Comparison of Standard ART Practice vs. Trophectoderm Biopsy and Whole Chromosome Analysis
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.
Recurrent Pregnancy Loss
Genetic: Next Generation Sequencing after Blastocyst biopsy
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Screening
|Official Title:||Comparison of Standard ART Practice vs. Trophectoderm Biopsy, Whole Chromosome Analysis by Next Generation Sequencing, and Replacement of a Single Euploid Embryo|
- improvement in ongoing implantation rates [ Time Frame: When a fetal heartbeat is detected for each patient. (8 weeks after implantation). ] [ Designated as safety issue: No ]
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).
- Determine specificity and sensitivity rates [ Time Frame: During a pregnancy term ] [ Designated as safety issue: No ]The pregnancy outcome of Controls patients with euploid embryos replaced will be compared to that of control patients with aneuploid embryos replaced. This will give us the specificity of the test (false positive rate) by obtaining the ongoing pregnancy rate of cycles with aneuploid embryos replaced, and the sensitivity of the test (false negative rate) by obtaining the miscarriage rate and ongoing pregnancy rate of cycles with euploid embryos replaced.
- Correlation of Mitochondrial DNA and implantation [ Time Frame: When a fetal heartbeat is detected (8 weeks after implantation) ] [ Designated as safety issue: No ]The third aim of this study is to determine retrospectively if mt DNA content is linked to implantation potential and if that is measurable by NGS. NGS provides the additional advantage that it can measure mitochondrial DNA, which it's content, seems to be inversely correlated with implantation (Fragouli et al 2013, ASRM).
|Study Start Date:||September 2013|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
|No Intervention: Control - Standard ART treatment|
Experimental: Test - PGS
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
PGD using blastocyst biopsy and testing of the biopsy by NGS
Other Name: PGD: Preimplantation Genetic Diagnosis
Patients following the inclusion criteria will be randomized into two groups:
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01946945
|United States, New Jersey|
|Livingston, New Jersey, United States, 07039|
|Contact: Allen Kung, BSc 973-758-7970 email@example.com|
|Principal Investigator: Santiago Munne, Ph.D|
|Study Director:||Santiago Munne, PhD||Reprogenetics|