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Preimplantation Genetic Diagnosis (PGD) by Array Comparative Genome Hybridization (CGH) and Blastocyst Biopsy

This study has been terminated.
(Not enough patients enrolling)
Sponsor:
Collaborators:
Reprogenetics Lationoamerica S.A.C, Lima, Peru
Pranor S.R.L., Lima, Peru
Yale University
McGill University
Information provided by (Responsible Party):
Reprogenetics
ClinicalTrials.gov Identifier:
NCT01332643
First received: April 7, 2011
Last updated: May 25, 2012
Last verified: May 2012
  Purpose

This study evaluates the effect of single embryo transfer (SET) with and without array CGH for the evaluation of the complete chromosome complement of the blastocyst. Patients will be allocated at random into two groups. The control group will consist of patients in which one embryo will be replaced on day 5 based on morphological and developmental characteristics, and the other embryos reaching blastocyst stage will be vitrified. The test group will consist of patients undergoing embryo biopsy at the blastocyst stage (day 5 of development, embryo freezing, and analysis of the biopsied cells with a comprehensive chromosome analysis technique (array Comparative Genome hybridization or aCGH). Only a chromosomally normal blastocyst will be replaced in a thawed cycle. Inclusion and exclusion criteria are described in the study population section.


Condition Intervention Phase
Infertility
Miscarriage
Genetic: Preimplantation Genetic Diagnosis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Comparison of Single Embryo Transfer With and Without Previous Analysis of All Chromosome Abnormalities Using Microarrays

Resource links provided by NLM:


Further study details as provided by Reprogenetics:

Primary Outcome Measures:
  • Implantation rate [ Time Frame: three weeks after embryo replacement ] [ Designated as safety issue: No ]
    number of embryos implanted divided by number of embryos replaced. An embryo implanted is measured as a fetal sac by ultrasound observation.


Secondary Outcome Measures:
  • miscarriage rate [ Time Frame: up to the end of second trimester ] [ Designated as safety issue: No ]
    lost pregnancies, defined as pregnancies with an observed fetal sac that did not progressed to third trimester.

  • Pregnancy rate per transfer [ Time Frame: three weeks after implantation ] [ Designated as safety issue: No ]
    pregnancy defined as the presence of a fetal sac. Pregancy rate per transfer defined as pregnancies divided by patients with a replacement of embryos.

  • Pregnancy rate per retrieval [ Time Frame: three weeks after transfer ] [ Designated as safety issue: No ]
    pregnancy defined as the presence of a fetal sac. Pregancy rate per retrieval defined as pregnancies divided by patients with an egg retrieval.

  • live birth rate [ Time Frame: 1 year after embryo transfer ] [ Designated as safety issue: No ]
    pregnancies that arrive to term divided by procedures with an egg retreival.


Estimated Enrollment: 120
Study Start Date: April 2011
Estimated Study Completion Date: September 2012
Estimated Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Test
The test group will consist of patients undergoing blastocyst biopsy followed by vitrification (embryo freezing), and in which the biopsied cells will be analyzed with a comprehensive chromosome analysis technique (array Comparative Genome hybridization or aCGH) and only one chromosomally normal embryo will be replaced in a thawed cycle.
Genetic: Preimplantation Genetic Diagnosis
All embryos in the test group reaching blastocyst stage will undergo embryo biopsy of 3-10 trophectoderm cells. The cells will be analyzed by array CGH to detect the presence or not of chromosome abnormalities. The embryos will be vitrified and those classified by array CGH as normal, thawed for replacement.
Other Name: array CGH from Bluegnome, UK
No Intervention: control
The control group will consist of patients in which one embryo will be replaced on day 5 based on morphological and developmental characteristics, and the other embryos reaching blastocyst stage will be vitrified. If patient does not become pregnant, successive embryo transfers of frozen embryos will be performed, but not as part of the study.

Detailed Description:

Rational for the study:

The goal of this study is to determine if the strategy employed for the Test group can solve two major problems in ART, one the still low implantation rate in women of advanced maternal age, and two the frequent occurrence of multiple pregnancies resulting from solving the first problem by replacing too many embryos.

Preimplantation Genetic Diagnosis (PGD) has been proposed as a potential means to achieve these goals, but so far, the results with day 3 biopsy and FISH analysis of 5-12 chromosomes has produced contradictory results, the difference between studies being explained by technical differences (Munne et al. 2010). Three technical developments have recently occurred that can change dramatically the efficacy of PGD. One, blastocyst laser assisted biopsy, which seems less detrimental than cleavage stage biopsy; Two, vitrification of embryos which allows those blastocysts to be frozen with little or no loss of viability, and three, chromosome comprehensive screening techniques, such as array CGH (Gutierrez-Mateo et al. 2011) which allow for the detection of all chromosome abnormalities.

Preliminary data from our center indicates that the technique to be used, an improvement on our prior technique CGH, will result in a very significant improvement in implantation rates and a reduction in miscarriage rates, thus justifying the use of single embryo transfer in this set up.

Supportive Preliminary Research:

In a recent study, the investigators observed a 1.6 fold increase (p < 0.001) in implantation rate when aCGH was applied to blastocyst embryos (Schoolcraft et al. 2010). The test group used CGH, an older and less sensitive iteration of the technique to be used in the proposed study - array CGH. Array CGH has a 6 megabase resolution and screens for 30% of all DNA bases (compared to 0.1% of SNP arrays). With array CGH the false positive and false negative rate is 0% when biopsying blastocysts, and 3% when biopsying day 3 embryos (Gutierrez Mateo et al, 2011). Based on our preliminary data, patients with 5 or more day 3 embryos and less than 43 years of age are the most likely to benefit from PGD, since they produce enough embryos and enough normal embryos so a selection technique, like PGD could chose them and improve their reproductive odds.

Also our PGD preliminary data shows a < 10% of embryo demise after implantation for a population 38 of age (expected would be about 28%).

Study Hypothesis The investigators foresee a significant increase in implantation rates in the Test group compared to the Control group. The investigators calculated that 60 patients in each arm would be needed to achieve a significant increase in implantation rates (p < 0.05) with a power of 80%, based on a comparative study in which the investigators observed a 1.6 fold increase in implantation rate (Schoolcraft et al. 2010).

Study population, interventions:

see below.

  Eligibility

Ages Eligible for Study:   30 Years to 42 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Couples with women 30-42 years of age
  • Follicle Stimulating Hormone (FSH) level <11IU/L on day 3 of cycle.

Exclusion Criteria:

  • TESA and TESE patients
  • Couples' carriers of chromosomal or genetic diseases
  • Couples that produce less than eight antral follicles on day 2-4 of cycle
  • Patients will be excluded if they produce no blastocysts by day 5
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01332643

Locations
Peru
Pranor
Lima, Peru
Sponsors and Collaborators
Reprogenetics
Reprogenetics Lationoamerica S.A.C, Lima, Peru
Pranor S.R.L., Lima, Peru
Yale University
McGill University
Investigators
Principal Investigator: Santiago Munne, PhD Reprogenetics
  More Information

Publications:
Responsible Party: Reprogenetics
ClinicalTrials.gov Identifier: NCT01332643     History of Changes
Other Study ID Numbers: Reprogenetics-02
Study First Received: April 7, 2011
Last Updated: May 25, 2012
Health Authority: United States: Institutional Review Board
Peru: Institutional Review Board

Keywords provided by Reprogenetics:
Preimplantation Genetic Diagnosis
recurrent pregnancy loss
infertility
genetic screening
trisomy 21
Down syndrome

Additional relevant MeSH terms:
Infertility
Genital Diseases, Female
Genital Diseases, Male

ClinicalTrials.gov processed this record on November 20, 2014