Trial record 1 of 5 for: niPGT-A

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Multi-center Study to Validate niPGT-A (niPGT-A)

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ClinicalTrials.gov Identifier: NCT03520933

Recruitment Status : Unknown

Verified January 2021 by Igenomix.
Recruitment status was: Recruiting

First Posted : May 11, 2018

Last Update Posted : January 19, 2021

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Igenomix

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
Aneuploidy Chromosome Abnormality Infertility	Diagnostic Test: PGT-A Diagnostic Test: niPGT-A

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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

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Study Type :	Observational
Estimated 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 :	April 27, 2018
Estimated Primary Completion Date :	September 2021
Estimated Study Completion Date :	September 2021

Groups and Cohorts

Group/Cohort	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.

Group/Cohort

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 :

Chromosomal status of the embryos [ Time Frame: 6 to 7 days of embryo development ]
Number and structure of the chromosomes

Secondary Outcome Measures :

Pregnancy rate [ Time Frame: 20 weeks ]
Number of pregnancies per embryo transfer
Clinical miscarriage [ Time Frame: 20 weeks ]
Number of clinical miscarriages per total number of pregnancies
POC (Products of Conception ) [ Time Frame: Up to 20 weeks ]
Placental and/or fetal tissue that remains in the uterus after a spontaneous pregnancy loss
Live birth rate [ Time Frame: 40 weeks ]
Number of babies born per embryo transfer

Biospecimen Retention: Samples With DNA

Culture media: Embryonic cell-free DNA (cfDNA)
Trophectoderm biopsy
Full blastocysts

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:	20 Years to 44 Years (Adult)
Sexes Eligible for Study:	Female
Gender Based Eligibility:	Yes
Gender Eligibility Description:	IVF patients
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

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).

Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03520933

Contacts

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Contact: Carlos Gomez, BSc MSc	+34963905310	carlos.gomez@igenomix.com
Contact: Diana Valbuena, MD PhD	+34963905310	diana.valbuena@igenomix.com

Locations

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United States, California
San Diego Fertility Center	Recruiting
San Diego, California, United States, 92130
Contact: William Venier, MSC 858-794-6363 bvenier@sdfertility.com
United States, Massachusetts
Boston IVF Fertility Clinic	Recruiting
Boston, Massachusetts, United States, 02109
Contact: Denny Sakkas, MD PhD 888-300-2438 DSakkas@BOSTONIVF.com
United States, Washington
Dominion Fertility	Recruiting
Arlington, Washington, United States, 22203
Contact: Natilie Sofia, BSc RN 703-920-3890 natalie@dominionfertility.com
Contact: Michael Dimattina, MD PhD +1 703-920-3890 mikedima@mac.com
Argentina
Pregna Medicina Reproductiva	Recruiting
Buenos Aires, Argentina, C1425DGQ
Contact: Laura Kopcow, MD PhD (+54) 4831-5900 lkopcow@pregna.com.ar
Brazil
Nilo Frantz - Centro de Reprodução Humana	Recruiting
Boa Vista, Porto Alegre, Brazil, 91330-002
Contact: Nilo Frantz, MD + 55 51 3328 4680 nilo@nilofrantz.com.br
Contact: Marcos Iuri Roos Kulmann, BS +55 51 3328.4680 marcosiuri@nilofrantz.com.br
Italy
Genera Rome	Recruiting
Rome, Roma, Italy, 00197
Contact: Laura Rienzi, MD PhD (+39) 063269791 rienzi@generaroma.it
Mexico
NASCERE	Recruiting
Mexico City, Cdmx, Mexico, 05120
Contact: Lucia Daniela Garcia Montes, BS PhD (+52) 15554521311 lucia.daniela.garcia.montes@gmail.com
Contact: Gerardo Barroso, MD PhD (+52) 15554521311 barrosog@me.com
Principal Investigator: Gerardo Barroso, MD PhD
Peru
Inmater - Clínica de Fertilidad	Recruiting
Lima, Peru, 15036
Contact: Luis Ernesto Escudero Velando, MD, MSc 51 01 4762727 ernestoescudero@hotmail.com
Principal Investigator: Luis Ernesto Escudero Velando, MD, MSc
Spain
ProcreaTec	Recruiting
Madrid, Spain, 28036
Contact: Alexandra Izquierdo, MD PhD (+34) 914585804 alexandraizquierdo@procreatec.com
Turkey
Bahçeci Group	Recruiting
Istanbul, Turkey, 07720
Contact: Necati Findikli, BS MSc PhD (+90) 2123103100 nfindikli@bahceci.com
Contact: Mustafa Bahceci, MD PhD (+90) 2123103166 mbahceci@bahceci.com

Sponsors and Collaborators

Igenomix

Investigators

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

More Information

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Responsible Party:	Igenomix
ClinicalTrials.gov Identifier:	NCT03520933
Other Study ID Numbers:	IGX1-NIP-CS-18-02-SUB1
First Posted:	May 11, 2018 Key Record Dates
Last Update Posted:	January 19, 2021
Last Verified:	January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Igenomix:


Embryo Blastocyst Non-invasive PGT-A	Chromosome Aneuploidy Spent culture medium Trophectoderm biopsy

Additional relevant MeSH terms:

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Infertility Chromosome Disorders Aneuploidy Chromosome Aberrations	Congenital Abnormalities Pathologic Processes Genetic Diseases, Inborn

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