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

September 8, 2014 updated by: Reprogenetics

Comparison of Standard ART Practice vs. Trophectoderm Biopsy, Whole Chromosome Analysis by Next Generation Sequencing, and Replacement of a Single Euploid Embryo

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

240

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New Jersey
      • Livingston, New Jersey, United States, 07039
        • Recruiting
        • Reprogenetics
        • Contact:
        • Principal Investigator:
          • Santiago Munne, Ph.D

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 42 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: SCREENING
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • PGD: Preimplantation Genetic Diagnosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
improvement in ongoing implantation rates
Time Frame: When a fetal heartbeat is detected for each patient. (8 weeks after implantation).

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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Determine specificity and sensitivity rates
Time Frame: During a pregnancy term
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.
During a pregnancy term

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation of Mitochondrial DNA and implantation
Time Frame: When a fetal heartbeat is detected (8 weeks after implantation)
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).
When a fetal heartbeat is detected (8 weeks after implantation)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Reprogenetics

Collaborators

Main Line Fertility Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2013

Primary Completion (ANTICIPATED)

December 1, 2014

Study Registration Dates

First Submitted

August 27, 2013

First Submitted That Met QC Criteria

September 17, 2013

First Posted (ESTIMATE)

September 20, 2013

Study Record Updates

Last Update Posted (ESTIMATE)

September 9, 2014

Last Update Submitted That Met QC Criteria

September 8, 2014

Last Verified

September 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Reprogenetics-3.109

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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