Weight Adjusted Low Molecular Weight Heparin in Recurrent Implantation Failure: a Randomized Open Labeled Trial

Prospective randomized study of patients with infertility candidates to Assisted ReproductiveTechniques (ART), screened for all inclusion and exclusion criteria, submitted to ART cycle with or without low molecular weight heparin (LMWH) administration. Aims of the study are to evaluate, primarily, pregnancy rate/embryo transfer, secondarily take home babies/embryo transfer, implantation rate, and the role of thrombophilic factors

Study Overview

• Status: Terminated
• Conditions: Infertility; Low Molecular Weight Heparin
• Intervention / Treatment: Drug: Parnaparin Sodium

Detailed Description

This is an interventional, stratified, randomized, open blind study. It will conducted on outpatients selected on the basis of inclusion and exclusion criteria.

Patients will be randomised according to a computer generated list of randomization to receive or not LMWH at prophylactic daily dosage (100 IU/kg).

For a correct selection and analysis some parameters have to be checked before randomization (see randomization check list at the end). The women in LMWH arm will treated starting the day before the beginning of stimulation phase of the cycle of ART until the result of the procedure is confirmed in terms of pregnancy yes or no, and if the pregnancy will be confirmed until the delivery or the end of pregnancy. Women in the control arm are administered routine hormonal support without LMWH.

Data will be collected on smoking habits, BMI, the number of retrieved oocytes, transferred embryos and implantation rate, ART outcome and parameters used for randomization on the basis of inclusion and exclusion criteria.

During the study blood will be collected for analysis at the randomization, the moment in wich patient will be assigned to one of the two arms, at the transfer and at the day of check for betaHCG and in in case of pregnancy all women will be checked at 12, 24, 36 week for testing of functional parameters of coagulation (protein C, protein S, AT, ddimer, fibrinogen, PT, aPTT, FVII, FVIII, FIX, and vonWillebrand factor antigen), blood cells count and of lipids (cholesterol and triglycerides).

The samples, identified with a sequential identification number, will be collected, processed and storage at -20/-80°C in the promoter center and will be destroyed after the analyses.

Study treatment Women in LMWH arm are administered with prophylactic weight adjusted dose of LMWH, starting the day before the beginning of stimulation phase of the cycle until the result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until the delivery or the end of pregnancy. Women in the LMWH arm will be tested for blood cell count twice in the first 10 days of therapy.

Initial dose and schedule Parnaparin will be administered at the dose of 100 IU/kg/day from the day before the beginning of stimulation phase of the cycle until the result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until delivery or the end of the pregnancy.

None of patients can receive concomitant acetylsalicylic acid (ASA) or steroids therapy Treatment duration

Women in LMWH arm are administered with prophylactic weight adjusted dose of parnaparin, starting the day before the beginning of stimulation phase of the cycle until the result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until the delivery or the end of the pregnancy.

Whatever the disease status, the treatment will always be discontinued in case of patient refusal excessive toxicity precluding further therapy, according to the responsible physicianother complications, according to the responsible physician

• Study Type: Interventional
• Enrollment (Actual): 271
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Women ≥18 years and ≤40 years, candidated to a fresh IVF/ICSI cycle with routine ovulation induction protocol

Exclusion Criteria:

v-vCouples candidated to a frozen IVF/ICSI cycle with routine ovulation induction protocol

• Testicular or frozen sperm (TESE procedure not allowed)
• Presence of hormonal disorders not compensated with specific therapy or history of immunological disease (autoimmune thyroiditis, connectivitis, RA, SLE, etc )
• Presence of antiphospholipides autoantibodies or other severe thrombophilia (AT, PS, PC deficiency or homozygous FV Leiden or FIIG20210A, or double eterozygous FV Leiden and FIIG20210A)
• Presence of abnormal platelets count and congenital or acquired coagulopathy ASA or steroid therapy administration

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: parnaparin sodium; Women in LMWH arm are administered with routine ovulation induction protocol and prophylactic dose of parnaparin sodium (LMWH), starting the day before the beginning of stimulation phase of the cycle until the result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until the delivery or the end of pregnancy. Women in the LMWH arm will be tested for blood cell count twice in the first 10 days of therapy. Parnaparin will be administered at the dose of 100 IU/kg/day from the day before the beginning of stimulation phase of the cycle until the result of the procedure is confirmed in terms of pregnancy yes or no and in case of pregnancy until delivery or the end of the pregnancy. Used dosages Parnaparin 0.4 4250 UI Parnaparin 0.6 6400 UI	Drug: Parnaparin Sodium; Parnaparin sodium ( Fluxum 4250 anti-Xa IU /0.4 mL or Fluxum 6400 anti-Xa IU /0.6mL; Alfa Wassermann S.p.A.) was administered at a dose of 100 IU/kg/day from the day before the beginning of the stimulation phase of the cycle until the result of the procedure was confirmed by pregnancy and, in the case of evolutive pregnancy, until delivery or the end of pregnancy; Other Names: Fluxum
No Intervention: no treatment; Women in the control arm are administered with routine ovulation induction protocol, without the addition of parnaparin sodium.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pregnancy rate/embryo transfer	the investigators measured the pregnancy rate/embryo transfer using betaHcg dosage 12 days after embryo transfer	12-14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
take home babies/embryo transfer	Live birth was defined as delivery of one or more live infants after 23 gestational weeks.	38-40 weeks after embryo transfer
implantation rate	ultrasound was performed to evaluate implantation rate calculated as as number of gestational sacs divided by number of transferred embryos multiplied by 100	3 weeks
role of thrombophilia in interfering with pregnancy rate/take home baby/implantation rate	All enrolled patients were previously screened for the presence or not of thrombophilic defects: protein C or protein S or AT deficiency, FV G1691A and FIIG20210A mutations, C677T MTHFR polymorphism,hyperhomocysteinemia, antiphospholipid antibodies. The investigators excluded from the enrollment patients with severe thrombophilia: protein C, protein S, AT deficiency or homozygous FV Leiden and FIIG20210A mutations or double heterozygosity for FV Leiden and FIIG20120 mutations because in this patients the international guide lines suggest and recommend the use of antithrombotic prophylaxis	12-14 days and 38-40 weeks and 3 weeks

Collaborators and Investigators

• Sponsor: Istituto Clinico Humanitas
• Investigators: Principal Investigator: corrado lodigiani, MD,PHD, Thrombosis Center

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: November 29, 2016
• First Submitted That Met QC Criteria: December 13, 2016
• First Posted (Estimate): December 14, 2016

Study Record Updates

• Last Update Posted (Estimate): December 14, 2016
• Last Update Submitted That Met QC Criteria: December 13, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; Body Weight; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Parnaparin
• Other Study ID Numbers: 876

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO