Comparison of Standard ART Practice vs. Trophectoderm Biopsy and Whole Chromosome Analysis

NCT01946945 | Unknown Phase 2 DMC

• 1 other identifier: Reprogenetics-3.109
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 1

Brief Summary

We propose to perform a clinical randomized trial to evaluate the effect of blastocyst biopsy and whole chromosome analysis by Next Generation Sequencing (NGS) in comparison to standard Assisted Reproductive Technologies (ART) methods on on implantation rates, miscarriage rates, and pregnancy rates. This will be three studies into one: a) a comparison of treatment (NGS) and no treatment, b) a non-selection study based on the control group for which we will replace without knowing the ploidy of the embryos, but we will know it later, c) a retrospective study about the use of Mitochondrial DNA as a selection tool.

Conditions

Infertility; Recurrent Pregnancy Loss

Keywords

infertility; recurrent pregnancy loss; miscarriage; Next Generation Sequencing

Outcome Measures

Primary Outcomes (1)

• improvement in ongoing implantation rates

  We foresee a significant increase in ongoing implantation rates in the Test group compared to the Control group based on several studies showing about a 50% improvement of implantation rates after Preimplantation Genetic Diagnosis (PGD) with blastocyst biopsy and comprehensive chromosome analysis techniques The center participating in the study has an average 41.5% implantation rate of blastocysts in patients 35-39 years of age without PGD. Assuming that NGS will increase the detection power of chromosome abnormalities, we expect a higher implantation rate in the test group. Furthermore, we expect a 6% miscarriage rate in the Test group, based on extensive data from array comparative genomic hybridization (aCGH) results (Hodes-Wertz et al. 2012), while about 21% in the Control group based on Society for Assisted Reproductive Technologies (SART) data (ages 35-40, SART 2011).

  When a fetal heartbeat is detected for each patient. (8 weeks after implantation).

Secondary Outcomes (1)

• Determine specificity and sensitivity rates

  During a pregnancy term

Other Outcomes (1)

• Correlation of Mitochondrial DNA and implantation

  When a fetal heartbeat is detected (8 weeks after implantation)

Study Arms (2)

Control - Standard ART treatment

NO INTERVENTION

Test - PGS

EXPERIMENTAL

All embryos will be hatched on day 3. Patients will have hatching blastocysts (\*) biopsied on day 5,/6. Embryos will be vitrified. Patients will have a single hatching euploid blastocyst (\*) replaced on a thawed cycle.

Genetic: Next Generation Sequencing after Blastocyst biopsy

Interventions

Next Generation Sequencing after Blastocyst biopsy GENETIC

PGD using blastocyst biopsy and testing of the biopsy by NGS

Also known as: PGD: Preimplantation Genetic Diagnosis

Test - PGS

Eligibility Criteria

• Age: 18 Years - 42 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• All patients medically cleared to do a fresh or frozen embryo transfer.
• Age up to 42 years

You may not qualify if:

• microsurgical epididymal sperm aspiration (MESA) and Testicular sperm extraction (TESE) patients
• At least one partner carrier of a chromosomal or genetic disease
• Abnormal ovarian reserve, defined as follicle stimulating hormone (FSH) of \>10 IU/L on day 2-4 of the cycle and anti-mullerian hormone (AMH) \< 1ng /ml (If only one of the two parameters altered then patients is acceptable). This is based on Mandy Katz abstract at American Society for Reproductive Medicine (ASRM) 2011 where they showed that these patients have 35% chance of having no euploid embryos - They are excluded only to make the study size smaller, otherwise, if an euploid embryo is found in these patients, they implant as well as patients with normal ovarian reserve. Not all centers do AMH testing - we recommend first to run FSH and only test AMH if FSH is abnormal.
• Egg donor cycle (sperm donor is acceptable)
• Gender selection cycles
• Thaw cycles

Sponsors & Collaborators

• Reprogenetics: lead
• Main Line Fertility Center: collaborator

Study Sites (1)

Reprogenetics

Livingston, New Jersey, 07039, United States

RECRUITING

Related Publications (18)

• Cohen J, Wells D, Munne S. Removal of 2 cells from cleavage stage embryos is likely to reduce the efficacy of chromosomal tests that are used to enhance implantation rates. Fertil Steril. 2007 Mar;87(3):496-503. doi: 10.1016/j.fertnstert.2006.07.1516. Epub 2006 Dec 4.

  PMID: 17141767 BACKGROUND

• De Vos A, Staessen C, De Rycke M, Verpoest W, Haentjens P, Devroey P, Liebaers I, Van de Velde H. Impact of cleavage-stage embryo biopsy in view of PGD on human blastocyst implantation: a prospective cohort of single embryo transfers. Hum Reprod. 2009 Dec;24(12):2988-96. doi: 10.1093/humrep/dep251. Epub 2009 Sep 21.

  PMID: 19773223 BACKGROUND

• Gutierrez-Mateo C, Colls P, Sanchez-Garcia J, Escudero T, Prates R, Ketterson K, Wells D, Munne S. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril. 2011 Mar 1;95(3):953-8. doi: 10.1016/j.fertnstert.2010.09.010. Epub 2010 Oct 25.

  PMID: 20971462 BACKGROUND

• Munne S, Wells D, Cohen J. Technology requirements for preimplantation genetic diagnosis to improve assisted reproduction outcomes. Fertil Steril. 2010 Jul;94(2):408-30. doi: 10.1016/j.fertnstert.2009.02.091. Epub 2009 May 5.

  PMID: 19409550 BACKGROUND

• Schoolcraft WB, Fragouli E, Stevens J, Munne S, Katz-Jaffe MG, Wells D. Clinical application of comprehensive chromosomal screening at the blastocyst stage. Fertil Steril. 2010 Oct;94(5):1700-6. doi: 10.1016/j.fertnstert.2009.10.015. Epub 2009 Nov 25.

  PMID: 19939370 BACKGROUND

• Ata B, Kaplan B, Danzer H, Glassner M, Opsahl M, Tan SL, Munne S. Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. Reprod Biomed Online. 2012 Jun;24(6):614-20. doi: 10.1016/j.rbmo.2012.02.009. Epub 2012 Feb 25.

  PMID: 22503277 BACKGROUND

• Cohen J, DeVane GW, Elsner CW, Kort HI, Massey JB, Norbury SE. Cryopreserved zygotes and embryos and endocrinologic factors in the replacement cycle. Fertil Steril. 1988 Jul;50(1):61-7. doi: 10.1016/s0015-0282(16)60009-2.

  PMID: 3384119 BACKGROUND

• Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, Treff NR, Scott RT Jr. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013 Jul;100(1):100-7.e1. doi: 10.1016/j.fertnstert.2013.02.056. Epub 2013 Mar 30.

  PMID: 23548942 BACKGROUND

• Fragouli E, Spath K, Alfarawati S, Wells D (2013) Quantification of mitochondrial DNA predicts the implantation potential of chromosomally normal embryos. Fertil Steril, in press (ASRM abstract)

  BACKGROUND

• Gardner DK and Schoolcraft WB. In vitro culture of human blastocysts. In: Jansen R, Mortimer D. eds. Towards Reproductive Certainty: Fertility and Genetics Beyond 1999. Carnforth, Parthenon Publishin, 1999, 378-88

  BACKGROUND

• Hodes-Wertz B, Grifo J, Ghadir S, Kaplan B, Laskin CA, Glassner M, Munne S. Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos. Fertil Steril. 2012 Sep;98(3):675-80. doi: 10.1016/j.fertnstert.2012.05.025. Epub 2012 Jun 7.

  PMID: 22683012 BACKGROUND

• SART (2011): https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0

  BACKGROUND

• Scott RT Jr, Ferry K, Su J, Tao X, Scott K, Treff NR. Comprehensive chromosome screening is highly predictive of the reproductive potential of human embryos: a prospective, blinded, nonselection study. Fertil Steril. 2012 Apr;97(4):870-5. doi: 10.1016/j.fertnstert.2012.01.104. Epub 2012 Feb 2.

  PMID: 22305103 BACKGROUND

• Treff NR, Su J, Tao X, Levy B, Scott RT Jr. Accurate single cell 24 chromosome aneuploidy screening using whole genome amplification and single nucleotide polymorphism microarrays. Fertil Steril. 2010 Nov;94(6):2017-21. doi: 10.1016/j.fertnstert.2010.01.052. Epub 2010 Feb 26.

  PMID: 20188357 BACKGROUND

• Treff NR, Ferry KM, Zhao T, Su J, Forman EJ, Scott RT (2011) Cleavage stage embryo biopsy significantly impairs embryonic reproductive potential while blasto- cyst biopsy does not: a novel paired analysis of cotransferred biopsied and non-biopsied sibling embryos. Fertil Steril, 96: Supplement, S2

  BACKGROUND

• Wells W, Kaur K, Fragouli E, Munné S (2013) Next generation sequencing. Reprod Biomed Online 26: Suppl 1, 55.

  BACKGROUND

• Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, Peck AC, Sills ES, Salem RD. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet. 2012 May 2;5(1):24. doi: 10.1186/1755-8166-5-24.

  PMID: 22551456 BACKGROUND

• Cornelisse S, Zagers M, Kostova E, Fleischer K, van Wely M, Mastenbroek S. Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation. Cochrane Database Syst Rev. 2020 Sep 8;9(9):CD005291. doi: 10.1002/14651858.CD005291.pub3.

  PMID: 32898291 DERIVED

MeSH Terms

Conditions

Infertility; Abortion, Spontaneous

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications

Study Officials

• Santiago Munne, PhD

  Reprogenetics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: SCREENING
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2013
• First Posted: September 20, 2013
• Study Start: September 1, 2013
• Primary Completion: December 1, 2014
• Last Updated: September 9, 2014

Record last verified: 2014-09

Locations

US (1)