Clinical Value of Mosaicism Diagnosis on the Trophectoderm Biopsies

Brief Title

Clinical Value of Mosaicism Diagnosis on the Trophectoderm Biopsies

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)

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.
    

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.
    


Study Type

Observational


Primary Outcome

Sustained implantation rate

Secondary Outcome

 Miscarriage rate

Condition

Aneuploidy

Intervention

PGT-A

Study Arms / Comparison Groups

 Euploid embryos analyzed by PGT-A
Description:  Embryos with a normal chromosome copy number. This embryos will be transferred to the uterus.

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

783

Start Date

September 3, 2018

Completion Date

May 20, 2020

Primary Completion Date

December 31, 2019

Eligibility 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.
      

Gender

Female

Ages

18 Years - 44 Years

Accepts Healthy Volunteers

No

Contacts

Antonio Capalbo, BSc PhD, , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT03673592

Organization ID

IGX14-MOS-AC-18-03


Responsible Party

Sponsor

Study Sponsor

Igenomix


Study Sponsor

Antonio Capalbo, BSc PhD, Principal Investigator, Igenomix S.L.


Verification Date

October 2020