Clinical trial NCT01946945: Comparison of Standard ART Practice vs. Trophectoderm Biopsy and Whole Chromosome Analysis
Official title: Comparison of Standard ART Practice vs. Trophectoderm Biopsy, Whole Chromosome Analysis by Next Generation Sequencing, and Replacement of a Single Euploid Embryo
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Infertility
Recurrent Pregnancy Loss
Keywords: infertility
recurrent pregnancy loss
miscarriage
Next Generation Sequencing
Lead sponsor: Reprogenetics
Sponsor class: INDUSTRY
Collaborators: name: Main Line Fertility Center
First posted: 2013-09-20
Enrollment: 240
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

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.

Detailed description: Patients following the inclusion criteria will be randomized into two groups:

1. Control group: All blastocyst embryos will be biopsied on day 5/6, but the biopsies will be frozen and will not be analyzed before replacement. Blastocyst embryos will be vitrified for future frozen embryo transfer (FET) cycle. Patients will have a single hatching blastocyst (\*) thawed and transferred into the uterus in a FET cycle based on standard embryo quality assessment without NGS. After transfer, all biopsied samples will be analyzed (the replaced embryo also, in order to do a non-selection study). If patients in the control group do not have a pregnancy to term from that FET cycle, euploid frozen blastocysts will be thawed and transferred on the next FET transfer.
2. Test group: All blastocyst embryos will be biopsied on day 5/6, and the biopsies will be analyzed using NGS. (\*) and Biopsied blastocyst embryos will be vitrified for a future frozen embryo transfer (FET) cycle. Patients will have a single hatching euploid blastocyst (\*) thawed and transferred into the uterus in a FET cycle

(\*) Hatching blastocysts as described by Gardner and Schoolcraft (1999)

The Primary efficacy endpoint of comparing the study group with the control will be ongoing implantation rate (# fetus reaching 2nd trimester / # embryos replaced).

All biopsied embryos from the test and control group will have their mitochondrial DNA analyzed, but that information will not be used for purposes of choosing embryos for replacement. Retrospectively but blindly (see blinding of results section), the information will be used at the end of the study to determine which embryos have a higher chance of implanting. If at that point the participating patients have remaining embryos frozen, they will be able to use that information for purposes of embryo selection.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

* 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

Primary outcomes:
measure: improvement in ongoing implantation rates
timeFrame: When a fetal heartbeat is detected for each patient. (8 weeks after implantation).
Secondary outcomes:
measure: Determine specificity and sensitivity rates
timeFrame: During a pregnancy term
Other outcomes:
measure: Correlation of Mitochondrial DNA and implantation
timeFrame: When a fetal heartbeat is detected (8 weeks after implantation)
Locations:
city: Livingston
country: United States
facility: Reprogenetics
state: New Jersey
Study officials:
affiliation: Reprogenetics
name: Santiago Munne, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
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citation: 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.