Multi-center Study to Validate niPGT-A

Sponsor
Igenomix (Industry)
Overall Status
Recruiting
CT.gov ID
NCT03520933
Collaborator
(none)
2,620
10
40.2
262
6.5

Study Details

Study Description

Brief Summary

Abnormal chromosome number, or aneuploidy, is common in human embryos. It is responsible for more than half of all miscarriages, and it is the leading cause of congenital birth defects. Besides, it has been described that aneuploidy may also affect embryo implantation. Therefore, selecting embryos that have the best chance of implanting and growing into a healthy baby is one of the most important steps in the field of assisted reproduction.

Recent advances in genetic technologies, such as Next-Generation Sequencing (NGS), have allowed aneuploidy to be detected with greater sensitivity. The application of this technique to trophectoderm biopsies, taken from embryos before transfer to the uterus, has provided insight into the clinical impact of chromosomal status. This process of screening embryos to make sure they have the right number of chromosomes and to look for any structural abnormalities in the chromosomes is called Preimplantation Genetic Testing for Aneuploidy (PGT-A). It requires specific equipment and trained personnel that will add costs and risks, so non-invasive techniques are sought as an alternative. These non-invasive procedures has been explored by some groups analyzing the spent culture medium where the embryo is incubated up to the time of transfer or freezing. In daily routine, this media is discarded after finishing the embryo culture, but it has been reported that contains traces of embryonic cell-free DNA (cfDNA) that can represent the genetic load of the embryo. However, at the moment there is a high variability in results across studies, with a percentage of concordant results between the media and the trophectoderm biopsy ranging from 3.5 to 85.7%.

Thus, the main objective of this project is to validate a new non-invasive method for PGT-A (niPGT-A), based on improved collection and analysis of the culture media to achieve higher rates of sensitivity and specificity and to decrease the effect of some intrinsic difficulties such as low embryonic cfDNA input, mosaicism and maternal contamination.

Condition or Disease Intervention/Treatment Phase
  • Diagnostic Test: PGT-A
  • Diagnostic Test: niPGT-A

Detailed Description

Human embryos have higher aneuploidy rates (20-80%) than other species. A considerable proportion of these aneuploid embryos have the ability to reach the blastocyst stage. However, depending on the aneuploidy type, some will fail to implant in the uterus, while others will implant but will be unable to carry out early embryonic development (miscarriage), or very rarely, result in liveborn children with specific abnormalities. It is therefore important to identify aneuploid embryos It is important to identify embryos at risk for aneuploid chromosomes in patients with advanced maternal age (AMA), recurrent implantation failure (RIF) or recurrent miscarriage (RM).

The identification of aneuploidies is especially important in embryos from patients with higher aneuploidy risk such as those with advanced maternal age (AMA), recurrent implantation failure (RIF), or recurrent miscarriage (RM). Therefore, normal embryo morphology and development are dependent on the chromosomal complement.

PGT-A technique analyse the full chromosome content of a single cell with high sensitivity and specificity but requires an invasive biopsy to obtain embryonic material for the genetic analysis. Thus, non-invasive methods to replace the existing invasive testing method would be useful in the improvement of maternal and fetal safety.

Recently, there have been many research advances in the field of genetic testing. Cell-free DNA (cfDNA) has been observed in spent embryo culture media. The origin of the cfDNA at the blastocyst stage could be attributed to apoptotic events which may occur during normal development. This has encouraged different research groups to carry out analysis spent culture media.

Various studies were initially carried out to detect specific genes associated with monogenic disorders (MTHFR9, HBA1/HBA210, SRY11). Recently, non-invasive PGT-A has been developed, with highly variable results on the concordance rate (3.5%,59.1%, and 85.7%, 30.6%). The chromosomal status of the embryo from the DNA present in the spent culture medium was compared to the one obtained following the standard protocol using trophectoderm biopsy. The difference in the reported results can be related to the different methodologies applied because different amplification and detection methods -aCGH or NGS- were used. Moreover, the concordance rates were defined differently on each study, i.e. aneuploid results in spent culture media and trophectoderm biopsy could be considered concordant despite of showing not the same aneuploid chromosomes.

The impact of culture conditions in the efficiency of the non-invasive approach has been investigated by Hammond et al, (2016). They found that there was consistently a very low level of DNA contamination (mitochondrial and nuclear DNA) in media controls, from three different types of commercial media, that had not been exposed to embryos. The low baseline level of DNA contamination observed is thought to originate from the protein supplement of the culture media.

Finally, there could be influence of two relevant factors on PGT-A: contamination with maternal DNA from granulosa cells (MCC) and mosaicism.

To improve the results of IVF (In vitro Fertilization) programs, there is a need to identify the embryo with highest implantation potential. Embryo chromosomal analysis allows the selection of euploid embryos, which have a higher implantation success rate.

The development of a non-invasive PGT-A protocol will improve the current methodologies used to identify those euploid embryos avoiding the detrimental effect of the biopsy on the embryo and decreasing the economic cost.

