hCG-activated PBMC-therapy in RIF Patients

NCT03267797 | Completed DMC

• 1 other identifier: SCARM-infertility-004
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Recurrent Implantation Failure

Keywords

Recurrent Implantation Failure; Peripheral blood mononuclear cell; Human chorionic gonadotropin

Outcome Measures

Primary Outcomes (2)

• pregnancy occurrence

  Laboratory tests (beta-hCG test)

  "12 days after embryo transfer"

• examination of inflammatory cytokines (IL-1B, TNF-a and INF-Y) secretion levels in supernatant

  ELISA technique

  "48 hours after culturing"

Secondary Outcomes (3)

• Clinical pregnancy rate in patients with recurrent implantation failure (RIF)

  "in 5-6 weeks"

• The live birth rate by patients with recurrent implantation failure (RIF)

  "After about 9 months of positive βHCG test"

• The miscarriage rate in patients with recurrent implantation failure (RIF)

  "When ever during the pregnancy period (up to 9 months)"

Study Arms (2)

Treatment group

EXPERIMENTAL

Peripheral blood mononuclear cells (PBMCs) were administered into the uterine cavity of RIF patients in this group.

Other: Peripheral Blood Monouclear Cell

Control group

PLACEBO COMPARATOR

Phosphate buffer saline (PBS) as placebo was injected into the uterine cavity of RIF patients in this group.

Other: Phosphate Baffer Saline

Interventions

Peripheral Blood Monouclear Cell OTHER

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.

Also known as: PBMC

Treatment group

Phosphate Baffer Saline OTHER

Only 500 microlitres PBS will be injected into the uterine cavity, instead of PBMCs, two days before embryo transfer (ET) using ET catheter.

Also known as: PBS

Control group

Eligibility Criteria

• Age: 20 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may not qualify if:

• Having at least three implantation failures following IVF
• Having primary infertility
• Age under 45 years old
• Having regular menstrual cycles
• BMI under 30
• 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

Sponsors & Collaborators

• SCARM Institute, Tabriz, Iran: lead

Study Sites (1)

Valiasr Hospital

Tabriz, Iran

Location

Related Publications (15)

• 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.

  PMID: 14629021 RESULT

• 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.

  PMID: 22464086 RESULT

• 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.

  PMID: 15670421 RESULT

• 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.

  PMID: 16820110 RESULT

• 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.

  PMID: 2064208 RESULT

• 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.

  PMID: 2419430 RESULT

• 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.

  PMID: 26469146 RESULT

• 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.

  PMID: 12525435 RESULT

• 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.

  PMID: 19467808 RESULT

• 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.

  PMID: 23909917 RESULT

• 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.

  PMID: 22035703 RESULT

• 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.

  PMID: 11756389 RESULT

• 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.

  PMID: 17021188 RESULT

• 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.

  PMID: 29714875 RESULT

• 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.

  PMID: 23028125 RESULT

Study Officials

• Mohammad Nouri, Ph.D

  Head of SCARM institute

  STUDY CHAIR

• Mehdi Yousefi, Ph.D

  SCARM institute

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: The participants and the person who analyzed the results were blinded in this study. Participants were aware of the study before being randomized and informed consent was obtained from them. It should be noted that the person analyzing the results had no other role in this study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2017
• First Posted: August 30, 2017
• Study Start: October 7, 2017
• Primary Completion: September 25, 2018
• Study Completion: July 11, 2019
• Last Updated: August 26, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

IR (1)