Endometrium Immunomodulation by in Utero Administration of Peripheral Blood Mononuclear Cells

• ClinicalTrials.gov Identifier: NCT04648566
• Recruitment Status: Completed
• First Posted: December 1, 2020
• Last Update Posted: December 1, 2020
• Sponsor: Fertilys
• Collaborator: Institut National de la Recherche Scientifique - Centre Armand Frappier Santé Biotechnologie
• Information provided by (Responsible Party): Fertilys

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Infertility	Procedure: Intrauterine administration of hCG-activated peripheral blood mononuclear cells; Procedure: Intrauterine administration of sperm washing medium	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 423 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Endometrium Immunomodulation Using in Utero Administration of Peripheral Blood Mononuclear Cells
• Actual Study Start Date: March 22, 2017
• Actual Primary Completion Date: February 1, 2020
• Actual Study Completion Date: February 1, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Biochemical pregnancy rate [ Time Frame: Two weeks following embryo transfer or 3 weeks following intrauterine insemination ]
2. Clinical pregnancy rate [ Time Frame: Six to 8 weeks of gestation ]

Secondary Outcome Measures :

1. Peripheral blood mononuclear cells populations distribution at Day 0 [ Time Frame: The day of the patient's ovulation ]
2. Peripheral blood mononuclear cells populations distribution at Day 2 [ Time Frame: After 48 hours of culture ]
3. Cytokines expression levels [ Time Frame: After 48 hours of culture ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Canada, Quebec

Fertilys inc.

Laval, Quebec, Canada, H7S1Z5

Sponsors and Collaborators

Fertilys

Institut National de la Recherche Scientifique - Centre Armand Frappier Santé Biotechnologie

Investigators

• Principal Investigator: Pierre Miron, MD, PhD; Fertilys inc

More Information

• Responsible Party: Fertilys
• ClinicalTrials.gov Identifier: NCT04648566
• Other Study ID Numbers: Immunomodulation
• First Posted: December 1, 2020
• Last Update Posted: December 1, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Infertility