transfer of good quality embryos, is a major cause of distress amongst infertile couples. While factors underlying implantation failure are many, most cases remain unexplained. In order to improve pregnancy outcomes and delivery rates in women with unexplained RIF, various investigational treatments have been proposed.

The investigators propose a prospective controlled randomized comparative study to evaluate the effect of Bemiparin on implantation rates in women with unexplained RIF. A total of 200 patients will be recruited and randomized between two groups. The study group will receive Bemiparin plus standard care; while the control group will receive only standard care. Treatment will start on the day following embryo transfer and will be continued until 12 weeks gestation in the event of pregnancy.

The primary objective is to determine the effect of Bemiparin on implantation rate in women with unexplained recurrent implantation failure.

• Study Type: Interventional
• Enrollment (Actual): 165
• Phase: Phase 4

Contacts and Locations

Study Locations

• Lebanon
  • Beirut, Lebanon
    • American University of Beirut Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 38 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• History of three or more consecutively failed In Vitro Fertilization (IVF) cycles after embryo transfer.
• Normal uterine cavity (as assessed by hysteroscopy or HSG).
• Normal hormonal investigation: TSH, PRL, FBS.
• Normal acquired/inherited thrombophilia profile: LAC, ACA IgG/IgM, Prot S, Antithrombin III, beta-2 glycoprotein, Factors V, II, MTHFR.
• Normal semen analysis and mild/moderate male factor (Total motile sperm count > 5 million/ml and/or normal WHO morphology >20%.
• Patient provides written informed consent.

Exclusion Criteria:

• Evidence of low ovarian reserve by at least one of the following: AMH ≤ 1,5 ng/mL and/or basal CD 3 FSH ≥ 10 mIU/mL and/or basal CD 3 Estradiol ≥ 60 ng/mL and/or previous egg collection yield ≤ 3 oocytes.
• Preexisting medical condition (thyroid disease, diabetes mellitus, hypertension, pulmonary conditions, cardiac condition…).
• Severe male factor infertility (Total motile sperm count < 5 million/ml and/or normal WHO morphology <20%).
• Hypersensitivity to Heparin or its derivatives.
• Acquired thrombophilia.
• Active hemorrhage or increased risk of bleeding due to impairment of homeostasis.
• Severe impairment of liver or pancreatic function.
• Severe renal insufficiency (Creatinine Clearance < 30 ml/min).
• Injuries to or operations on the central nervous system, eyes and ears within the last 2 months.
• Disseminated Intravascular Coagulation (DIC) attributable to heparin-induced thrombocytopenia.
• Acute bacterial endocarditis and endocarditis lenta.
• Any organic lesion with high risk of bleeding (e.g.: active peptic ulcer, hemorrhagic stroke, cerebral aneurysm or cerebral neoplasms).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low molecular weight heparin; Bemiparin sodium 3,500 IU anti Xa/0.2 ml solution (Hibor; Laboratories Rovi Pharmaceuticals) for injection in pre-filled syringes.	Drug: Bemiparin sodium; Bemiparin sodium 3,500 IU will be started on the evening of the same day of embryo transfer and until the day of pregnancy test. If the test is positive, Bemiparin will be discontinued by the end of the 12th week of gestation.; Other Names: Hibor
No Intervention: No intervention group; Control group receiving standard care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Implantation rate (%)	Number of intrauterine gestational sacs observed by transvaginal ultrasonography divided by the number of transferred embryos	Vaginal ultrasound at 8 weeks gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth rate (%)	birth of live born	Time of delivery up to 42 weeks gestation
Ongoing pregnancy rate (%)	Fetal heart beat seen by ultrasound at 20 weeks gestation	Vaginal ultrasound at 20 weeks of gestation
Clinical pregnancy rate (%)	Fetal heart beat seen by ultrasound at 8 weeks gestation	Vaginal ultrasound at 8 weeks gestation
Total pregnancy rate (%)	Positive hCG titer	Up to 15 days from oocyte collection

Collaborators and Investigators

• Sponsor: American University of Beirut Medical Center
• Investigators: Principal Investigator: Johnny Awwad, MD, AUBMC

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): July 1, 2022
• Study Completion (Actual): July 1, 2022

Study Registration Dates

• First Submitted: November 11, 2015
• First Submitted That Met QC Criteria: November 16, 2015
• First Posted (Estimated): November 18, 2015

Study Record Updates

• Last Update Posted (Actual): July 20, 2023
• Last Update Submitted That Met QC Criteria: July 19, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Pregnancy; Assisted Reproductive Technology; low molecular weight heparin; Implantation; Recurrent Implantation Failure; In vitro Fertilization
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Infertility; Anticoagulants; Bemiparin
• Other Study ID Numbers: AmericanUBMCRIF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No