The initial estimated sample size calculated was 3245 embryos (each embryo is considered as a subject in the study), considering a dropout rate of 30%.

Data will be grouped and analyzed at Igenomix at three time points of the study: once 25 embryos of each center have been processed (to assess the implementation of the methodology), after the 30% of the samples have been processed (as an interim to check the results) and at the end of the study for the final analysis including the follow up of the clinical outcome.

After the interim analysis performed at 30% of recruitment, the total sample size has been recalculated as 2620 samples, considering a drop-out rate of 5% according to the drop-out rate observed during the interim analysis. Results of the interim analysis published in Rubio et al., AJOG 2020.

Study Design

Study Type:
Observational
Anticipated Enrollment :
2620 participants
Observational Model:
Other
Time Perspective:
Prospective
Official Title:
A Prospective, Observational, Multi-center, International Study to Validate a Non-invasive Preimplantation Genetic Test for Embryo Aneuploidy in the Spent Culture Media (niPGT-A).
Actual Study Start Date :
Apr 27, 2018
Anticipated Primary Completion Date :
Sep 1, 2021
Anticipated Study Completion Date :
Sep 1, 2021

Arms and Interventions

Arm Intervention/Treatment
Embryos undergoing PGT-A / niPGT-A

Embryos from IVF patients between 20 and 44 years of age, undergoing PGT-A for any medical indication, with own oocytes or ovum donation cycles and with single embryo transfer (SET)

Diagnostic Test: PGT-A
PGT-A will be carried out following the usual clinical practice: Trophectoderm biopsy samples from blastocysts are analyzed by NGS to screen for numerical chromosomal abnormalities.

Diagnostic Test: niPGT-A
Non-invasive preimplantation genetic test for embryo aneuploidy analyzing the spent culture media where the embryo is incubated up to the time of transfer or freezing. This media contains traces of embryonic cell-free DNA (cfDNA) that can represent the genetic load of the embryo.

Outcome Measures

Primary Outcome Measures

  1. Chromosomal status of the embryos [6 to 7 days of embryo development]

    Number and structure of the chromosomes

Secondary Outcome Measures

  1. Pregnancy rate [20 weeks]

    Number of pregnancies per embryo transfer

  2. Clinical miscarriage [20 weeks]

    Number of clinical miscarriages per total number of pregnancies

  3. POC (Products of Conception ) [Up to 20 weeks]

    Placental and/or fetal tissue that remains in the uterus after a spontaneous pregnancy loss

  4. Live birth rate [40 weeks]

    Number of babies born per embryo transfer

Eligibility Criteria

Criteria

Ages Eligible for Study:
20 Years to 44 Years
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • PGT-A cases with trophectoderm biopsy and SET for any medical indication and signed written informed consent form approved by the EC/IRB after having been duly informed of the nature of the research and voluntarily accepted to participate in the study.

  • ICSI (Intra Cytoplasmic Sperm Injection), IVF (In Vitro Fertilization) or ICSI/IVF performed in fresh oocytes from couples are allowed.

Note: Donor sperm is allowed.

  • Only fresh oocytes allowed.

  • Fresh and Deferred Embryo Transfer are allowed. Note: In case of Deferred Embryo Transfer, embryos must be vitrified always after the blastocyst biopsy.

  • Age: 20-44 years of age (both included).

Exclusion Criteria:
  • A known abnormal karyotype in a member of the couple.

  • Preimplantation Genetic Testing for Monogenic diseases (PGT-M) or Preimplantation Genetic Testing for Structural Rearrangements (PGT-SR) cases excluded.

Contacts and Locations

Locations

Site City State Country Postal Code
1 San Diego Fertility Center San Diego California United States 92130
2 Boston IVF Fertility Clinic Boston Massachusetts United States 02109
3 Dominion Fertility Arlington Washington United States 22203
4 Pregna Medicina Reproductiva Buenos Aires Argentina C1425DGQ
5 Nilo Frantz - Centro de Reprodução Humana Boa Vista Porto Alegre Brazil 91330-002
6 Genera Rome Rome Roma Italy 00197
7 NASCERE Mexico City Cdmx Mexico 05120
8 Inmater - Clínica de Fertilidad Lima Peru 15036
9 ProcreaTec Madrid Spain 28036
10 Bahçeci Group Istanbul Turkey 07720

Sponsors and Collaborators

  • Igenomix

Investigators

  • Principal Investigator: Carmen Rubio, BSc PhD, Igenomix
  • Study Chair: Carlos Simón, MD PhD, Igenomix

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Igenomix
ClinicalTrials.gov Identifier:
NCT03520933
Other Study ID Numbers:
  • IGX1-NIP-CS-18-02-SUB1
First Posted:
May 11, 2018
Last Update Posted:
Jan 19, 2021
Last Verified:
Jan 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Igenomix
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jan 19, 2021