niPGT-A_RCT: RCT Study to Validate niPGT-A Clinical Benefit.

Sponsor

Igenomix (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04000152

Collaborator

(none)

1,108

Enrollment

Locations

Arms

47.6

Anticipated Duration (Months)

85.2

Patients Per Site

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Chromosomal aneuploidies are linked with spontaneous miscarriages and abnormal offspring in human pregnancies. In addition, some types of aneuploidy are reported to prevent implantation. Thus, there is a need to identify the embryos with highest implantation potential on in vitro fertilization (IVF) programs.

Since embryo morphology and kinetics have a weak association with embryo ploidy, trophectoderm biopsy plus Next-Generation Sequencing (NGS) is becoming a very popular approach to determine the embryo chromosomal status. This technique is called Preimplantation Genetic Testing for Aneuploidy (PGT-A). Although shown to be efficient, it is invasive for the embryo, requires specific technical skills and it remains expensive. Therefore, the development of a non-invasive, rapid and cheaper method for assessing embryo ploidy status would represent a progress in the field of IVF.

The non-invasive approach has been explored by some groups that analyzed the Spent Blastocyst Medium (SBM) where the embryo was incubated up to the time of transfer or freezing. In daily routine, this media is discarded after finishing the culture of the embryo. Importantly, though, this media reportedly contains traces of embryonic cell-free DNA (cfDNA) that can represent the genetic load of the embryo.

On the basis of that, the hypothesis of this study is that embryo prioritization according to the analysis of the embryonic cfDNA in the SBM could improve ongoing pregnancy rate in 10 percentual points compared to standard blastocyst transfer based on morphology.

Condition or Disease	Intervention/Treatment	Phase
Aneuploidy Chromosome Abnormality Infertility	Diagnostic Test: niPGT-A Other: Morphology criteria	N/A

Detailed Description

Current Preimplantation Genetic Testing for Aneuploidy (PGT-A) techniques analyze the full chromosome content of a single or few cells with high sensitivity and specificity using Next-Generation Sequencing (NGS). Although shown to be efficient, the technique suffers from some limitations. It requires an embryo biopsy, specific technical skills and it still remains expensive. Therefore, non-invasive techniques for assessing embryo ploidy status are sought as an alternative. Such non-invasive approaches would have various advantages over current strategies, including the elimination of a costly micromanipulation biopsy procedure and the avoidance of risks associated with cell removal. Furthermore, it would be more advantageous, especially for those patients who undergo in vitro fertilization (IVF) treatment but do not have PGT-A indication or they are not willing to have their embryos tested with invasive techniques.

One of the recent advances in the field is the identification of embryonic cell-free DNA (cfDNA) during embryo culture in the lab. It is released to the culture drop (SBM) and represents the chromosome content of the embryo. In a recent pilot study, we analyzed the concordance rates between trophectoderm (TE) biopsy and SBM. In SBM collected on day 6/7 of development, the results were concordant with TE biopsies in 84% of samples, with a false-positive rate of 8.6% and a false-negative rate of 2.5%. These findings are encouraging and were the base for the design of the current RCT study.

The main objective of this study is to evaluate the potential clinical benefits of a new non-invasive method for PGT-A, based on the analysis of the embryonic cfDNA released into SBM.

Considering a dropout rate of around 30% (treatment or monitoring failures and no day 6/7 blastocysts to transfer), a total of 872 participants will be randomized before the ovum pick-up. They will be allocated on a balanced way (1:1 ratio) in one of the two arms: 1) Single Embryo Transfer (SET) on day 6/7 with deferred blastocyst transfer based on the chromosomal status according to the analysis of the SBM; 2) SET on day 6/7 with deferred blastocyst transfer based on embryo morphology. Reproductive outcomes (defined following The International Glossary on Infertility and Fertility Care, 2017) will be compared between the two groups.

Data exported from the clinical histories and source documents will be duly codified to protect the clinical and personal information of patients in accordance with the current legislation. This information will be exported to an electronic Case Report Form (eCRF). An interim analysis of this data is planned once 30% of the recruitment has been reached. Besides, the study will be overseen by an independent Data Monitoring Committee after 30% of patients´ recruitment.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1108 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

Randomized Controlled Clinical Study to Assess the Benefit of Non-invasive PGT-A, by the Analysis of Spent Blastocyst Media, as a Tool for Embryo Prioritization in Infertile Patients Undergoing Assisted Reproduction.

