Clinical Application of Non-invasive PGT-A

• ClinicalTrials.gov Identifier: NCT04856696
• Recruitment Status: Unknown
• First Posted: April 23, 2021
• Last Update Posted: March 9, 2022
• Sponsor: Kaohsiung Veterans General Hospital.
• Collaborator: Sofiva Genomics Co., Ltd.
• Information provided by (Responsible Party): Li-Te Lin, Kaohsiung Veterans General Hospital.

Tracking Information

• First Submitted Date: April 19, 2021
• First Posted Date: April 23, 2021
• Last Update Posted Date: March 9, 2022
• Actual Study Start Date: March 24, 2021
• Estimated Primary Completion Date: December 31, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 22, 2021)

Ongoing pregnancy rate [ Time Frame: through study completion, an average of 1.5 year ]

continuous presence of a fetal heartbeat over 12 weeks of a pregnancy

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 22, 2021)

• Clinical pregnancy rate [ Time Frame: through study completion, an average of 1.5 year ]
  the presence of a fetal heartbeat at 6-7 weeks of a pregnancy
• Miscarriage rate [ Time Frame: through study completion, an average of 1.5 year ]
  pregnancy loss before 24 weeks of gestation

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Clinical Application of Non-invasive PGT-A
• Official Title: Clinical Application of Non-invasive Preimplantation Genetic Testing for Aneuploidies
• Brief Summary: The study aims to investigate the difference of in vitro fertilization (IVF) outcomes among non-invasive PGT-A, PGT-A and combined non-invasive PGT-A and PGT-A.

Detailed Description

Background Chromosome abnormality is a leading cause of implantation failure and miscarriage. Chromosome abnormality increases with age, resulting in reduced pregnancy rate. Nowadays, preimplantation genetic testing for aneuploidies (PGT-A) could be used for detection of aneuploidy. However, PGT-A needs embryo biopsy which is invasive and may cause embryo damage. It was found that cell free DNA could be isolated from culture media. The cell free DNA from culture media also could be used to detect embryo ploidy, called non-invasive PGT-A.

Objective The study aims to investigate the difference of in vitro fertilization (IVF) outcomes among non-invasive PGT-A, PGT-A and combined non-invasive PGT-A and PGT-A. Another aim of this study is to check the concordance rate between non-invasive PGT-A and PGT-A.

Methods The prospective cohort study will be performed at the reproductive medical center of Kaohsiung Veterans General Hospital, in Kaohsiung, Taiwan. Participants who plan to receive an IVF cycle and preimplantation genetic testing for aneuploidies will be enrolled in this study. The investigators will divide the participants into 3 groups: (1) combined non-invasive PGT-A and PGT-A; (2) PGT-A; (3) non-invasive PGT-A. Basal characteristics, infertility history, ovarian reserve and embryo development of the three groups will be recorded. The samples will be detected ploidy by using next generation sequencing (NGS). Then, the investigators will choose embryo to transfer according to the embryo ploidy and follow the pregnancy outcomes after embryo transfer.

Outcome

1. Concordance rate between non-invasive PGT-A and PGT-A
2. The relationship between morphological grade and ploidy of non-invasive PGT-A
3. IVF outcomes among non-invasive PGT-A, PGT-A and combined non-invasive PGT-A and PGT-A

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Screening
• Condition: Genetic Testing

Intervention

• Diagnostic Test: PGT-A
  trophectoderm biopsy in blastocyst stage for euploidy testing using next generation sequencing platform
• Diagnostic Test: non-invasive PGT-A
  cell-free DNA collected from spent culture media for euploidy testing using next generation sequencing platform

Study Arms

• Experimental: combined non-invasive PGT-A & PGT-A
  Infertility women who underwent both non-invasive PGT-A and PGT-A
  Interventions:

  • Diagnostic Test: PGT-A
  • Diagnostic Test: non-invasive PGT-A
• Experimental: non-invasive PGT-A
  Infertility women who underwent non-invasive PGT-A only
  Intervention: Diagnostic Test: non-invasive PGT-A
• Active Comparator: PGT-A
  Infertility women who underwent PGT-A only
  Intervention: Diagnostic Test: PGT-A

Publications *

• Fesahat F, Montazeri F, Hoseini SM. Preimplantation genetic testing in assisted reproduction technology. J Gynecol Obstet Hum Reprod. 2020 May;49(5):101723. doi: 10.1016/j.jogoh.2020.101723. Epub 2020 Feb 26.
• Sciorio R, Dattilo M. PGT-A preimplantation genetic testing for aneuploidies and embryo selection in routine ART cycles: Time to step back? Clin Genet. 2020 Aug;98(2):107-115. doi: 10.1111/cge.13732. Epub 2020 Apr 6.
• Homer HA. Preimplantation genetic testing for aneuploidy (PGT-A): The biology, the technology and the clinical outcomes. Aust N Z J Obstet Gynaecol. 2019 Apr;59(2):317-324. doi: 10.1111/ajo.12960. Epub 2019 Feb 27.
• Fragouli E, Munne S, Wells D. The cytogenetic constitution of human blastocysts: insights from comprehensive chromosome screening strategies. Hum Reprod Update. 2019 Jan 1;25(1):15-33. doi: 10.1093/humupd/dmy036.
• Sullivan-Pyke C, Dokras A. Preimplantation Genetic Screening and Preimplantation Genetic Diagnosis. Obstet Gynecol Clin North Am. 2018 Mar;45(1):113-125. doi: 10.1016/j.ogc.2017.10.009.
• Rubio C, Navarro-Sanchez L, Garcia-Pascual CM, Ocali O, Cimadomo D, Venier W, Barroso G, Kopcow L, Bahceci M, Kulmann MIR, Lopez L, De la Fuente E, Navarro R, Valbuena D, Sakkas D, Rienzi L, Simon C. Multicenter prospective study of concordance between embryonic cell-free DNA and trophectoderm biopsies from 1301 human blastocysts. Am J Obstet Gynecol. 2020 Nov;223(5):751.e1-751.e13. doi: 10.1016/j.ajog.2020.04.035. Epub 2020 May 26.
• Rubio C, Rienzi L, Navarro-Sanchez L, Cimadomo D, Garcia-Pascual CM, Albricci L, Soscia D, Valbuena D, Capalbo A, Ubaldi F, Simon C. Embryonic cell-free DNA versus trophectoderm biopsy for aneuploidy testing: concordance rate and clinical implications. Fertil Steril. 2019 Sep;112(3):510-519. doi: 10.1016/j.fertnstert.2019.04.038. Epub 2019 Jun 11.
• Leaver M, Wells D. Non-invasive preimplantation genetic testing (niPGT): the next revolution in reproductive genetics? Hum Reprod Update. 2020 Jan 1;26(1):16-42. doi: 10.1093/humupd/dmz033.
• Kuznyetsov V, Madjunkova S, Abramov R, Antes R, Ibarrientos Z, Motamedi G, Zaman A, Kuznyetsova I, Librach CL. Minimally Invasive Cell-Free Human Embryo Aneuploidy Testing (miPGT-A) Utilizing Combined Spent Embryo Culture Medium and Blastocoel Fluid -Towards Development of a Clinical Assay. Sci Rep. 2020 Apr 29;10(1):7244. doi: 10.1038/s41598-020-64335-3.
• Liang B, Gao Y, Xu J, Song Y, Xuan L, Shi T, Wang N, Hou Z, Zhao YL, Huang WE, Chen ZJ. Raman profiling of embryo culture medium to identify aneuploid and euploid embryos. Fertil Steril. 2019 Apr;111(4):753-762.e1. doi: 10.1016/j.fertnstert.2018.11.036. Epub 2019 Jan 22.
• Jiao J, Shi B, Sagnelli M, Yang D, Yao Y, Li W, Shao L, Lu S, Li D, Wang X. Minimally invasive preimplantation genetic testing using blastocyst culture medium. Hum Reprod. 2019 Jul 8;34(7):1369-1379. doi: 10.1093/humrep/dez075.
• Huang L, Bogale B, Tang Y, Lu S, Xie XS, Racowsky C. Noninvasive preimplantation genetic testing for aneuploidy in spent medium may be more reliable than trophectoderm biopsy. Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14105-14112. doi: 10.1073/pnas.1907472116. Epub 2019 Jun 24.
