AzTrials
AzTrials

Recurrent Implantation FailurePhase 2NCT03161340

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

A Phase 2 study testing Rapamycin in people with Recurrent Implantation Failure, run by Mehdi Yousefi at 2 sites in Iran.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 20 to 41 years, women only
Conditions the study is for
Recurrent Implantation Failure
What is being tested?
Rapamycin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
121 participants
Where
2 sitesIran
Study dates
11 Jul 2017to 20 Jun 2018
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 20 to 41 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.

Who cannot join

  • 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

Trial locations and contacts

2 sites in 1 country.

Iran2 sites

  • Qom ACECR ART Center

    Qom

  • Estern Azarbaijan ACECR ART center

    Tabriz

Other trials in Iran

About this study

Official title: 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.

Read more

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.

Being tested
Rapamycin
Keywords
Recurrent Implantation Failure, Rapamycin, Pregnancy Rate

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RapamycinDrug

    Also called Treatment group

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

Study groups in NCT03161340
Study groupRoleWhat they receive
Treatment groupExperimentalRapamycin group
Receives: Drug: Rapamycin
Control groupNo interventionPatients who do not receive any treatment despite a history of Recurrent Implantation Failure problem

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Changes in Treg cells

    Flowcytometry

    Measured: 2 days before IVF until 15 days after IVF

  2. Changes in mRNA expression of cytokines related to Treg cells

    quantitative polymerase chain reaction (qPCR)

    Measured: 2 days before IVF until 15 days after IVF

  3. Changes in mRNA expression of cytokines related to Th17 cells

    quantitative polymerase chain reaction (qPCR)

    Measured: 2 days before IVF until 15 days after IVF

  4. Changes in secretion levels of cytokines related to Treg cells

    Elisa

    Measured: 2 days before IVF until 15 days after IVF

  5. Changes in secretion levels of cytokines related to Th17 cells

    Elisa

    Measured: 2 days before IVF until 15 days after IVF

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

    quantitative polymerase chain reaction (qPCR)

    Measured: 2 days before IVF until 15 days after IVF

  7. Changes in mRNA expression levels of transcription factors related to Treg cells

    quantitative polymerase chain reaction (qPCR)

    Measured: 2 days before IVF until 15 days after IVF

  8. Changes in expression levels of miRNAs

    quantitative polymerase chain reaction (qPCR)

    Measured: 2 days before IVF until 15 days after IVF

Secondary outcomes (3)

  1. Pragnancy rate

    Beta-human Chorionic Gonadotrophin (ΒHCG) protein assay

    Measured: 2 days before IVF until 15 days after IVF

  2. Pregnancy Rate

    Ultrasonography

    Measured: 2 days before IVF until 15 days after IVF

  3. Live birth

    The birth of a living child

    Measured: After about 9 months of positive βhCG test

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 May 2017
  2. Study start11 Jul 2017
  3. Primary completion9 May 2018
  4. Study completion20 Jun 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Care provider
Enrolment
121 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03161340
Sponsor's protocol ID
TabrizUMS-infertility-001
Status last verified
Apr 2019
First submitted
18 May 2017
Last updated
10 Apr 2019
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 19710204

  • 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.

    PubMed 22889462

  • 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.

    PubMed 21514552

  • 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.

    PubMed 21314851

  • 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.

    PubMed 24762139

  • 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.

    PubMed 25965838

  • 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.

    PubMed 17510057

  • 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.

    PubMed 25394810

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Rapamycin in people with Recurrent Implantation Failure, run by Mehdi Yousefi at 2 sites in Iran.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Iran. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Changes in Treg cells (time frame: 2 days before IVF until 15 days after IVF). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03161340, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Apr 2019.

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