Development of a Microbiome Non-invasive Diagnosis Tool

NCT03330444 | Completed

• 1 other identifier: IGX1-MIC-CS-17-05
• Study Type: observational
• Target: 452
• Locations: 8 countries
• Sites: 13

Brief Summary

Although the endometrium tissue has been traditionally considered free of bacteria, recent studies have documented the presence of an endometrial microbiome. In a pilot study conducted by our research team, the microorganisms present in the endometrium were analysed in samples of endometrial fluid (EF) using next generation sequencing (NGS).Consistent with previously published studies, in normal conditions the endometrium is mainly composed of different species of the genus Lactobacillus. It was further noted that the presence of other pathogenic bacteria such as Streptococcus, and/or Gardnerella may alter the endometrial microbiome and can disrupt the uterine environment, affecting implantation rates and pregnancy success. This project aims to validate the microbiome found in the endometrium of women of reproductive age and try to corroborate the relationship between the endometrial microbiome and the reproductive outcomes in patients undergoing assisted reproduction treatment (ART). The use of Endometrial Receptivity Analysis (ERA) tool, together with the analysis of the endometrial flora before the embryo transfer will allow to evaluate the impact of the presence of endometrial pathogens on implantation in receptive patients. Therefore, the focus of this project is the development and clinical validation of a non-invasive diagnosis tool to analyse the microbiota, adding the microbiome study to the ERA analysis.

Conditions

Infertility of Uterine Origin

Keywords

Endometrial microbiota; Bacterial pathogens; Assisted reproductive techniques; Dysbiosis; Endometrial receptivity; Endometrial diagnosis

Outcome Measures

Primary Outcomes (1)

• Development of a new non-invasive diagnosis test of Endometrial Microbiome (EM) in infertile patients

  Bacterial DNA analysis by Next Generation Sequencing (NGS) using endometrial fluid for the EM diagnose. This will be measured by the percentage of each bacterial DNA in EF samples

  24 months

Secondary Outcomes (7)

• Live birth rate

  40 weeks

• Implantation rate

  12 weeks

• Pregnancy rate

  20 weeks

• Biochemical pregnancies

  20 weeks

• Ectopic pregnancies

  20 weeks

Study Arms (2)

LD microbiome receptive to the ERA test

Receptive patients by the ERA test with an endometrial microbiota mainly composed of different species of the genus Lactobacillus, determined by NGS sequencing.

Procedure: Endometrial biopsy and endometrial fluid collection

NLD microbiome receptive to the ERA test

Receptive patients by the ERA test with an endometrial microbiota composed of different pathogenic bacteria such as Streptococcus and Gardnerella, or not dominated by bacteria of the genus Lactobacillus, determined by NGS sequencing.

Procedure: Endometrial biopsy and endometrial fluid collection

Interventions

Endometrial biopsy and endometrial fluid collection PROCEDURE

On the same day that the EB for ERA is indicated, in day 5 of a HRT cycle with 5 days of progesterone, according to the common clinical practice, a sample of EF will be aspirated immediately prior to EB for ERA. This EF sample will be used for the non-invasive diagnosis of the microbiome, also a small portion of the endometrial tissue obtained for the endometrial receptivity diagnosis by ERA will be used as a control for the study of the endometrial microbiome. Those patients with a receptive endometrium will continue their ART according to the standard clinical protocol. Those patients with non-receptive endometrium will follow the recommendation derived of the ERA test for the election of the day for a second EB sample, in which the collection of EF sample will be repeated. Finally, the receptivity and microbiome results in EF will be correlated with that on the endometrial tissue, and with the reproductive outcomes of these patients after the embryo transfer.

LD microbiome receptive to the ERA test; NLD microbiome receptive to the ERA test

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

ART patients, with indication of diagnosis of endometrial receptivity by ERA that will receive embryo transfer with frozen blastocyst stage embryos (day 5/day 6).

You may qualify if:

• Patients in In Vitro Fertilization (IVF) / IntraCytoplasmic Sperm Injection (ICSI) or OVODON with indication of ERA, with or without Preimplantation genetic screening (PGS) indication, which receive embryo transfer with frozen blastocyst stage embryos (day 5/day 6) on a hormone replacement therapy (HRT) cycle.
• Maternal Age: ≤40 years (IVF/ICSI patients)
• Maternal Age: ≤50 years (OVODONATION patients)
• Body Mass Index (BMI): 18.5 - 30 kg / m2 (both inclusive)
• Negative serological tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), Rapid plasma reagin (RPR) for syphilis
• Women with regular menstrual formula (3-4 / 26- 35 days)
• Sperm concentration: \> 2 million spermatozoa/ml

You may not qualify if:

• Patients who are Intra-Uterine Device (IUD) carriers in the last 3 months
• Patients who have taken prescribed antibiotics in the last 3 months before the sample collection. (May be accepted those cases where the patient has received previous prophylactic antibiotics to ovarian puncture in the stimulation cycle, according to the standard clinical practice of the centre. The administration of this antibiotic should be at least 1 month before the sample collection).
• Existence of bacterial, fungal or viral infections severe or uncontrolled that, in the opinion of the principal investigator, could interfere with the patient's participation in the study or the assessments of the study results.
• Any illness or medical condition that is unstable or can put patient safety at risk and compliance in the study.

Sponsors & Collaborators

• Igenomix: lead

Study Sites (13)

RMA Connecticut

Norwalk, Connecticut, 06861, United States

Location

IVF Florida

Margate, Florida, 33063, United States

Location

Missouri Center for Reproductive Medicine (MCRM Fertility)

Chesterfield, Missouri, 63005, United States

Location

Dominion Fertility

Arlington, Washington, 22203, United States

Location

Gestanza Medicina Reproductiva

Rosario, Santa Fe Province, Argentina

Location

Pregna Medicina Reproductiva

Buenos Aires, C1425DGQ, Argentina

Location

Pacific Center for Reproductive Medicine

Burnaby, British Columbia, V5G 4X7, Canada

Location

oak Clinic Sumiyoshi

Osaka, Osaka, 557-0045, Japan

Location

Alpha Fertility Center

Petaling Jaya, Selangor, 47810, Malaysia

Location

New Hope Fertility Center

Mexico City, 11000, Mexico

Location

Clinica Fertia

Fuengirola, Malaga, 29640, Spain

Location

ProcreaTec

Madrid, 28036, Spain

Location

Bahçeci Fulya IVF Center

Istanbul, Turkey (Türkiye)

Location

Biospecimen

Retention: SAMPLES WITH DNA

DNA from endometrial fluid and biopsy to analyze the endometrial microbiome. These samples will be completely exhausted during the analysis.

MeSH Terms

Conditions

Dysbiosis

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Carlos Simón, MD PhD

  Igenomix

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2017
• First Posted: November 6, 2017
• Study Start: August 4, 2017
• Primary Completion: May 17, 2019
• Study Completion: June 25, 2020
• Last Updated: October 9, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

MY (1); ME (1); CA (1); US (4); TU (1); JP (1); ES (2); AR (2)