• Fang R, Yang W, Zhao X, Xiong F, Guo C, Xiao J, Chen L, Song X, Wang H, Chen J, Xiao X, Yao B, Cai LY. Chromosome screening using culture medium of embryos fertilised in vitro: a pilot clinical study. J Transl Med. 2019 Mar 8;17(1):73. doi: 10.1186/s12967-019-1827-1.
• Vera-Rodriguez M, Diez-Juan A, Jimenez-Almazan J, Martinez S, Navarro R, Peinado V, Mercader A, Meseguer M, Blesa D, Moreno I, Valbuena D, Rubio C, Simon C. Origin and composition of cell-free DNA in spent medium from human embryo culture during preimplantation development. Hum Reprod. 2018 Apr 1;33(4):745-756. doi: 10.1093/humrep/dey028.
• Belandres D, Shamonki M, Arrach N. Current status of spent embryo media research for preimplantation genetic testing. J Assist Reprod Genet. 2019 May;36(5):819-826. doi: 10.1007/s10815-019-01437-6. Epub 2019 Mar 21.
• Farra C, Choucair F, Awwad J. Non-invasive pre-implantation genetic testing of human embryos: an emerging concept. Hum Reprod. 2018 Dec 1;33(12):2162-2167. doi: 10.1093/humrep/dey314. Erratum In: Hum Reprod. 2019 Mar 1;34(3):590.
• Xu J, Fang R, Chen L, Chen D, Xiao JP, Yang W, Wang H, Song X, Ma T, Bo S, Shi C, Ren J, Huang L, Cai LY, Yao B, Xie XS, Lu S. Noninvasive chromosome screening of human embryos by genome sequencing of embryo culture medium for in vitro fertilization. Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11907-11912. doi: 10.1073/pnas.1613294113. Epub 2016 Sep 29.
• Shamonki MI, Jin H, Haimowitz Z, Liu L. Proof of concept: preimplantation genetic screening without embryo biopsy through analysis of cell-free DNA in spent embryo culture media. Fertil Steril. 2016 Nov;106(6):1312-1318. doi: 10.1016/j.fertnstert.2016.07.1112. Epub 2016 Aug 24.
• Youssef MM, Mantikou E, van Wely M, Van der Veen F, Al-Inany HG, Repping S, Mastenbroek S. Culture media for human pre-implantation embryos in assisted reproductive technology cycles. Cochrane Database Syst Rev. 2015 Nov 20;2015(11):CD007876. doi: 10.1002/14651858.CD007876.pub2.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: April 22, 2021): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 30, 2023
• Estimated Primary Completion Date: December 31, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Infertile women who undergo IVF with PGT
• BMI:18~30 kg/m2

Exclusion Criteria:

• Primary ovarian insufficiency
• Congenital uterine anomaly
• Severe male infertility (azoospermia)
• One of the couples with chromosome abnormality
• Malignancy

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 30 Years to 44 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Taiwan

Administrative Information

• NCT Number: NCT04856696
• Other Study ID Numbers: KSVGH20-CT12-16
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Li-Te Lin, Kaohsiung Veterans General Hospital.
• Original Responsible Party: Same as current
• Current Study Sponsor: Kaohsiung Veterans General Hospital.
• Original Study Sponsor: Same as current
• Collaborators: Sofiva Genomics Co., Ltd.

Investigators

• Study Director: Kuan-Hao Tsui; Kaohsiung Veterans General Hospital.

• PRS Account: Kaohsiung Veterans General Hospital.
• Verification Date: March 2022