Clinical trial NCT06097559: International Non-selection Study for ERA® Test in Patients with Previous Implantation Failures
Official title: A Multicenter, Prospective, Non-selection Study for Endometrial Receptivity Analysis Test in Patients with Previous Implantation Failures
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Infertility of Uterine Origin
Implantation Failure
Keywords: Infertility
Implantation failure
Uterine microbiome
Preimplantational Genetic Testing for Aneuploidies
Endometrial factor
Window of implantation
Endometrial receptivity
Personalized embryo transfer
Frozen embryo transfer
Endometrial Receptivity Analysis (ERA)
Lead sponsor: Igenomix
Sponsor class: INDUSTRY
First posted: 2023-10-24
Enrollment: 738
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 41
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Infertile women scheduled for an in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle with one or more previous failed euploid/low-range mosaic embryo transfer(s) or with two or more previous failed transfers with non-tested good quality embryos, who will receive a transfer of a frozen euploid/low-range mosaic blastocyst (day 5/6) in an HRT cycle.

Brief summary: Women´s period comprises different hormonal stages, being one of them the stage for maximum receptivity and proper embryo implantation. This stage is named window of implantation (WOI), and is characterized by a specific molecular pattern than can be assessed by the Endometrial Receptivity Analysis (ERA® test), developed by Igenomix. Determining the WOI allows to schedule a personalized embryo transfer (pET) when the endometrium is most receptive for the implantation.

The main objective of the present study is to improve our knowledge on the endometrial factor in an infertile population with previous implantation failures. To do so, a diagnosis of the endometrial receptivity to determine the WOI (ERA®) and the microbiome (EMMA®) of each participant will be performed, assessing its impact on deferred embryo transfers in terms of reproductive outcomes.

Participants will follow their previously programmed IVF/ICSI treatment and, only when one embryo with no major anomalies is reported by PGT-A (Preimplantation Genetic Testing for Aneuploidies), they will be asked to attend to the specific study visit for endometrial fluid and biopsy samples collection. These samples will be used to determine the patient's WOI (ERA®) and endometrial microbiome (EMMA®). The results of neither of the tests will be disclosed to the patient or the doctor, being only used for the study purpose. After this visit, the patient will follow the pre-established schedule for an embryo transfer and pregnancy assessment.

Detailed description: Endometrial receptivity takes place in a self-limited period of time during the endometrial mid-secretory stage. This period, named as window of implantation (WOI), is modulated by molecular changes allowing embryo implantation. The Igenomix group developed a molecular tool able to classify the endometrium based on its transcriptomic profile, the Endometrial Receptivity Analysis (ERA®). This molecular tool analyzes, by next generation sequencing (NGS), the expression of 248 genes related to implantation, coupled to a computational predictor, to identify the specific transcriptomic profile for each endometrial phase. This test has been applied clinically since 2010 to improve clinical implantation, helping to synchronize a viable embryo with a receptive endometrium through the personalized embryo transfer (pET).

Apart from receptivity, there are other approaches to study the impact of the endometrial factor in infertility. One of those is the analysis of the endometrial microbiome (set of microorganisms that live in the endometrium). A reduced presence of certain beneficial microorganisms (mostly, bacteria of the genus Lactobacillus) or even the presence of a pathogenic microbiota in the endometrium could be associated with worse reproductive outcomes, affecting embryo implantation, pregnancy and consequently reducing the number of births. Igenomix has also developed the Endometrial Microbiome Metagenomic Analysis (EMMA®) as a diagnostic method to assess the microbiome content of the endometrium. Both, ERA® and EMMA® analyses, can be performed with a single endometrial tissue sample collected when maximum receptivity is commonly expected.

The main questions this study aims to answer are:

1. If a pET in a specific receptive endometrial transcriptomic profile is related to a higher Ongoing Pregnancy Rate (OPR) (≥ 12 gestational weeks; fetal heartbeat diagnosis) in patients with at least one previous implantation failure. This may help to fine-tune the ERA computational analysis for some specific endometrial receptivity profiles.
2. To identify new potential biomarkers and other factors that, if related with the WOI, could help to predict an optimal embryo implantation.

Once the study is approved by the competent Research Ethics Committee of each center, the recruitment and selection of patients will follow. Every potential participant will be asked to sign the study informed consent. To comply with the study design and the proposed hypothesis, a total number of 738 patients has been estimated, considering a 30% dropout rate.

This is a multicenter, international, competitive, non-selection (prospective cohort) study designed with two phases:

* Non-selection phase (double-blinded design). Participants will follow their previously programmed IVF/ICSI treatment and the resulting embryo/s will be tested for chromosomic anomalies with the Preimplantation Genetic Testing for Aneuploidies (PGT-A) at Igenomix. When at least one euploid/low-range mosaic blastocyst is reported, the patient will be scheduled for the only additional visit related to the study to collect the endometrial fluid and biopsy samples that will be used to determine the patient's WOI (ERA®) and endometrial microbiome (EMMA®). The results of neither of the tests will be disclosed to the patient or the doctor. Therefore, regardless of the endometrial status, the patient will follow the pre-established schedule for a subsequent regular frozen embryo transfer (FET) within the standard WOI (after 120±6 hours of progesterone exposure) in a hormone replacement therapy (HRT) cycle. After the FET, participants will be followed up as routine by their gynecologist.
* Rescue phase (open design). The ERA® test result may be disclosed, under request, to those patients who did not achieve an ongoing pregnancy on the non-selection phase. These results could guide a subsequent personalized euploid/low-range mosaic blastocyst transfer (pET) in a new HRT cycle, when the patient is most receptive.

