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

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ClinicalTrials.gov Identifier: NCT03161340
Recruitment Status : Completed
First Posted : May 19, 2017
Last Update Posted : April 10, 2019
Sponsor:
Information provided by (Responsible Party):
Mehdi Yousefi, Tabriz University of Medical Sciences

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Recurrent Implantation Failure Drug: Rapamycin Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 121 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: Effect of Rapamycin on Pregnancy Rate of Patient With Recurrent Implantation Failure With Immunological Causes
Actual Study Start Date : July 11, 2017
Actual Primary Completion Date : May 9, 2018
Actual Study Completion Date : June 20, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment group
Rapamycin group
Drug: Rapamycin
Patients will take Rapamycin 2 days before IVF until 15 days after IVF
Other Name: Treatment group

No Intervention: Control group
Patients who do not receive any treatment despite a history of Recurrent Implantation Failure problem



Primary Outcome Measures :
  1. Changes in Treg cells [ Time Frame: 2 days before IVF until 15 days after IVF ]
    Flowcytometry

  2. 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)

  3. 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)

  4. Changes in secretion levels of cytokines related to Treg cells [ Time Frame: 2 days before IVF until 15 days after IVF ]
    Elisa

  5. Changes in secretion levels of cytokines related to Th17 cells [ Time Frame: 2 days before IVF until 15 days after IVF ]
    Elisa

  6. 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)

  7. 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)

  8. Changes in expression levels of miRNAs [ Time Frame: 2 days before IVF until 15 days after IVF ]
    quantitative polymerase chain reaction (qPCR)


Secondary Outcome Measures :
  1. Pragnancy rate [ Time Frame: 2 days before IVF until 15 days after IVF ]
    Beta-human Chorionic Gonadotrophin (ΒHCG) protein assay

  2. Pregnancy Rate [ Time Frame: 2 days before IVF until 15 days after IVF ]
    Ultrasonography

  3. Live birth [ Time Frame: After about 9 months of positive βhCG test ]
    The birth of a living child



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 41 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03161340


Locations
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Iran, Islamic Republic of
Qom ACECR ART Center
Qom, Iran, Islamic Republic of
Estern Azarbaijan ACECR ART center
Tabriz, Iran, Islamic Republic of
Sponsors and Collaborators
Mehdi Yousefi
Investigators
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Study Director: Mohammad Nouri, Ph.D SCARM institute
Study Director: Mehdi Yousefi, Ph.D SCARM institute
Publications of Results:

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Responsible Party: Mehdi Yousefi, Tabriz University of Medical Sciences
ClinicalTrials.gov Identifier: NCT03161340    
Other Study ID Numbers: TabrizUMS-infertility-001
First Posted: May 19, 2017    Key Record Dates
Last Update Posted: April 10, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mehdi Yousefi, Tabriz University of Medical Sciences:
Recurrent Implantation Failure
Rapamycin
Pregnancy Rate
Additional relevant MeSH terms:
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Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs