Endometrium Immunomodulation by in Utero Administration of Peripheral Blood Mononuclear Cells

Endometrium Immunomodulation Using in Utero Administration of Peripheral Blood Mononuclear Cells

One of the most limiting factors in the field of assisted reproduction is implantation failure. A new approach to increase the chances of success involves the use of cells from the patient's blood, peripheral blood mononuclear cells (PBMC), which once isolated can be cultured for a few days and then inseminated back into the uterine cavity prior to embryo implantation. It has been shown that the immune system plays a major role in the process of embryo implantation. To date, at least three international clinical trials appear to confirm the usefulness of intrauterine administration of PBMC in the setting of repeated implantation failure (RIF) in in vitro fertilization (IVF) (RIF: absence of active pregnancy after ≥ 3 embryo transfers). The clinical pregnancy rate would be doubled or even tripled. This treatment has never been studied in a randomized double-blind clinical trial, in the context of fertilization without RIF or in a classic treatment such as intrauterine insemination (IUI) with the partner sperm.

Our hypothesis is that the creation of an endometrial inflammatory reaction by the administration of PBMC in the uterine cavity allows a better receptivity and consequently a better implantation following an embryo transfer as part of an IVF treatment.

The objective is to evaluate whether intrauterine administration of PBMC improves embryo implantation following assisted reproduction treatment.

The investigators plan to recruit 148 women undergoing IVF and 220 patients undergoing UII with partner sperm to test our hypothesis. The investigators also plan to recruit all RIF patients accepting to participate in the clinical trial. The study will be prospective, randomized and double-blind. The treated group will receive an intrauterine administration of PBMC while the control group will be administered with sperm washing medium only. PBMC will be obtained from a blood sample (maximum 10 ml) a few days before embryo transfer in IVF cases or on the day of sperm insemination in IUI cases. PBMC will then be isolated in the laboratory on a Ficoll gradient in order to eliminate platelets, polynuclear cells and red blood cells. PBMCs will then be stimulated with phytohemagglutinin (PHA) and human chorionic gonadotropin hormone (hCG) for 48 hours. Lymphocyte phenotyping will be assessed before and after cell activation. In addition, the cytokine profile will be established from the supernatant of the stimulated cells. These data will make it possible to establish a link between the pro-versus anti-inflammatory cytokine profile and implantation success versus failure for each patient. Two days after cell seeding, PBMC will be administered into the uterine cavity of the patient. Embryo transfer will be performed in the same way as the standard treatment on day 3 or 5 according to the criteria established by the IVF laboratory and in agreement with the doctor.

Study Overview

• Status: Completed
• Conditions: Infertility
• Intervention / Treatment: Procedure: Intrauterine administration of sperm washing medium; Procedure: Intrauterine administration of hCG-activated peripheral blood mononuclear cells

• Study Type: Interventional
• Enrollment (Actual): 423
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Laval, Quebec, Canada, H7S1Z5
      • Fertilys inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• All infertile patients undergoing in vitro fertilization (IVF) or intrauterine insemination (IUI) with partner's sperm at Fertilys, agreeing to participate in the study and having signed the study participation consent form.
• Study participants must be over 18 years old.
• For the recurrent implantation failure (RIF) group only: Patients described as having RIF, i.e. having had ≥ 3 good quality embryo transfers.

Exclusion Criteria:

• For the randomized IUI and IVF groups only: Patients described as having RIF, i.e. having had ≥ 3 embryo transfers or having had a transfer of more than 3 embryos of good quality.
• Patients requiring a donation of gametes (eggs or spermatozoa).
• Couples in which one or the other has a chromosomal abnormality.
• Patients who are starting an IUI cycle under ovulation testing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: IIU control group	Procedure: Intrauterine administration of sperm washing medium; Administration of sperm washing medium instead of PBMC in the uterine cavity of the patient
Active Comparator: IIU PBMC group	Procedure: Intrauterine administration of hCG-activated peripheral blood mononuclear cells; Administration of hCG-activated peripheral blood mononuclear cells in the uterine cavity of the patient
Placebo Comparator: FIV control group	Procedure: Intrauterine administration of sperm washing medium; Administration of sperm washing medium instead of PBMC in the uterine cavity of the patient
Active Comparator: FIV PBMC group	Procedure: Intrauterine administration of hCG-activated peripheral blood mononuclear cells; Administration of hCG-activated peripheral blood mononuclear cells in the uterine cavity of the patient
Active Comparator: RIF group	Procedure: Intrauterine administration of hCG-activated peripheral blood mononuclear cells; Administration of hCG-activated peripheral blood mononuclear cells in the uterine cavity of the patient

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Biochemical pregnancy rate	Two weeks following embryo transfer or 3 weeks following intrauterine insemination
Clinical pregnancy rate	Six to 8 weeks of gestation

Secondary Outcome Measures

Outcome Measure	Time Frame
Peripheral blood mononuclear cells populations distribution at Day 0	The day of the patient's ovulation
Peripheral blood mononuclear cells populations distribution at Day 2	After 48 hours of culture
Cytokines expression levels	After 48 hours of culture

Collaborators and Investigators

• Sponsor: Fertilys
• Collaborators: Institut National de la Recherche Scientifique - Centre Armand Frappier Santé Biotechnologie
• Investigators: Principal Investigator: Pierre Miron, MD, PhD, Fertilys inc

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2017
• Primary Completion (Actual): February 1, 2020
• Study Completion (Actual): February 1, 2020

Study Registration Dates

• First Submitted: November 18, 2020
• First Submitted That Met QC Criteria: November 23, 2020
• First Posted (Actual): December 1, 2020

Study Record Updates

• Last Update Posted (Actual): December 1, 2020
• Last Update Submitted That Met QC Criteria: November 23, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility
• Other Study ID Numbers: Immunomodulation

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