- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03267797
hCG-activated PBMC-therapy in RIF Patients
August 21, 2019 updated by: SCARM Institute, Tabriz, Iran
Intrauterine Administration of Autologous hCG-activated Peripheral Blood Mononuclear Cells Improves Pregnancy Outcomes in Patients With Recurrent Implantation Failure; a Double-blind Randomized Control Trial Study
Despite the many research done in the field of infertility and in vitro fertilization (IVF), more than half of the embryos transmitted in the IVF and intracytoplasmic sperm injection (ICSI) do not implant successfully.
Currently, pregnancy failure following at least three IVF/ET cycle, so that one or two high-quality embryos transmitted in each cycle is defined as recurrent implantation failure (RIF).
Maternal and fetal factors can be a reason for implantation failure; maternal factors include endometrial receptivity, uterine anatomic abnormalities, and immunologic factors.
Implantation failure with embryonic reasons includes genetic abnormalities and any factor that affects the implantation and growth of the embryo within the uterus.
In recent years, the involvement of immune-related factors mainly natural killer cells (NK), dendritic cells (DCs), macrophages (MQ), regulatory T cells (Treg) and Th-1, in the endometrial differentiation and development and endometrial receptivity, as well as induction of immunological tolerance to the fetus, have been reported.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
248 women with the history of implantation failure volunteered to receive PBMC-therapy.
After immunologic consultation and doing flow cytometry analysis, 100 women with at least three IVF/ET failure who had low Th-17/Treg ratio in comparison with healthy control were enrolled in this study.
These 100 patients divided randomly into two groups, 50 patients received PBMC and 50 patients as the control group received PBS.
PBMCs were obtained from patients themselves five days before embryo transfer (ET) and were cultured with hCG for 48 hours.
Frothy-eight hours later, PBMCs were then administered into the uterine cavity of that patient from the study group two days before ET.
PBS was inseminated into the uterine cavity of the control group instead of PBMC.
The concentration of inflammatory cytokines was examined in the supernatant of cultured PBMCs 2, 24 and 48 hour after incubation by ELISA.
The pregnancy occurrence was confirmed 12 days after ET through positive pregnancy test (β-hCG test).
The success of implantation and the occurrence of clinical pregnancy were evaluated by ultrasound through the observation of the number and the location of gestational sacs at 5-6 weeks and confirming the embryo heart pulsation.
Study Type
Interventional
Enrollment (Actual)
100
Phase
- Not Applicable
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
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Tabriz, Iran, Islamic Republic of
- Valiasr Hospital
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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
18 years to 43 years (Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
Female
Description
All patients were evaluated in accordance with the following inclusion and exclusion criteria;
Inclusion Criteria:
- Having at least three implantation failures following IVF
- Having primary infertility
- Age under 45 years old
- Having regular menstrual cycles
- BMI under 30
Exclusion Criteria:
- Having polycystic ovary syndrome
- The presence of uterine pathology;
- Poor ovarian reserve
- Having chromosomal abnormalities
- Presence of auto anti-bodies such as anti-TPO, anti-TG, ACA, APA, ANA, and anti-dsDNA
- Presence of mutations involving the coagulation system such as deficiency of factor XII, Pro C, Pro S
- Positive HIV, HCV or HBV tests
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 |
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Experimental: Treatment group
Peripheral blood mononuclear cells (PBMCs) were administered into the uterine cavity of RIF patients in this group.
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Blood samples (20 mL) were taken from individual patients at the time of ovulation induction.
Then PBMC were isolated and cultured (20-30 million cells) 48 hour at the presence of hCG (10IU/ml daily).
Afterward,15-20 million PBMCs in 500 microlitres PBS were injected into the uterine cavity two days before embryo transfer (ET) using ET catheter.
Other Names:
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Placebo Comparator: Control group
Phosphate buffer saline (PBS) as placebo was injected into the uterine cavity of RIF patients in this group.
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Only 500 microlitres PBS will be injected into the uterine cavity, instead of PBMCs, two days before embryo transfer (ET) using ET catheter.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
pregnancy occurrence
Time Frame: "12 days after embryo transfer"
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Laboratory tests (beta-hCG test)
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"12 days after embryo transfer"
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examination of inflammatory cytokines (IL-1B, TNF-a and INF-Y) secretion levels in supernatant
Time Frame: "48 hours after culturing"
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ELISA technique
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"48 hours after culturing"
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Clinical pregnancy rate in patients with recurrent implantation failure (RIF)
Time Frame: "in 5-6 weeks"
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detection the number and location of gestational sacs by ultrasound
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"in 5-6 weeks"
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The live birth rate by patients with recurrent implantation failure (RIF)
Time Frame: "After about 9 months of positive βHCG test"
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By gynecologists and obstetricians will monitor
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"After about 9 months of positive βHCG test"
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The miscarriage rate in patients with recurrent implantation failure (RIF)
Time Frame: "When ever during the pregnancy period (up to 9 months)"
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By gynecologists and obstetricians will monitor
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"When ever during the pregnancy period (up to 9 months)"
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Study Director: Mehdi Yousefi, 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
- Simon A, Laufer N. Repeated implantation failure: clinical approach. Fertil Steril. 2012 May;97(5):1039-43. doi: 10.1016/j.fertnstert.2012.03.010. Epub 2012 Mar 30.
