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

NCT03161340 | Completed Phase 2 DMC

• 1 other identifier: TabrizUMS-infertility-001
• Study Type: interventional
• Target: 121
• Locations: 1 country
• Sites: 2

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.

Conditions

Recurrent Implantation Failure

Keywords

Recurrent Implantation Failure; Rapamycin; Pregnancy Rate

Outcome Measures

Primary Outcomes (8)

• Changes in Treg cells

  Flowcytometry

  2 days before IVF until 15 days after IVF

• Changes in mRNA expression of cytokines related to Treg cells

  quantitative polymerase chain reaction (qPCR)

  2 days before IVF until 15 days after IVF

• Changes in mRNA expression of cytokines related to Th17 cells

  quantitative polymerase chain reaction (qPCR)

  2 days before IVF until 15 days after IVF

• Changes in secretion levels of cytokines related to Treg cells

  Elisa

  2 days before IVF until 15 days after IVF

• Changes in secretion levels of cytokines related to Th17 cells

  Elisa

  2 days before IVF until 15 days after IVF

• Changes in mRNA expression levels of transcription factors related to Th17 cells

  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

  quantitative polymerase chain reaction (qPCR)

  2 days before IVF until 15 days after IVF

• Changes in expression levels of miRNAs

  quantitative polymerase chain reaction (qPCR)

  2 days before IVF until 15 days after IVF

Secondary Outcomes (3)

• Pragnancy rate

  2 days before IVF until 15 days after IVF

• Pregnancy Rate

  2 days before IVF until 15 days after IVF

• Live birth

  After about 9 months of positive βhCG test

Study Arms (2)

Treatment group

EXPERIMENTAL

Rapamycin group

Drug: Rapamycin

Control group

NO INTERVENTION

Patients who do not receive any treatment despite a history of Recurrent Implantation Failure problem

Interventions

Rapamycin DRUG

Patients will take Rapamycin 2 days before IVF until 15 days after IVF

Also known as: Treatment group

Treatment group

Eligibility Criteria

• Age: 20 Years - 41 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Mehdi Yousefi: lead

Study Sites (2)

Qom ACECR ART Center

Qom, Iran

Location

Estern Azarbaijan ACECR ART center

Tabriz, Iran

Location

Related Publications (8)

• Santos MA, Kuijk EW, Macklon NS. The impact of ovarian stimulation for IVF on the developing embryo. Reproduction. 2010 Jan;139(1):23-34. doi: 10.1530/REP-09-0187.

  PMID: 19710204 RESULT

• Sugiura-Ogasawara M, Suzuki S, Ozaki Y, Katano K, Suzumori N, Kitaori T. Frequency of recurrent spontaneous abortion and its influence on further marital relationship and illness: the Okazaki Cohort Study in Japan. J Obstet Gynaecol Res. 2013 Jan;39(1):126-31. doi: 10.1111/j.1447-0756.2012.01973.x. Epub 2012 Aug 13.

  PMID: 22889462 RESULT

• Calleja-Agius J, Muttukrishna S, Pizzey AR, Jauniaux E. Pro- and antiinflammatory cytokines in threatened miscarriages. Am J Obstet Gynecol. 2011 Jul;205(1):83.e8-16. doi: 10.1016/j.ajog.2011.02.051. Epub 2011 Feb 23.

  PMID: 21514552 RESULT

• Winger EE, Reed JL. Low circulating CD4(+) CD25(+) Foxp3(+) T regulatory cell levels predict miscarriage risk in newly pregnant women with a history of failure. Am J Reprod Immunol. 2011 Oct;66(4):320-8. doi: 10.1111/j.1600-0897.2011.00992.x. Epub 2011 Feb 14.

  PMID: 21314851 RESULT

• Ozkan ZS, Deveci D, Simsek M, Ilhan F, Risvanli A, Sapmaz E. What is the impact of SOCS3, IL-35 and IL17 in immune pathogenesis of recurrent pregnancy loss? J Matern Fetal Neonatal Med. 2015 Feb;28(3):324-8. doi: 10.3109/14767058.2014.916676. Epub 2014 May 22.

  PMID: 24762139 RESULT

• Winger EE, Reed JL, Ji X. First-trimester maternal cell microRNA is a superior pregnancy marker to immunological testing for predicting adverse pregnancy outcome. J Reprod Immunol. 2015 Aug;110:22-35. doi: 10.1016/j.jri.2015.03.005. Epub 2015 Apr 16.

  PMID: 25965838 RESULT

• Wang L, Harris TE, Roth RA, Lawrence JC Jr. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007 Jul 6;282(27):20036-44. doi: 10.1074/jbc.M702376200. Epub 2007 May 17.

  PMID: 17510057 RESULT

• Nakagawa K, Kwak-Kim J, Ota K, Kuroda K, Hisano M, Sugiyama R, Yamaguchi K. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios. Am J Reprod Immunol. 2015 Apr;73(4):353-61. doi: 10.1111/aji.12338. Epub 2014 Nov 14.

  PMID: 25394810 RESULT

MeSH Terms

Interventions

Sirolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Mohammad Nouri, Ph.D

  SCARM institute

  STUDY DIRECTOR

• Mehdi Yousefi, Ph.D

  SCARM institute

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Tabriz University of Medical Sciences

Study Record Dates

• First Submitted: May 18, 2017
• First Posted: May 19, 2017
• Study Start: July 11, 2017
• Primary Completion: May 9, 2018
• Study Completion: June 20, 2018
• Last Updated: April 10, 2019

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will not share

Locations

IR (2)