Data exported from the medical records and source documents will be duly codified to protect the clinical and personal information of patients in accordance with the current legislation on data protection. This information will be exported to an electronic Case Report Form (eCRF). An interim data analysis will be carried out once the 30% of the embryo transfers corresponding to the non-selection phase is achieved. It will help us to assess the enrollment rate, protocol compliance and an early evaluation of the study objectives.

Patient´s participation will comprise an estimated total time of up to 18 months, corresponding to 1 month for the stimulation cycle and PGT-A, 1-2 months for endometrial samples collection, 1-2 months for the embryo transfer and up to 13 months to follow-up the clinical outcomes.

Eligibility criteria: Inclusion Criteria:

* Study ICF signature.
* Female age between 18 and 41 years (both included).
* IVF/ICSI (own or donated gametes) patients with ≥1 previous failed euploid/low-range mosaic embryo transfer(s) or ≥2 previous failed transfers with non-tested good quality embryos. (ROPA method is allowed).
* ≥1 PGT-A tested euploid/low-range mosaic blastocyst (day 5/6) available to be transferred (SET or DET according to medical recommendation).
* BMI 18.0 - 30.0 Kg/m2.
* Negative serological tests for HIV, HBV, HCV, RPR.

Exclusion Criteria:

* No HRT in the biopsy and/or the embryo transfer cycle.
* Intrauterine device (IUD) carriers within 3 months before sample collection.
* Surrogate pregnancy (in those countries where it is allowed).
* Adenomyosis or any pathological finding affecting the endometrial cavity such as polyps/sub-mucosal myomas, intramural myomas \> 4 cm, or hydrosalpinx. (Note: Patients are allowed to participate if the pathology is previously operated at least 3 months before the endometrial samples are obtained).
* Recurrent Pregnancy Loss (RPL ≥2 previous intrauterine miscarriages).
* Active endometritis and salpingitis at the moment of the inclusion.
* Endometriosis stage \> I (stages II, III and IV) according to ASRM classification.
* Atrophic endometrium (\< 6 mm) in the ERA® and/or embryo transfer cycle.
* Endometrial receptivity test and/or microbiome test done before ICF signature.
* Preimplantation Genetic Testing for Chromosomal Structural Rearrangements (PGT-SR) or Preimplantation Genetic Testing for Monogenic Disorders (PGT-M) concomitant indications.
* DuoStim IVF protocol (double ovarian stimulation and two egg retrievals in the same ovarian cycle).
* Any illness or medical condition that is unstable or which, according to medical criteria, may put at risk the patient's safety and her compliance in the study.

Primary outcomes:
measure: Refinement of the ERA® computational analysis
timeFrame: At least 12 gestational weeks
Secondary outcomes:
measure: Pregnancy rate (PR) in the FET
timeFrame: 2 weeks after the embryo transfer
measure: Implantation rate (IR) in the FET
timeFrame: Up to 4 weeks after the embryo transfer
measure: Biochemical pregnancy rate (BPR) in the FET
timeFrame: 4 weeks after the embryo transfer
measure: Ectopic pregnancy rate (EPR) in the FET
timeFrame: 4-5 weeks after the embryo transfer
measure: Clinical miscarriage rate (CMR) in the FET
timeFrame: Up to 22 gestational weeks
measure: Ongoing Pregnancy Rate (OPR) in the FET
timeFrame: Over 12 gestational weeks
measure: Live Birth Delivery Rate (LBDR) in the FET
timeFrame: 40 gestational weeks
measure: Pregnancy rate (PR) in the pET
timeFrame: 2 weeks after the embryo transfer
measure: Implantation rate (IR) in the pET
timeFrame: Up to 4 weeks after the embryo transfer
measure: Biochemical pregnancy rate (BPR) in the pET
timeFrame: 4 weeks after the embryo transfer
measure: Ectopic pregnancy rate (EPR) in the pET
timeFrame: 4-5 weeks after the embryo transfer
measure: Clinical miscarriage rate (CMR) in the pET
timeFrame: Up to 22 gestational weeks
measure: Ongoing Pregnancy Rate (OPR) in the pET
timeFrame: Over 12 gestational weeks
measure: Identification of new potential actionable biomarkers for endometrial receptivity
timeFrame: 1-2 months
measure: Clinical reproductive outcomes according to the microbiome profile by the EMMA® test
timeFrame: Up to 40 gestational weeks
measure: Microbiome analysis concordance between endometrial fluid and biopsy
timeFrame: 1-2 months
measure: Determination of immune and metabolic changes related to endometrial receptivity
timeFrame: 1-2 months
measure: Cost-effectiveness of OP per patient
timeFrame: At least 12 gestational weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Center for Fertility Studies
state: Arizona
city: Buenos Aires
country: Argentina
facility: In Vitro Buenos Aires
city: Melbourne
country: Australia
facility: Number 1 Fertility
state: Victoria
city: Boa Vista
country: Brazil
facility: Nilo Frantz - Centro de Reprodução Humana
state: Porto Alegre
city: Panama City
country: Panama
facility: The Fertile Group
city: San Borja
country: Peru
facility: Inmater
state: Lima
city: Marbella
country: Spain
facility: Ovoclinic Marbella
state: Málaga
city: Madrid
country: Spain
facility: Ovoclinic Madrid
city: Málaga
country: Spain
facility: URE Centro Gutenberg
city: Sevilla
country: Spain
facility: Vida Recoletas Sevilla
city: Valladolid
country: Spain
facility: Vida Recoletas Valladolid
city: London
country: United Kingdom
facility: Lister Fertility Clinic at The Portland Hospital
Study officials:
affiliation: Igenomix
name: Maria Ruiz, MSc
role: PRINCIPAL_INVESTIGATOR
References: