RCT Study to Validate niPGT-A Clinical Benefit.

Brief Title

RCT Study to Validate niPGT-A Clinical Benefit.

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.

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.
    

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 Type

Interventional


Primary Outcome

Non-invasive analysis of the chromosomal status of the embryo

Secondary Outcome

 NGS results of the SBM

Condition

Aneuploidy

Intervention

niPGT-A

Study Arms / Comparison Groups

 Control group (group 1)
Description:  Deferred single blastocyst transfer with blastocyst selection according to morphology.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

1108

Start Date

June 14, 2019

Completion Date

June 2023

Primary Completion Date

April 2023

Eligibility Criteria

        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.
      

Gender

Female

Ages

20 Years - 40 Years

Accepts Healthy Volunteers

No

Contacts

Carmen Rubio, PhD, +34 963905310, [email protected]

Location Countries

Argentina

Location Countries

Argentina

Administrative Informations


NCT ID

NCT04000152

Organization ID

IGX1-NIP-CS-18-05


Responsible Party

Sponsor

Study Sponsor

Igenomix


Study Sponsor

Carmen Rubio, PhD, Principal Investigator, Igenomix S.L.


Verification Date

December 2020