AneuploidyNS-MOSAICISMNCT03673592
Clinical Value of Mosaicism Diagnosis on the Trophectoderm Biopsies
An observational study of Aneuploidy and Chromosome Abnormality, run by Igenomix at 3 sites in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 44 years, women only
- Conditions the study is for
- Aneuploidy, Chromosome Abnormality
- What is being tested?
- PGT-A
- How many people
- 783 participants
- Where
- 3 sitesItaly
- Study dates
- 3 Sep 2018to 20 May 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 44 years
- Women only
- No healthy volunteers
- Adult
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.
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
3 sites in 1 country.
Italy3 sites
Demetra
Florence, 50141
Genera
Roma, 00197
Humanitas Fertility Center
Roma
About this study
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)
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.
Read the 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.
- Conditions
- Aneuploidy, Chromosome Abnormality
- Being tested
- PGT-A
- Keywords
- Mosaicism, PGT-A, Blastocyst biopsy, Aneuploidy testing, Preimplantation genetics
- Medical subject headings
- Aneuploidy, Chromosome Aberrations
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PGT-ADiagnostic test
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.
| Study group | Role | What they receive |
|---|---|---|
| Euploid embryos analyzed by PGT-A | Embryos with a normal chromosome copy number. This embryos will be transferred to the uterus. Receives: Diagnostic Test: PGT-A | |
| Low-grade mosaic embryos (PGT-A) | Embryos with a lower aneuploidy percentage (<50%). This embryos will be considered for transfer to the uterus. Receives: Diagnostic Test: PGT-A | |
| High-grade mosaic embryos (PGT-A) | Embryos with a high aneuploidy percentage (50-70%). This embryos will be discarded for transfer. Receives: Diagnostic Test: PGT-A | |
| Aneuploid embryos analyzed by PGT-A | Embryos with an abnormal number of chromosomes. This embryos will be discarded for transfer. Receives: Diagnostic Test: PGT-A |
What is being measured
The primary outcome is the main question the study is designed to answer.
Sustained implantation rate
Presence of a viable pregnancy after 20 weeks of gestation measured by ultrasound scan
Measured: 20 weeks after the embryo transfer
Secondary outcomes (1)
Miscarriage rate
The spontaneous loss of an intra-uterine pregnancy prior to 20 completed weeks of gestational age.
Measured: 20 weeks after the embryo transfer
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Sep 2018
- Study start3 Sep 2018
- Primary completion31 Dec 2019
- Study completion20 May 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for AneuploidyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 783 participants (actual)
Sponsor and investigators
- Lead sponsor
- Igenomix
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Antonio Capalbo, BSc PhD, Principal investigator, Igenomix S.L.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03673592
- Sponsor's protocol ID
- IGX14-MOS-AC-18-03
- Acronym
- NS-MOSAICISM
- Status last verified
- Oct 2020
- First submitted
- 13 Sep 2018
- Last updated
- 19 Oct 2020
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Capalbo A, Poli M, Rienzi L, Girardi L, Patassini C, Fabiani M, Cimadomo D, Benini F, Farcomeni A, Cuzzi J, Rubio C, Albani E, Sacchi L, Vaiarelli A, Figliuzzi M, Findikli N, Coban O, Boynukalin FK, Vogel I, Hoffmann E, Livi C, Levi-Setti PE, Ubaldi FM, Simon C. Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial. Am J Hum Genet. 2021 Dec 2;108(12):2238-2247. doi: 10.1016/j.ajhg.2021.11.002. Epub 2021 Nov 18.
PubMed 34798051
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT03673592
- Acronym / sponsor ID
- NS-MOSAICISM / IGX14-MOS-AC-18-03
- Conditions
- Aneuploidy, Chromosome Abnormality
- Keywords
- Mosaicism, PGT-A, Blastocyst biopsy, Aneuploidy testing, Preimplantation genetics
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 783 participants (actual)
- Lead sponsor
- IgenomixIndustry (pharma, biotech, devices)
- Study start
- 3 Sep 2018 (actual)
- Primary completion
- 31 Dec 2019 (actual)
- Study completion
- 20 May 2020 (actual)
- First posted
- 17 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Euploid embryos analyzed by PGT-A | – | Diagnostic Test: PGT-AEmbryos with a normal chromosome copy number. This embryos will be transferred to the uterus. |
| Low-grade mosaic embryos (PGT-A) | – | Diagnostic Test: PGT-AEmbryos with a lower aneuploidy percentage (<50%). This embryos will be considered for transfer to the uterus. |
| High-grade mosaic embryos (PGT-A) | – | Diagnostic Test: PGT-AEmbryos with a high aneuploidy percentage (50-70%). This embryos will be discarded for transfer. |
| Aneuploid embryos analyzed by PGT-A | – | Diagnostic Test: PGT-AEmbryos with an abnormal number of chromosomes. This embryos will be discarded for transfer. |
Who may qualify
- Ages
- 18 to 44 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
- 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.
Key inclusion criteria (6 listed)
- 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).
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PGT-APGT-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 | Aneuploid embryos analyzed by PGT-A, Euploid embryos analyzed by PGT-A, High-grade mosaic embryos (PGT-A), Low-grade mosaic embryos (PGT-A) |
Primary outcome
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
1 secondary outcome
Miscarriage rate
Time frame: 20 weeks after the embryo transfer
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2020.
- Derived from this study: PubMed 34798051Capalbo A, Poli M, Rienzi L, Girardi L, Patassini C, Fabiani M, Cimadomo D, Benini F, Farcomeni A, Cuzzi J, Rubio C, Albani E, Sacchi L, Vaiarelli A, Figliuzzi M, Findikli N, Coban O, Boynukalin FK, Vogel I, Hoffmann E, Livi C, Levi-Setti PE, Ubaldi FM, Simon C. Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial. Am J Hum Genet. 2021 Dec 2;108(12):2238-2247. doi: 10.1016/j.ajhg.2021.11.002. Epub 2021 Nov 18.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Antonio Capalbo, BSc PhD principal investigator
Igenomix S.L.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Aneuploidy and Chromosome Abnormality, run by Igenomix at 3 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Sustained implantation rate (time frame: 20 weeks after the embryo transfer). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03673592, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2020.