Prospective International Multi-center Clinical Trial of PGT-A Upgrade

Official title

Efficacy of PGT-A Upgrade in Preimplantation Genetic Testing of Embryos: An International Multicenter Prospective Clinical Study

Overview

The goals of this international multicenter cross-sectional study are: 1. To provide patients with a comprehensive PGT solution capable of simultaneously detecting embryonic chromosomal aneuploidy, mosaicism, microdeletions/ microduplications, heteroploidy, and heterozygosity (LOH) in a single assay, thereby reducing miscarriage and birth defects; 2. To perform PGT analysis on abnormally fertilized embryos, select euploid embryos with normal ploidy, and calculate embryo utilization rates; 3. To reduce the false-positive rate through confirmation of mosaic embryos and subsequent analysis of its origin, thereby minimizing embryo wastage; 4. To provide molecular genetic evidence for expert consensus on clinical management of atypically fertilized embryos, of pathogenic/likely pathogenic small CNVs, optimize mosaic embryo transfer strategies, and inform preconception intervention; 5. To enhance international PGT testing standards through international multi-center collaboration. The study will enroll patients undergoing PGT-A from seven domestic and international centers, with patient enrollment expected to be completed within one year. PGT-A upgrade testing will be performed on embryos from enrolled patients, and the incidence rates of Incidence of microdeletions/microduplications, heteroploidy, LOH will be statistically analyzed. All patients who undergo embryo transfer will be followed up for clinical outcomes and birth defects.

Detailed description

The study will enroll 6,694 embryos derived from typical fertilization (2PN) that meet the inclusion and exclusion criteria in patients undergoing PGT-A, as well as all embryos derived from atypical fertilization (0PN/1PN/3PN). In contrast to conventional PGT-A testing, PGT-A upgrade testing will be performed on the embryos to comprehensively analyze multiple embryonic abnormalities in a single detection, including aneuploidy, mosaicism, microdeletion/microduplication, heteroploidy, and loss of heterozygosity (LOH), and to calculate their respective incidence rates.

In addition to embryos derived from 2PN, embryos from 0PN/1PN/3PN will also be cultured to the blastocyst stage for trophectoderm (TE) cell biopsy. Euploid embryos identified by PGT-A upgrade testing will be recorded, and the utilization rate of atypically fertilized embryos will be evaluated.

For mosaic embryos, a previously established parental haplotype origin algorithm will be applied to distinguish true versus false mosaicism and identify the origin of abnormalities, thereby recognizing "false-positive" mosaic embryos and further increasing the number of transferable embryos.

Patients will receive euploid embryo transfer (from 2PN) in accordance with routine clinical practice. In cases where no 2PN-derived euploid embryos are available, transfer of 0PN/1PN/3PN-derived euploid embryos and embryos classified as "false-positive" mosaic may be considered after the patient has been fully informed of the risks and provided informed consent.

All transfer cycles will be followed up for prenatal diagnosis results and birth defects. The primary outcome measures are the incidence rates of microdeletion/microduplication, heteroploidy, and LOH. The secondary outcome measures include embryo utilization rate, clinical pregnancy rate, ongoing pregnancy rate, live birth rate, miscarriage rate, concordance rate between prenatal diagnosis results and PGT-A results, and birth defect rate.

The maximum follow-up duration will be 1 year after embryo transfer. Clinical and embryology laboratory procedures during the study will not be altered and will be performed in accordance with each center's routine practice.

Interventions

• Other PGT-A upgrade
  A comprehensive PGT solution capable of simultaneously detecting embryonic chromosomal aneuploidy, mosaicism, microdeletions/ microduplications, heteroploidy, and LOH in a single assay.

Primary outcome measures

• Incidence of microdeletions/microduplications [Time frame: Two months after oocyte retrieval]
• Incidence of heteroploidy [Time frame: Two months after oocyte retrieval]
• Incidence of loss of heterozygosity [Time frame: Two months after oocyte retrieval]

Secondary outcome measures (7)

• Transferable embryo rate [Time frame: Two months after oocyte retrieval]
• Clinical pregnancy rate [Time frame: 28-30 days after embryo transfer]
• Ongoing pregnancy rate [Time frame: 12 weeks after the embryo transfer]
• Live birth rate [Time frame: Two weeks after the newborn's birth]
• Early miscarriage rate [Time frame: 12 weeks of after the embryo transfer]
• Concordance between prenatal diagnosis results and PGT-A results [Time frame: 16-24 weeks of gestation]
• Birth defect rate [Time frame: At 1 year postpartum]

Eligibility criteria

Inclusion criteria

(1) Any one of the following conditions being met is sufficient:

• advanced maternal age (AMA, age ≥35 years),
• recurrent implantation failure (RIF),
• recurrent miscarriage (RM),
• severe male factor (SMF). (2) And at least one blastocyst is available.

