A Randomized Double Blind Comparison of Atosiban in Patients With RIF Undergoing IVF Treatment

September 7, 2016 updated by: chen zhi qin, Shanghai First Maternity and Infant Hospital

A Randomized Double Blind Comparison of Atosiban in Patients With Repeated Implantation Failure Undergoing IVF Treatment

This study intends to carry out a prospective, randomized, double blind and controlled study to compare the influence of Atosiban and placebo on uterine contraction frequency, endometrial blood flow perfusion, oxytocin and serum concentration of PGF2α, embryo implantation rate and clinical pregnancy rate on the RIF population after fresh embryo transfer, so as to further clarify the curative effect of Atosiban in the treatment of RIF and provide evidence-based basis for Atosiban for application in RIF population.

Study Overview

Status

Unknown

Intervention / Treatment

Detailed Description

Background and Rationale With the rapid development of the technology of reproductive medicine, in vitro fertilization embryo transfer (IVF-ET) and its related derivatives have become the most important means for the treatment of infertility. IVF-ET pregnancy rate increased from the initial 10% to current more than 50%, but the repeated implantation failure (RIF) has occurred occasionally, which has become a difficult that perplex IVF-ET clinical practices. There is no uniform definition of RIF at present. Coughlan et al called that the women below 40 years old who experienced at least 3 fresh or frozen periods and failed to transplant 4 and more than 4 high-quality embryos as RIF in 2014 [1]. At present, most of the patients have started the reason screening and inspection spontaneously if the transplantation fails after of transplanting 2 high-quality embryos. But the embryo implantation is a complex process, the etiology of RIF can be roughly summed as the embryo factors, uterine factors, genetic factors, immunological factors and so on, the symptomatic treatment according to different causes can improve the success rate of re-transplantation system [2]. However, in most cases, the etiology of RIF still cannot be explained [3].

In recent years, the influence of uterine contraction on embryo implantation has attracted more and more attention. Studies have shown that no matter it's natural menstrual cycle or fertility cycle, moderate Uterine Contraction (UC) is conducive to embryo implantation, but excessive or strong UC will have a negative impact on embryo implantation, and even the embryos to be implanted to the fallopian tube, cervical or vaginal, and even be discharged of the uterus [4-6].

The estrogen levels of excessively physiological state during the process of ovulation induction of IVF can induce the production ofoxytocin in the endometrial cells, and indirectly lead to the synthesis and release of prostaglandin PGF2α, resulting in increased uterine contraction frequency [7-9]. In 1998, Fanchin et al. found that the frequency of uterine contraction of about 30% of the embryos transplantation patients was higher than 5 times /min, which was significantly correlated to the success rate of low pregnancy [5]. The follow-up studies confirmed by ultrasound showed that the frequency of endometrial contraction induced by ovulation induction cycle of IVF[10] is 5-6 times of the natural cycle. Therefore, in addition to the soft operation of the transplant process, the reduction of uterine excessive contraction by drugs may be an effective measure to improve the success rate of IVF pregnancy.

Atosiban is the antagonist of mixed receptor of pitressin VIA and oxytocin, it competes the oxytocin receptor located on the uterine muscle cell membranes, foetal membrane and deciduas with oxytocin to inhibit contraction of the uterus; at the same time, it inhibits the generation of oxytocin induced uterine endometrial prostate element PGF2 α to increase the endometrial blood flow perfusion. Pierzynski et al first applied Atosiban to the field of reproduction in 2007 for the first time, which made the uterine contraction frequency of a RIF patient who failed to transplant for seven times before the oocyte donation embryo transplant decreased significantly, and successful became pregnant [11]. This report immediately caused the reproductive scientists to apply Atosiban to the clinical study of in vitro assisted reproduction. For the general population, there are still disputes on whether use Atosiban during the embryo transplant [12-14]. The prospective and randomized study of He Ye et al showed that Atosiban can significantly reduce the oxytocin of patients with endometriosis and serum concentrations of PGF2 α, reduce the frequency of uterine contraction and improve the implantation rate of quality blastocyst after freeze-thaw treatment and clinical pregnancy rate [15]. In the RIF population, the retrospective study and prospective cohort studies have shown that using low doses of Atosiban during IVF-ET can increase the implantation rate of fresh and thawed quality embryos and clinical pregnancy rate [16-18], which may improve pregnancy outcomes in patients with RIF. But these studies were not randomized placebo-controlled studies, and their conclusions are still to be verified.

Atosiban is currently a safe and effective tocolytic drug for uncomplicated preterm patients, the patients had accelerated heartbeat, nausea, vomiting, headache, dizziness, flushing, anxiety, tremor and other side effects occasionally. Randomized and double blind controlled trial showed that the side effects with application of Atosiban and placebo in the maternal and child was similar, the difference was not statistically significant [15]. Preclinical studies haven't found that Atosiban has any toxicity to human sperm motility or embryo development in rabbits [20]. It hasn't found the literatures that report the fetal congenital malformations associated with the application of Atosiban. Therefore, the therapeutic dose of Atosiban should be able to be safely used in embryo transfer.

In summary, this study intends to carry out a prospective, randomized, double blind and controlled study to compare the influence of Atosiban and placebo on uterine contraction frequency, endometrial blood flow perfusion, oxytocin and serum concentration of PGF2α, embryo implantation rate and clinical pregnancy rate on the RIF population after fresh embryo transfer, so as to further clarify the curative effect of Atosiban in the treatment of RIF and provide evidence-based basis for Atosiban for application in RIF population.

Study Type

Interventional

Enrollment (Anticipated)

200

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 Contact

Study Contact Backup

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 40 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  1. 3 or more than 3 embryo implantation failure histories previously (or the number of high-quality embryos transplanted is >4);
  2. Age <40 years;
  3. Ultrasound or HSG showed normal uterine cavity, endometrium on transplantation day is ≥ 8mm;
  4. There's at least one good quality embryo on transplantation day.

Exclusion Criteria:

  1. Patients using donor sperm or donor eggs;
  2. Patients have obvious uterine cavity abnormalities;
  3. There was a clear hydrosalpinx;
  4. Natural cycles or IVM patients;
  5. Patients who cancel the due to the transfer due to various reasons, such as the failure of fertilization, or ovarian transitional stimulus syndrome (OHSS);
  6. Abnormal karyotype;
  7. Blastocyst transplantation patients.

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: atosiban

Give drugs 30 minutes before the start of the embryo transfer. First step: give a 37.5 mg Atosiban (Ferring, Germany) to take 0.9 ml, that is, 6.75 mg, conduct intravenous injection in one minute.

Second step: for the remaining 4.1 ml, namely 30.75 mg, dilute to 41 ml, use the venous pump to adjust to 24 ml/h, infuse for 1 hour, namely 18 mg.

Third step: for the remaining 17 ml, use the venous pump to adjust to 8 ml/h, infuse 2.1 hours, namely 12.75 mg. Total administration time is 3 hours, total dose is 37.5 mg.

give drugs 30 minutes before the start of the embryo transfer,and intravenous infusion in total dose of 37.5 mg is set in certain infusion rate, and complete the infusion in 3 hours.
Other Names:
  • oxytocin antagonist
Placebo Comparator: 0.9% salain
intravenous injection of 0.9% saline in one minute before transfer. Then use the same dose of normal saline for intravenous infusion to set the same infusion rate with experimental group, complete the infusion in 3 hours.
give drugs 30 minutes before the start of the embryo transfer,and intravenous infusion is set in the same rate with experimental group, complete the infusion in 3 hours.
Other Names:
  • Nacl

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical pregnancy rate
Time Frame: 4 weeks after embryo transfer
cases of clinical pregnancies / number of transplantation cycles(per patient)
4 weeks after embryo transfer

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
implantation rate
Time Frame: 4 weeks after embryo transfer
number of pregnancy fetal bursa / total number of transplantation embryos
4 weeks after embryo transfer
abortion rate
Time Frame: 6 weeks after embryo transfer
abortion cases / number of clinical pregnancy cycles
6 weeks after embryo transfer
ectopic pregnancy rate
Time Frame: 6 weeks after embryo transfer
ectopic pregnancy cases / number of clinical pregnancy cycle
6 weeks after embryo transfer
frequency of uterine contraction (4 minutes)
Time Frame: 1 hour before and 1 hour after intervention
times of uterine contraction/4 minutes
1 hour before and 1 hour after intervention

Other Outcome Measures

Outcome Measure
Time Frame
uterine artery blood flow index
Time Frame: 1 hour before and 1 hour after intervention
1 hour before and 1 hour after intervention
oxytocin and PGF2 α serum concentration.
Time Frame: 1 hour before and 1 hour after intervention
1 hour before and 1 hour after intervention

Collaborators and Investigators

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

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, 2017

Primary Completion (Anticipated)

January 1, 2018

Study Completion (Anticipated)

December 1, 2018

Study Registration Dates

First Submitted

August 31, 2016

First Submitted That Met QC Criteria

September 7, 2016

First Posted (Estimate)

September 8, 2016

Study Record Updates

Last Update Posted (Estimate)

September 8, 2016

Last Update Submitted That Met QC Criteria

September 7, 2016

Last Verified

September 1, 2016

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

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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