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Clinical Value of Mosaicism Diagnosis on the Trophectoderm Biopsies (NS-MOSAICISM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03673592
Recruitment Status : Completed
First Posted : September 17, 2018
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
Igenomix

Brief Summary:

Mosaicism within an embryo is defined as the presence of two or more cell populations with different genotypes. Blastocysts classified as mosaic by Preimplamtation Genetic Testing for Aneuploidy (PGT-A) have been reported to implant less and miscarry more frequently than embryos classified as euploid. Because of the unknown impact of mosaicism on embryo development, these embryos are given low priority and are discarded for transfer. However, recent papers on the transfer of human embryos classified by PGT-A as mosaic suggest that embryos with a low fraction of abnormal cells resulting in viable, chromosomally normal ongoing pregnancies, and high-level mosaics resulting in fewer viable pregnancies, but so far none producing mosaic babies.

The apparent presence of mosaicism in an embryo is used as a selection criteria for embryo transfer (ET), introducing a strong bias in terms of patient prognosis and embryo quality. Additionally, it is also possible that some embryos are incorrectly classified as "mosaic" due to technical variability derived from the processing of a uniform aneuploid embryo.

The aims of this study is to provide evidences about the clinical significance of chromosomal mosaicism in PGT-A cycles by a prospective non-selection based methodology.


Condition or disease Intervention/treatment
Aneuploidy Chromosome Abnormality Diagnostic Test: PGT-A

Detailed Description:

One of the most common reasons why in vitro fertilization (IVF) is unsuccessful, or why miscarriages occur, is because of chromosomal abnormalities in the embryo. Embryos with less than 20% aneuploidy are considered as euploid, while those between 20-80% are reported as mosaic, and those over 80% as aneuploid. Embryos with the correct number of chromosomes (euploid) have a higher chance of leading to a successful pregnancy than those with the incorrect number of chromosomes (aneuploid) or mosaics.

Mosaicism within an embryo is defined as the presence of two or more cell populations with different genotypes. Preliminary data suggested that embryos identified as mosaic by Preimplamtation Genetic Testing for Aneuploidy (PGT-A) may have a reduced chance of implantation compared with euploid and may play a significant role in pregnancy loss.

Because of the unknown impact of mosaicism on embryo development, these embryos are given low priority and are discarded for transfer. They are transferred mostly in poor prognosis patients, explaining the reported lower clinical performances. However, other recent data regarding the transfer of embryos diagnosed as mosaic has shown that embryos with a low fraction of abnormal cells may result in viable, chromosomally normal ongoing pregnancies.

The apparent presence of mosaicism in an embryo is used as a selection criteria for embryo transfer (ET), introducing a strong bias in terms of patient prognosis and embryo quality. Additionally, it is also possible that some embryos are incorrectly classified as mosaic due to technical variability derived from the processing of a uniform aneuploid embryo. Thus, there is an urgent need to understand how to appropriately select and counsel patients regarding such embryos.

This study aims to provide evidences about the clinical significance of chromosomal mosaicism in PGT-A cycles by a prospective non-selection based methodology.

The objectives are to investigate the clinical predictive value for intermediate copy number results consistent with the presence of low mosaicism in TE biopsies, and to validate the thresholds for the classification of embryos in relation with their reproductive potential, providing comprehensive data for clinicians and patients. To demonstrate these objectives, a total of 878 participants are expected to be recruited in 18 months. As the datapoints required for comparison concern embryo transfers rather than participants, this number could be lower depending on the number of embryo transfers received by each participant.

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Study Type : Observational
Actual Enrollment : 783 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Prospective Non-selection Study to Investigate the Clinical Predictive Value of Chromosome Copy Number Values Consistent With the Presence of Mosaicism Within the Trophectoderm Biopsy (NON-SELECTION MOSAICISM)
Actual Study Start Date : September 3, 2018
Actual Primary Completion Date : December 31, 2019
Actual Study Completion Date : May 20, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Biopsy

Group/Cohort Intervention/treatment
Euploid embryos analyzed by PGT-A
Embryos with a normal chromosome copy number. This embryos will be transferred to the uterus.
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.

Low-grade mosaic embryos (PGT-A)
Embryos with a lower aneuploidy percentage (<50%). This embryos will be considered for transfer to the uterus.
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.

High-grade mosaic embryos (PGT-A)
Embryos with a high aneuploidy percentage (50-70%). This embryos will be discarded for transfer.
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.

Aneuploid embryos analyzed by PGT-A
Embryos with an abnormal number of chromosomes. This embryos will be discarded for transfer.
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.




Primary Outcome Measures :
  1. Sustained implantation rate [ Time Frame: 20 weeks after the embryo transfer ]
    Presence of a viable pregnancy after 20 weeks of gestation measured by ultrasound scan


Secondary Outcome Measures :
  1. Miscarriage rate [ Time Frame: 20 weeks after the embryo transfer ]
    The spontaneous loss of an intra-uterine pregnancy prior to 20 completed weeks of gestational age.


Biospecimen Retention:   Samples With DNA
DNA analysis of each patient's embryos


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:   18 Years to 44 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Embryos from IVF patients up to 44 years of age (also included) undergoing PGT-A.
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Embryos from In Vitro Fertilization (IVF) patients up to 44 years old (also included) with medical indication of PGT-A and own oocytes.
Criteria

Inclusion Criteria:

  • PGT-A cases for any medical indication and sign the written informed consent form approved by the Ethics Committee (EC) after having been duly informed of the nature of the research and voluntarily accepted to participate in the study.
  • Only PGT-A cycles with own oocytes.
  • Female age up to 44 years old (also included).
  • ICSI treatment must be done in all oocytes.
  • Have at least one euploid blastocyst or one low-grade mosaicism diagnosis for a single chromosome after PGT-A analysis (excluding aneuploidies compatible with life, e.g. chromosomes 13, 18, 21 and X/Y).
  • Single or Double Embryo Transfer (SET or DET). The patient remains included in the study until the 4th ET (fresh or frozen) from the initial stimulation cycle or until patient's enrolment period ends (whichever comes first). The data collected until one of these points will be included in the study, whilst clinical outcomes from additional ET will be disregarded.

Exclusion Criteria:

  • No embryo reaching blastocyst stage with a proper morphology for trophectoderm biopsy.
  • Embryo transfer coming from the worst grade blastocyst morphology according to Gardner's criteria (Annex 1) will be excluded.
  • DET resulting in singletons. (Note: DET resulting in dizygotic twins or implantation failure to the both embryos transferred will be allowed).
  • Any illness or medical condition that is unstable or can put patient safety at risk and compliance in the study.

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): NCT03673592


Locations
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Italy
Demetra
Florence, Italy, 50141
Genera
Roma, Italy, 00197
Humanitas Fertility Center
Roma, Italy
Sponsors and Collaborators
Igenomix
Investigators
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Principal Investigator: Antonio Capalbo, BSc PhD Igenomix S.L.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Igenomix
ClinicalTrials.gov Identifier: NCT03673592    
Other Study ID Numbers: IGX14-MOS-AC-18-03
First Posted: September 17, 2018    Key Record Dates
Last Update Posted: October 19, 2020
Last Verified: October 2020
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:
Mosaicism
PGT-A
Blastocyst biopsy
Aneuploidy testing
Preimplantation genetics
Additional relevant MeSH terms:
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Chromosome Disorders
Aneuploidy
Chromosome Aberrations
Congenital Abnormalities
Pathologic Processes
Genetic Diseases, Inborn