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CompletedNCT03267797Updated Aug 26, 2019

hCG-activated PBMC-therapy in RIF Patients

An interventional study of Peripheral Blood Monouclear Cell and Phosphate Baffer Saline in Recurrent Implantation Failure, sponsored by SCARM Institute, Tabriz, Iran. Completed at 1 site in Iran, Islamic Republic of. Open to female participants aged 20 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-08-26.

Sponsored by SCARM Institute, Tabriz, Iran · Not applicable, Interventional, and Treatment

Phase
Not applicable
Study type
Interventional
Enrollment
100
Allocation
Randomized
Ages
20 Years to 45 Years
Sex
Female
01

Study 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.

Read the 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.

02

Conditions studied

  • Recurrent Implantation Failure

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Keywords

  • Recurrent Implantation Failure
  • Peripheral blood mononuclear cell
  • Human chorionic gonadotropin
03

Who can participate

Ages eligible
20 Years to 45 Years
Sexes eligible
Female
Accepts healthy volunteers
Yes

All patients were evaluated in accordance with the following inclusion and exclusion criteria;

Inclusion criteria

Inclusion Criteria:

  1. Having at least three implantation failures following IVF
  2. Having primary infertility
  3. Age under 45 years old
  4. Having regular menstrual cycles
  5. BMI under 30

Exclusion criteria

Exclusion Criteria:

  1. Having polycystic ovary syndrome
  2. The presence of uterine pathology;
  3. Poor ovarian reserve
  4. Having chromosomal abnormalities
  5. Presence of auto anti-bodies such as anti-TPO, anti-TG, ACA, APA, ANA, and anti-dsDNA
  6. Presence of mutations involving the coagulation system such as deficiency of factor XII, Pro C, Pro S
  7. Positive HIV, HCV or HBV tests
04

Study design

Phase
Not applicable
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Outcomes assessor)
Enrollment
100 participants (actual)

Study arms

  • Experimental
    Treatment group

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

    Other: Peripheral Blood Monouclear Cell

  • Placebo comparator
    Control group

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

    Other: Phosphate Baffer Saline

Interventions

  • OtherPeripheral Blood Monouclear Cell

    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

  • OtherPhosphate Baffer Saline

    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

05

What researchers measure

Primary outcomes

  1. pregnancy occurrence

    Laboratory tests (beta-hCG test)

    Time frame: "12 days after embryo transfer"

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

    ELISA technique

    Time frame: "48 hours after culturing"

Secondary outcomes

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

    detection the number and location of gestational sacs by ultrasound

    Time frame: "in 5-6 weeks"

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

    By gynecologists and obstetricians will monitor

    Time frame: "After about 9 months of positive βHCG test"

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

    By gynecologists and obstetricians will monitor

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

06

Study locations

1 site
  • Valiasr Hospital
    Tabriz, Iran, Islamic Republic of
07

References and documents

Publications

  • 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. PubMed 14629021 ↗
  • 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. PubMed 22464086 ↗
  • 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. PubMed 15670421 ↗
  • 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. PubMed 16820110 ↗
  • 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. PubMed 2064208 ↗
  • 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. PubMed 2419430 ↗
  • 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. PubMed 26469146 ↗
  • 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. PubMed 12525435 ↗
  • 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. PubMed 19467808 ↗
  • 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. PubMed 23909917 ↗
  • 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. PubMed 22035703 ↗
  • 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. PubMed 11756389 ↗
  • 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. PubMed 17021188 ↗
  • 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. PubMed 29714875 ↗
  • 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. PubMed 23028125 ↗

Individual participant data

Plan to share: No

08

Registry details

Key details

Study ID
NCT03267797
Lead sponsor
SCARM Institute, Tabriz, Iran
Responsible party
Sponsor
First posted
Aug 30, 2017
Start date
Oct 7, 2017
Primary completion
Sep 25, 2018
Completion
Jul 11, 2019
Last update
Aug 26, 2019

Study contacts

Mohammad Nouri, Ph.D
study chair · Head of SCARM institute
Mehdi Yousefi, Ph.D
study director · SCARM institute

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
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