- Chaouat G, Ledee-Bataille N, Zourbas S, Ostojic S, Dubanchet S, Martal J, Frydman R. Cytokines, implantation and early abortion: re-examining the Th1/Th2 paradigm leads to question the single pathway, single therapy concept. Am J Reprod Immunol. 2003 Sep;50(3):177-86. doi: 10.1034/j.1600-0897.2003.00080.x.
- Hoozemans DA, Schats R, Lambalk CB, Homburg R, Hompes PG. Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. Reprod Biomed Online. 2004 Dec;9(6):692-715. doi: 10.1016/s1472-6483(10)61781-6.
- Tomassetti C, Meuleman C, Pexsters A, Mihalyi A, Kyama C, Simsa P, D'Hooghe TM. Endometriosis, recurrent miscarriage and implantation failure: is there an immunological link? Reprod Biomed Online. 2006 Jul;13(1):58-64. doi: 10.1016/s1472-6483(10)62016-0.
- Bulmer JN, Longfellow M, Ritson A. Leukocytes and resident blood cells in endometrium. Ann N Y Acad Sci. 1991;622:57-68. doi: 10.1111/j.1749-6632.1991.tb37850.x. No abstract available.
- Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348-57.
- Chou CH, Chen SU, Shun CT, Tsao PN, Yang YS, Yang JH. Divergent endometrial inflammatory cytokine expression at peri-implantation period and after the stimulation by copper intrauterine device. Sci Rep. 2015 Oct 15;5:15157. doi: 10.1038/srep15157.
- Kosaka K, Fujiwara H, Tatsumi K, Yoshioka S, Higuchi T, Sato Y, Nakayama T, Fujii S. Human peripheral blood mononuclear cells enhance cell-cell interaction between human endometrial epithelial cells and BeWo-cell spheroids. Hum Reprod. 2003 Jan;18(1):19-25. doi: 10.1093/humrep/deg002.
- Ideta A, Sakai S, Nakamura Y, Urakawa M, Hayama K, Tsuchiya K, Fujiwara H, Aoyagi Y. Administration of peripheral blood mononuclear cells into the uterine horn to improve pregnancy rate following bovine embryo transfer. Anim Reprod Sci. 2010 Jan;117(1-2):18-23. doi: 10.1016/j.anireprosci.2009.04.004. Epub 2009 May 3.
- Yu N, Yang J, Guo Y, Fang J, Yin T, Luo J, Li X, Li W, Zhao Q, Zou Y, Xu W. Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves endometrial receptivity in mice with embryonic implantation dysfunction. Am J Reprod Immunol. 2014 Jan;71(1):24-33. doi: 10.1111/aji.12150. Epub 2013 Aug 1.
- Okitsu O, Kiyokawa M, Oda T, Miyake K, Sato Y, Fujiwara H. Intrauterine administration of autologous peripheral blood mononuclear cells increases clinical pregnancy rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J Reprod Immunol. 2011 Dec;92(1-2):82-7. doi: 10.1016/j.jri.2011.07.001. Epub 2011 Oct 27.
- Nakayama T, Fujiwara H, Maeda M, Inoue T, Yoshioka S, Mori T, Fujii S. Human peripheral blood mononuclear cells (PBMC) in early pregnancy promote embryo invasion in vitro: HCG enhances the effects of PBMC. Hum Reprod. 2002 Jan;17(1):207-12. doi: 10.1093/humrep/17.1.207.
- Yoshioka S, Fujiwara H, Nakayama T, Kosaka K, Mori T, Fujii S. Intrauterine administration of autologous peripheral blood mononuclear cells promotes implantation rates in patients with repeated failure of IVF-embryo transfer. Hum Reprod. 2006 Dec;21(12):3290-4. doi: 10.1093/humrep/del312. Epub 2006 Oct 4.
- Al-Azemi M, Raghupathy R, Azizieh F. Pro-inflammatory and anti-inflammatory cytokine profiles in fetal growth restriction. Clin Exp Obstet Gynecol. 2017;44(1):98-103.
- Granot I, Gnainsky Y, Dekel N. Endometrial inflammation and effect on implantation improvement and pregnancy outcome. Reproduction. 2012 Dec;144(6):661-8. doi: 10.1530/REP-12-0217. Epub 2012 Oct 1.
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)
October 7, 2017
Primary Completion (Actual)
September 25, 2018
Study Completion (Actual)
July 11, 2019
Study Registration Dates
First Submitted
August 27, 2017
First Submitted That Met QC Criteria
August 29, 2017
First Posted (Actual)
August 30, 2017
Study Record Updates
Last Update Posted (Actual)
August 26, 2019
Last Update Submitted That Met QC Criteria
August 21, 2019
Last Verified
August 1, 2019
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- SCARM-infertility-004
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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