Exclusion criteria

• Couples undergoing PGT-SR due to chromosomal structural abnormalities carried by either one or both members, such as balanced translocations, Robertsonian translocations, inversions, complex chromosomal rearrangements, and pathogenic microdeletions or microduplications;
• Couples undergoing PGT-M;
• Conditions with established impact on uterine morphology or endometrial receptivity, including untreated uterine malformations (septate uterus, unicornuate uterus, didelphic uterus, etc.) and untreated hydrosalpinx;
• Embryos coming from oocyte or sperm (gametes) donation;
• Individuals with contraindications to pregnancy or assisted reproduction technology.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Other

Study locations

China · 3 centers

• CITIC-Xiangya Reproductive & Genetic Hospital — Changsha
• Nanjing Women and Children's Healthcare Hospital — Nanjing
• First People's Hospital of Yunnan Province — Kunming

Argentina · 1 center

• Biocódices — Buenos Aires

Malaysia · 1 center

• Thomson Hospital — Petaling Jaya

South Korea · 1 center

• Miracle — Daegu

Spain · 1 center

• Institute Bernabéu — Alicante

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. 20 PMID 34798051
• Capalbo A, Cimadomo D, Coticchio G, Ottolini CS. An expert opinion on rescuing atypically pronucleated human zygotes by molecular genetic fertilization checks in IVF. Hum Reprod. 2024 Sep 1;39(9):1869-1878. doi: 10.1093/humrep/deae157. PMID 39043217
• Zhang J, Mu F, Guo Z, Cai Z, Zeng X, Du L, Wang F. Chromosome analysis of foetal tissue from 1903 spontaneous abortion patients in 5 regions of China: a retrospective multicentre study. BMC Pregnancy Childbirth. 2023 Nov 25;23(1):818. doi: 10.1186/s12884-023-06108-0. PMID 38007414
• Fan Y, Li R, Huang J, Yu Y, Qiao J. Diploid, but not haploid, human embryonic stem cells can be derived from microsurgically repaired tripronuclear human zygotes. Cell Cycle. 2013 Jan 15;12(2):302-11. doi: 10.4161/cc.23103. Epub 2012 Jan 15. PMID 23255130
• Huan Q, Gao X, Wang Y, Shen Y, Ma W, Chen ZJ. Comparative evaluation of human embryonic stem cell lines derived from zygotes with normal and abnormal pronuclei. Dev Dyn. 2010 Feb;239(2):425-38. doi: 10.1002/dvdy.22175. PMID 19941346
• Canon C, Thurman A, Li A, Hernandez-Nieto C, Lee JA, Roth RM, Slifkin R, Briton-Jones C, Stein D, Copperman AB. Assessing the clinical viability of micro 3 pronuclei zygotes. J Assist Reprod Genet. 2023 Jul;40(7):1765-1772. doi: 10.1007/s10815-023-02830-y. Epub 2023 May 25. PMID 37227570
• Destouni A, Dimitriadou E, Masset H, Debrock S, Melotte C, Van Den Bogaert K, Zamani Esteki M, Ding J, Voet T, Denayer E, de Ravel T, Legius E, Meuleman C, Peeraer K, Vermeesch JR. Genome-wide haplotyping embryos developing from 0PN and 1PN zygotes increases transferrable embryos in PGT-M. Hum Reprod. 2018 Dec 1;33(12):2302-2311. doi: 10.1093/humrep/dey325. PMID 30383227
• Yao G, Xu J, Xin Z, Niu W, Shi S, Jin H, Song W, Wang E, Yang Q, Chen L, Sun Y. Developmental potential of clinically discarded human embryos and associated chromosomal analysis. Sci Rep. 2016 Apr 5;6:23995. doi: 10.1038/srep23995. PMID 27045374

Identifiers

NCT: NCT07533630 · LL-SC-2026-003-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