Actual Study Start Date :

Jun 14, 2019

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Control group (group 1) Deferred single blastocyst transfer with blastocyst selection according to morphology.	Other: Morphology criteria Embryos for transfer will be selected by the only applicable technique, the assessment of morphology according to Gardner´s criteria, which is the most standardized method.
Experimental: Intervention group (group 2) Deferred single blastocyst transfer with blastocyst selection according to the analysis of the spent culture media (niPGT-A).	Diagnostic Test: niPGT-A Two scenarios should be considered according to the results in the SBM analysis: The couple decides to transfer the blastocyst selected according to the SBM result (blastocyst prioritization system). The couple decides to biopsy the blastocysts (if SBM results show low euploidy score). This PGT-A analysis will be offered for free but the outcome of these transfers will be excluded for the analysis per completed protocol. However, all transfers will be included in the intention-to-treat analysis.

Arm

Intervention/Treatment

Active Comparator: Control group (group 1)

Deferred single blastocyst transfer with blastocyst selection according to morphology.

Other: Morphology criteria

Embryos for transfer will be selected by the only applicable technique, the assessment of morphology according to Gardner´s criteria, which is the most standardized method.

Experimental: Intervention group (group 2)

Deferred single blastocyst transfer with blastocyst selection according to the analysis of the spent culture media (niPGT-A).

Diagnostic Test: niPGT-A

Two scenarios should be considered according to the results in the SBM analysis: The couple decides to transfer the blastocyst selected according to the SBM result (blastocyst prioritization system). The couple decides to biopsy the blastocysts (if SBM results show low euploidy score). This PGT-A analysis will be offered for free but the outcome of these transfers will be excluded for the analysis per completed protocol. However, all transfers will be included in the intention-to-treat analysis.

Outcome Measures

Primary Outcome Measures

Non-invasive analysis of the chromosomal status of the embryo [7 days]
Number and structure of the embryo chromosomes
Ongoing pregnancy rate [Over 12 weeks]
Number of ongoing pregnancies per single embryo transfer

Secondary Outcome Measures

NGS results of the SBM [7 days at least]
Informativity rates and prioritization category of the SBM analysis results with embryo development, culture conditions and collection time
Non-Invasive Prenatal Testing (NIPT) [Up to 12 weeks]
Incidence of chromosomal abnormalities in NIPT within ongoing pregnancy cases
Clinical miscarriage rate [Up to 6 months after the ovum pick-up]
Number of clinical miscarriages per total number of ongoing pregnancies
Analysis of the Products of Conception (POC) [Up to 20 weeks]
Incidence of chromosomal abnormalities in POC within miscarriage cases
Cumulative ongoing pregnancy rate [Over 6 months after the ovum pick-up]
Cumulative ongoing pregnancy rate per patient in the 6 months after the pick-up
Time to get an ongoing pregnancy [Up to 6 months after the ovum pick-up]
Time to get an ongoing pregnancy within the 6 months after the pick-up
Live birth rate [Over 40 weeks]
Number of babies born per embryo transfer
Cumulative live birth rate [Over 6 months after the ovum pick-up]
Cumulative live birth rate per patient in the 6 months after the pick-up
Obstetrical outcomes comparison [Over 40 weeks]
To compare birth weight, gestational age, APGAR, type of delivery, pregnancy complications, etc.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 40 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
IVF patients intending to undergo deferred day 6/7 blastocyst SET for any medical indication.
All the oocytes/embryos from the cycle should follow the laboratory protocol described in the study (embryo culture and vitrification on day 6/7).
ICSI, IVF or ICSI/IVF performed in fresh own oocytes from couples not undergoing PGT-A. Note: Donor sperm is allowed.
Female age: 20-40 years, both included.

Exclusion Criteria:

A known abnormal karyotype if the couple provides it at consultation. If not, karyotype is not compulsory.
Couples planning to undergo PGT-M or PGT-SR cases will be excluded.
Surrogate pregnancy (in those countries where it is allowed).
ERA test and embryo transfer according to ERA result.
Time-lapse culture systems are not allowed after day 4 of culture.
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 can 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fertility Associates of California (FSAC)	Thousand Oaks	California	United States	91361
2	South Florida Institute for Reproductive Medicine (IVFMD)	Florida City	Florida	United States	33458
3	Boston IVF Fertility Clinic	Boston	Massachusetts	United States	02109
4	Crecer: Centro de Reproducción y Genética Humana	Mar Del Plata	Buenos Aires	Argentina
5	Saresa - Reproducción Humana Asistida	Salta		Argentina	4400
6	Nilo Frantz - Centro de Reprodução Humana	Boa Vista	Porto Alegre	Brazil	91330-002
7	Vida - Centro de Fertilidade	Rio De Janeiro		Brazil	22793-080
8	Hôpital Foch	Suresnes		France	92150
9	Società Italiana Studi di Medicina della Riproduzione (S.I.S.M.e.R.)	Bologna		Italy	40138
10	Centro Procreazione Assistita DEMETRA	Firenze		Italy	50141
11	Promea S.p.A	Torino		Italy	10126
12	Hospital Ruber Internacional	Madrid		Spain	28035
13	Bahçeci Health Group	Istanbul		Turkey	34394