Clinical trial NCT03530254: Clinical Study of PGT-A Versus PGT-A+ERA
Official title: International Multi-center, Randomized and Controlled Clinical Study, to Evaluate the Clinical Benefit of the ERA Test in Infertile Patients Undergoing Assisted Reproduction Treatment and Medical Indication of PGT-A.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Infertility of Uterine Origin
Keywords: Endometrial receptivity
Preimplantation Genetic Diagnosis (PGD)
Preimplantation Genetic Testing for Aneuploidy (PGT-A)
Embryo Transfer (ET)
Endometrial Receptivity Analysis (ERA)
Endometrial Diagnosis
Live Newborn Rate (LBR)
Lead sponsor: Igenomix
Sponsor class: INDUSTRY
First posted: 2018-05-21
Enrollment: 368
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: Patients who have shown previous implantation failures, despite transferring good quality and chromosomally normal embryos (diagnosed by PGT-A), could have a displaced Window of Implantation (WOI) and consequently, alterations in their endometrial receptivity. The correction of this displacement can improve the results of the Assisted Reproduction Treatments (ART).

The ERA test (Endometrial Receptivity Analysis) evaluates the transcriptomic endometrial profile to determine if the patient's uterus is receptive when the embryo is transferred during an In Vitro Fertilization (IVF) process, and identifies the personalized WOI of the patient. This process is called Personalized Embryo Transfer (pET).

The Preimplantation Genetic Test of Aneuploidies or PGT-A (Preimplantation Genetic Testing for Aneuploidy), is currently carried out using Next Generation Sequencing (NGS) and serves to identify chromosomally normal embryos prior to their transfer in an IVF treatment. Aneuploidies are rarely compatible with life or can cause congenital diseases. So, the identification of chromosomally normal embryos, improves the success of reproduction in cases in which infertility is caused by such aneuploidies.

Therefore, the aim of this study is to determine, in a randomized and prospective way, the clinical benefit of adding the ERA test to the embryonic aneuploidies test for patients with a PGT-A indication.

Detailed description: The lack of receptivity of the uterus and chromosomal abnormalities in the embryo are the two main causes of implantation failure. Patients with implantation failure, should consider the PGT-A test to identify and select euploid embryos. In addition, it should be evaluated the endometrium receptivity state at the time of Embryo Transfer (ET).

The PGT-A is an important genetic test that was developed to select embryos during IVF treatment and avoid embryonic chromosomal abnormalities that lead to miscarriage or life born with chromosomal diseases. Embryonic aneuploidy is linked to maternal age. The most common consequences are implantation failure, miscarriage or life born with multiple congenital anomalies. The transfer of euploid embryos (chromosomally normal) diagnosed by PGT-A has shown an increase in implantation rates.

Morphology is the most traditional and routine method of embryo selection being used. However, it is difficult to distinguish normal and abnormal embryos by observing their morphology under a microscope. Therefore, morphological analysis should not be the only technique used to decide which embryo should be transferred. Application of NGS in PGT-A cycles demonstrates that this methodology is reliable, allowing identification and transfer of euploid embryos resulting in ongoing pregnancies. However, despite the transfer of morphologically normal euploid embryos, it is not always possible to acquire optimal results in Assisted Reproductive Techniques (ART).

On the other hand, the endometrial gene expression profile allows the diagnosis of the endometrium receptivity status. This is carried out by a molecular tool developed and patented by Igenomix (PCT/ES2009/00386). The ERA test is a customized expression microarray that identifies the transcriptomic expression profile signature of the personalized Window of Implantation (pWOI). A bioinformatic predictor determines the moment of maximum receptivity, indicating the best time to perform a pET.

If the result of the ERA test is "Receptive", the WOI and the moment of taking the biopsy overlap. Nevertheless, if the result is "Pre-Receptive", the optimal implantation window is expected to be after the moment in which the biopsy is taken, and if the diagnosis is "Post-Receptive", the optimal window of implantation is prior to the biopsy. In a subsequent cycle, a pET will be performed according to the ERA test results.

