Immunomodulatory Effects of Rapamycin on Pregnancy Rate of Patient With Recurrent Implantation Failure

April 8, 2019 updated by: Mehdi Yousefi

Effect of Rapamycin on Pregnancy Rate of Patient With Recurrent Implantation Failure With Immunological Causes

Repeated implantation failure (RIF) is determined as failure to achieve pregnancy following at least 3 embryo transfers of high quality embryos in IVF cycles. Successful implantation and pregnancy depend on the activity of a variety of factors such as adhesion molecules, cytokines and immune cells.The process by which the foreign conceptus is accepted requires the appropriate function of regulatory T cells (Treg), which are known as the mediators of immune regulation. Tregs are capable of inducing maternal tolerance toward the fetus and their systemic expansion has been observed in early pregnancy. Furthermore, Th17 cells that play important roles in mounting inflammation are involved in the maintenance of pregnancy as a subset of effector T cells.The mammalian target of rapamycin (mTOR) inhibitors are immunosuppressive agents used after solid organ transplantation. Sirolimus as the most common mTOR inhibitor is able to effectively prevent allograft rejection and possesses significant antitumor properties. Pregnancy is a state of immunosuppression and the dysregulated immune responses has been observed in women with RIF. Accordingly, modulation of the immune system by an immunosuppressant drug may present an approach to overcome implantation failure. In this context, the use of Sirolimus might offer promise to achieve a better pregnancy outcome among women with implantation failure who undergo IVF. Based on previous findings, we hypothesized that Sirolimus may be beneficial for the improvement of pregnancy rate in women with IVF failure.

In the current study, we performe randomized phase II clinical trial to determine whether Sirolimus could be used as a bona fide treatment to increase the success rate of IVF in women with RIF of immune etiologies.A total 121 patients with a history of at least 3 RIF after IVF/ET cycles that will refer to Eastern Azerbaijan ACECR ART center, Alzahra Hospital of Tabriz University of Medical Sciences and Infertility Treatment center ACER Qom from July 2017 to June 2018 were select and enroll in this multicenter, randomized, double-blind, phase II study.

Normal ranges for Th17/Treg cell ratios establish using 50 normal fertile women who had a history of normal delivery by natural conception.

In patients with elevated Th17/Treg ratios, half of them treat with Sirolimus (Rapamune®; Pfizer, UK) and rest of patients not treat (control group). The patients in the treatment group will began Sirolimus 2 days prior to embryo transfer (ET) and will continue until the day of pregnancy test (15 day after ET), for a total of 17 days Sirolimus administe in a daily dose of 2mg.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

121

Phase

  • Phase 2

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

  • Iran, Islamic Republic of
      • Qom, Iran, Islamic Republic of
        • Qom ACECR ART Center
      • Tabriz, Iran, Islamic Republic of
        • Estern Azarbaijan ACECR ART 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

16 years to 37 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • The patients selected for this study will be with elevated Th17/Treg ratio
  • Enrolled patients will experience at least 3 times we have consecutive defeats implantation.
  • Patients in the study will record their medical history do not have any type of immunotherapy.

Exclusion Criteria:

  • Our criteria for exclusion of patients from the study include the following:
  • Patients aged 20 years and above 41 years
  • Patients or their spouse has abnormal karyotype or chromosomal and genetically disorders.
  • Patients who have bleeding problems.
  • Patients who have chronic disorders those are forced to use the specific drug.
  • Patients who test HIV, hepatitis C virus (HCV) or hepatitis C virus (HBV) are positive.
  • Patients who have a history of asthma and allergies to certain drugs.
  • Patients who have abnormalities of the uterus

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: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment group
Rapamycin group
Drug: Rapamycin
Patients will take Rapamycin 2 days before IVF until 15 days after IVF
Other Names:
  • Treatment group
No Intervention: Control group
Patients who do not receive any treatment despite a history of Recurrent Implantation Failure problem

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Treg cells
Time Frame: 2 days before IVF until 15 days after IVF
Flowcytometry
2 days before IVF until 15 days after IVF
Changes in mRNA expression of cytokines related to Treg cells
Time Frame: 2 days before IVF until 15 days after IVF
quantitative polymerase chain reaction (qPCR)
2 days before IVF until 15 days after IVF
Changes in mRNA expression of cytokines related to Th17 cells
Time Frame: 2 days before IVF until 15 days after IVF
quantitative polymerase chain reaction (qPCR)
2 days before IVF until 15 days after IVF
Changes in secretion levels of cytokines related to Treg cells
Time Frame: 2 days before IVF until 15 days after IVF
Elisa
2 days before IVF until 15 days after IVF
Changes in secretion levels of cytokines related to Th17 cells
Time Frame: 2 days before IVF until 15 days after IVF
Elisa
2 days before IVF until 15 days after IVF
Changes in mRNA expression levels of transcription factors related to Th17 cells
Time Frame: 2 days before IVF until 15 days after IVF
quantitative polymerase chain reaction (qPCR)
2 days before IVF until 15 days after IVF
Changes in mRNA expression levels of transcription factors related to Treg cells
Time Frame: 2 days before IVF until 15 days after IVF
quantitative polymerase chain reaction (qPCR)
2 days before IVF until 15 days after IVF
Changes in expression levels of miRNAs
Time Frame: 2 days before IVF until 15 days after IVF
quantitative polymerase chain reaction (qPCR)
2 days before IVF until 15 days after IVF

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pragnancy rate
Time Frame: 2 days before IVF until 15 days after IVF
Beta-human Chorionic Gonadotrophin (ΒHCG) protein assay
2 days before IVF until 15 days after IVF
Pregnancy Rate
Time Frame: 2 days before IVF until 15 days after IVF
Ultrasonography
2 days before IVF until 15 days after IVF
Live birth
Time Frame: After about 9 months of positive βhCG test
The birth of a living child
After about 9 months of positive βhCG test

Collaborators and Investigators

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

Sponsor

Mehdi Yousefi

Investigators

  • Study Director: Mehdi Yousefi, Ph.D, SCARM Institute
  • Study Director: Mohammad Nouri, Ph.D, SCARM Institute

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 (Actual)

July 11, 2017

Primary Completion (Actual)

May 9, 2018

Study Completion (Actual)

June 20, 2018

Study Registration Dates

First Submitted

May 18, 2017

First Submitted That Met QC Criteria

May 18, 2017

First Posted (Actual)

May 19, 2017

Study Record Updates

Last Update Posted (Actual)

April 10, 2019

Last Update Submitted That Met QC Criteria

April 8, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TabrizUMS-infertility-001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

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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