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

Primary Purpose

Infertility, Miscarriage

Status
Terminated
Phase
Phase 3
Locations
Peru
Study Type
Interventional
Intervention
Preimplantation Genetic Diagnosis
Sponsored by
Reprogenetics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infertility focused on measuring Preimplantation Genetic Diagnosis, recurrent pregnancy loss, infertility, genetic screening, trisomy 21, Down syndrome

Eligibility Criteria

30 Years - 42 Years (Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Pranor

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

No Intervention

Arm Label

Test

control

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Implantation rate
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
lost pregnancies, defined as pregnancies with an observed fetal sac that did not progressed to third trimester.
Pregnancy rate per transfer
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
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
pregnancies that arrive to term divided by procedures with an egg retreival.

Full Information

First Posted
April 7, 2011
Last Updated
May 25, 2012
Sponsor
Reprogenetics
Collaborators
Reprogenetics Lationoamerica S.A.C, Lima, Peru, Pranor S.R.L., Lima, Peru, Yale University, McGill University
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1. Study Identification

Unique Protocol Identification Number
NCT01332643
Brief Title
Preimplantation Genetic Diagnosis (PGD) by Array Comparative Genome Hybridization (CGH) and Blastocyst Biopsy
Official Title
Comparison of Single Embryo Transfer With and Without Previous Analysis of All Chromosome Abnormalities Using Microarrays
Study Type
Interventional

2. Study Status

Record Verification Date
May 2012
Overall Recruitment Status
Terminated
Why Stopped
Not enough patients enrolling
Study Start Date
April 2011 (undefined)
Primary Completion Date
August 2012 (Anticipated)
Study Completion Date
September 2012 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Reprogenetics
Collaborators
Reprogenetics Lationoamerica S.A.C, Lima, Peru, Pranor S.R.L., Lima, Peru, Yale University, McGill University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infertility, Miscarriage
Keywords
Preimplantation Genetic Diagnosis, recurrent pregnancy loss, infertility, genetic screening, trisomy 21, Down syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Test
Arm Type
Active Comparator
Arm Description
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.
Arm Title
control
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Genetic
Intervention Name(s)
Preimplantation Genetic Diagnosis
Other Intervention Name(s)
array CGH from Bluegnome, UK
Intervention Description
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.
Primary Outcome Measure Information:
Title
Implantation rate
Description
number of embryos implanted divided by number of embryos replaced. An embryo implanted is measured as a fetal sac by ultrasound observation.
Time Frame
three weeks after embryo replacement
Secondary Outcome Measure Information:
Title
miscarriage rate
Description
lost pregnancies, defined as pregnancies with an observed fetal sac that did not progressed to third trimester.
Time Frame
up to the end of second trimester
Title
Pregnancy rate per transfer
Description
pregnancy defined as the presence of a fetal sac. Pregancy rate per transfer defined as pregnancies divided by patients with a replacement of embryos.
Time Frame
three weeks after implantation
Title
Pregnancy rate per retrieval
Description
pregnancy defined as the presence of a fetal sac. Pregancy rate per retrieval defined as pregnancies divided by patients with an egg retrieval.
Time Frame
three weeks after transfer
Title
live birth rate
Description
pregnancies that arrive to term divided by procedures with an egg retreival.
Time Frame
1 year after embryo transfer

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
42 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Santiago Munne, PhD
Organizational Affiliation
Reprogenetics
Official's Role
Principal Investigator
Facility Information:
Facility Name
Pranor
City
Lima
Country
Peru

12. IPD Sharing Statement

Citations:
PubMed Identifier
20971462
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.
Results Reference
background
PubMed Identifier
19939370
Citation
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.
Results Reference
background
PubMed Identifier
19409550
Citation
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.
Results Reference
background

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

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