Recently, it has been conducted a pilot study in patients with previous implantation failures with PGT-A and euploid embryo transfer (ET). The results of the ERA test have shown that a high percentage of these patients have been diagnosed as Non-receptive (90%). This percentage is higher than the expected in the normal population (12-20%) or in the Repeated Implantation Failure (RIF) patients without PGT-A (25-30%). Once the pET was performed according to the results of the ERA test, the gestation rate was 55.55%.

So, the objective of the present study is to validate these preliminary results in a prospective, multi-center, randomized and controlled study to demonstrate the value of the endometrial factor and the improvement of the results obtained in patients with PGT-A indication. If confirmed, it would be recommended the ERA test for all ART patients, not only for those with PGT-A, demonstrating the significance in searching for the pWOI to improve reproductive outcomes.

Considering a maximum drop-out rate of 30%, a total of 750 participants are expected to be included. According to the approved protocol, an interim analysis is planned at 50% of the total enrolment.

Eligibility criteria: Inclusion Criteria:

* Majority of age patients whose written informed consent approved by the Ethics Committee (EC) has been obtained, after having been duly informed of the nature of the study and voluntarily accepted to participate after being fully aware of the potential risks, benefits and any discomfort involved.
* Patients who already have frozen euploid blastocysts (day 5/6 development) analysed by PGT-A.
* Patients with embryos obtained from their own oocytes fertilized by Intracytoplasmic Sperm Injection (ICSI) or In vitro fertilization (IVF).
* Patients with an expected embryo transfer of one or two embryos (Single ET or Double ET) in a HRT cycle.
* Body Mass Index: 18,5-30 Kg/m2.

Exclusion Criteria:

* Presence of pathologies or malformations that affect the uterine cavity such as polyps, intramural myomas ≥ 4cm or submucosal, septum or hydrosalpinx during the patient's participation in the study. Patients suffering these pathologies before or after their inclusion in the study are allowed to participate if the pathology is corrected before performing any study procedure.
* 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: Live birth rate
timeFrame: 40 weeks
Secondary outcomes:
measure: Implantation rate
timeFrame: 12 weeks
measure: Clinical pregnancy
timeFrame: 20 weeks
measure: Biochemical pregnancy
timeFrame: 20 weeks
measure: Clinical miscarriages
timeFrame: 20 weeks
measure: Ectopic pregnancies
timeFrame: 20 weeks
measure: Obstetric complications
timeFrame: 40 weeks
Other outcomes:
Locations:
city: Newport Beach
country: United States
facility: Ovation Fertility Newport Beach
state: California
city: Reading
country: United States
facility: Fertility Centers of New England
state: Massachusetts
city: Caba
country: Argentina
facility: Pregna Medicina Reproductiva
city: São Paulo
country: Brazil
facility: Vida Bem Vinda
city: Vancouver
country: Canada
facility: Olive Fertility Center
city: Vitacura
country: Chile
facility: Shady Grove Fertility Chile
city: Tbilisi
country: Georgia
facility: Georgian- American Center for Reproductive Medicine ReproART
city: Defence Colony
country: India
facility: Mother And Child Hospital
state: Delhi
city: Banjara Hills
country: India
facility: OASIS centre for reproductive medicine
state: Hyderabad
city: Mexico City
country: Mexico
facility: NASCERE
state: Cdmx
city: Alcobendas
country: Spain
facility: Milenium Centro Médico y de Bienestar de Alcobendas - Sanitas
state: Madrid
city: Badajoz
country: Spain
facility: Instituto Extremeño de Reproducción Asistida S.L. (IERA)
city: Zhubei
country: Taiwan
facility: Taiwan IVF Group
city: Istanbul
country: Turkey
facility: Bahceci Group
city: Hà Nội
country: Vietnam
facility: Vinmec Time City International Hospital
Study officials:
affiliation: Igenomix
name: Carlos Simón, MD PhD
role: STUDY_CHAIR
References: