<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01664546</url>
  </required_header>
  <id_info>
    <org_study_id>Funsare - 001</org_study_id>
    <nct_id>NCT01664546</nct_id>
  </id_info>
  <brief_title>Study of the Best Blastocyst Post Transfer by aCGH</brief_title>
  <official_title>Study of the Best Blastocyst Post Transfer by aCGH</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Buenos Aires</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fecunditas Instituto de Medicina Reproductiva</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital del Mar</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Red Latinoamericana de Reproducción Asistida</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Buenos Aires</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      An Observational, blind and prospective study of Preimplantational Aneuploidy Screening by&#xD;
      aCGH in Trophectoderm Biopsy&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The hypothesis that preimplantational aneuploidy screening could improve the pregnancy rate&#xD;
      post procedures IVF/ICSI is based on two main reasons: 1)50% chromosomal risk that exists&#xD;
      during fertilization in reproductive age, increases with the age and 2)the evidence that most&#xD;
      chromosome abnormalities are spontaneously aborted. Therefore, to encourage the establishment&#xD;
      of the pregnancy, the majority of the reproductive centers transfer at least two embryos.&#xD;
      However this attitude is risky because it increases multiple pregnancies with medical and&#xD;
      social disadvantages.&#xD;
&#xD;
      Embryo selection based on morphology and degree of development is not sufficient to identify&#xD;
      chromosomally normal embryo.&#xD;
&#xD;
      The experience gained in the last 10 years with PGS using FISH technique has concluded that&#xD;
      it has no clinical value even in selected populations of advanced maternal age, repeated&#xD;
      failure in IVF/ICSI, recurrent abortion or severe male factor. The three main arguments were:&#xD;
      1)the limitation of the technique to enumerate the 24 chromosomes, 2)the reduced ability of&#xD;
      implantation after biopsy performed on the third day of the in vitro development and 3)the&#xD;
      discarding of embryos that could have been self-corrected.&#xD;
&#xD;
      The possibility of amplifying the entire genome from one or two cells of the embryo permits&#xD;
      the use of methodologies for the screening of 24 chromosomes, such as, comparative genomic&#xD;
      hybridization-performed on metaphase plates (mCGH) or on slides with thousands of probes&#xD;
      corresponding to human chromosome segments cloned in bacteria (BAC array) or array of single&#xD;
      nucleotide polymorphisms (aSNP), besides the classic or real time qPCR.&#xD;
&#xD;
      Other important developments include the culture of pre-embryos to the blastocyst stage. This&#xD;
      allows more cells to be obtained and studied when hatching the trophectoderm, and the&#xD;
      efficiency achieved with the vitrification allows the transfer in another cycle,&#xD;
      unstimulated, with better results than fresh transfer. These last two facts are important,&#xD;
      the first from a practical point of view because the study is performed on an embryo that has&#xD;
      reached the highest degree of development in vitro, and the second because the receptivity of&#xD;
      the endometrium is better in an unstimulated cycle, and also it avoids the potential&#xD;
      iatrogenic effect of the drugs used in ovarian stimulation cycle. On this last point, it is&#xD;
      interesting that the finding reported by the last Australian Register about the risk of birth&#xD;
      defects after reproductive technologies, show that the rate of abnormalities of the thawed&#xD;
      embryos is not different from those born without reproductive technology, while the rate of&#xD;
      birth anomalies with fresh embryos transfer is greater than those without assisted&#xD;
      reproductive technologies. Furthermore, the non embryo transfer in the fresh cycle permits&#xD;
      more time for study and implementation of different genetic methodologies that previously&#xD;
      could not be performed due to time constraints. This new option allows us to organize the&#xD;
      work better and obviously gain greater efficiency. This possibility is very important to&#xD;
      geneticists who are willing to work every day when necessary. Considering the above mentioned&#xD;
      arguments, we propose to perform on couples that require IVF/ICSI the embryo biopsy at the&#xD;
      blastocyst stage, the immediate vitrification thereof, and to transfer the best blastocyst,&#xD;
      evaluated by its expansion and the quality of the trophectoderm and inner cell mass, in a&#xD;
      subsequent cycle with physiologically primed endometrium. The molecular karyotype (aCGH) will&#xD;
      be performed after the embryo transfer. The result of the karyotype of embryos transferred&#xD;
      will be determined when the patient take the pregnancy test. In this way, we will know the&#xD;
      proportion and type of chromosomal abnormalities in three groups of patients after blastocyst&#xD;
      transfer: a) those that could not get pregnant, b) those that got pregnant but miscarried and&#xD;
      c) those that successfully gave birth. We suggest that this trial design will allow further&#xD;
      clarification of the biological behavior of preimplantational aneuploidies and to assess&#xD;
      whether it really has clinical value. If preimplantation chromosome abnormalities have&#xD;
      clinical value, the proportion and types of aneuploidies should be different in the three&#xD;
      groups of patients mentioned above.&#xD;
&#xD;
      We will offer free to all pregnant women the amniocentesis to confirm whether the fetal&#xD;
      karyotype is consistent with the trophectoderm, especially those who have had an aneuploid&#xD;
      blastocyst transfer. Those who refuse to be assessed prenatally, testing will be made at the&#xD;
      time of delivery via umbilical cord blood. In contrast, the patients who have miscarried,&#xD;
      depending on the gestational age, will be offered a study of the aborted product obtained by&#xD;
      curettage, chorionic villus puncture, amniocentesis or fetal biopsy.&#xD;
&#xD;
      The patients who did not achieve pregnancy or who lost it spontaneously due to chromosome&#xD;
      abnormality, can benefit in a subsequent transfer with the remaining vitrified euploid&#xD;
      embryos or with those obtained during a new stimulation cycle performing the aCGH before&#xD;
      transfer. Patients who achieved &quot;take home a baby&quot; and who decide to have more children may&#xD;
      also take advantage of the remaining euploid devitrified blastocyst.&#xD;
&#xD;
      We prefer in this clinical trial not to transfer during the stimulated cycle because a pilot&#xD;
      study, with unstimulated cycle transfer, yielded better results in terms of pregnancy rate&#xD;
      compared to historical data of PGD with fresh transfer. Other recent studies of devitrified&#xD;
      blastocyst transfer in a natural cycle or with endometrium physiologically prepared also show&#xD;
      better pregnancy rates and besides, are less iatrogenic than the fresh embryo transfer.&#xD;
&#xD;
      The hypothesis of embryonic aneuploidy screening for selecting the best embryo is correct and&#xD;
      is supported by the published data of cytogenetic studies on gametes and/or human embryos.&#xD;
      When the couple produce enough blastocysts of good quality, the selection of the euploid&#xD;
      blastocyst for transfer is beneficial, but if the couple produce only one aneuploid&#xD;
      blastocyst we are not sure of discarding it until we are able to demonstrate the behavior of&#xD;
      aneuploidies in preimplantational period, especially if the chromosomal abnormality found is&#xD;
      not part of the pathology of the newborn, otherwise we would be eliminating the last chance&#xD;
      for the couple to become genetic parents.&#xD;
&#xD;
      We believe that once demonstrated, the clinical value of the embryo molecular karyotype and&#xD;
      its application, could be beneficial in achieving a better ongoing pregnancy rate in selected&#xD;
      patient groups such as women of advanced reproductive age, recurrent abortions and severe&#xD;
      male factor.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>September 2012</start_date>
  <completion_date type="Anticipated">September 2014</completion_date>
  <primary_completion_date type="Anticipated">September 2013</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical pregnancy</measure>
    <time_frame>Five weeks after blastocyst transfer</time_frame>
    <description>Gestational sac with a heartbeat</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Trophectoderm molecular karyotype</measure>
    <time_frame>After blastocyst transfer</time_frame>
    <description>Trophectoderm ploidy Imbalanced chromosome complement</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Spontaneous miscarriage</measure>
    <time_frame>During pregnancy</time_frame>
    <description>Absence of vital signs&#xD;
Abortion product&#xD;
Stillbirth</description>
  </other_outcome>
  <other_outcome>
    <measure>Non pregnancy</measure>
    <time_frame>Two weeks after transfer</time_frame>
    <description>Beta hCG</description>
  </other_outcome>
  <other_outcome>
    <measure>Fetal karyotype</measure>
    <time_frame>Sixteenth week of pregnancy</time_frame>
    <description>Karyotype in amniocytes obtained by amniocentesis</description>
  </other_outcome>
  <other_outcome>
    <measure>Newborn karyotype</measure>
    <time_frame>At delivery</time_frame>
    <description>Lymphocyte culture of cord blood</description>
  </other_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Pregnancy</condition>
  <condition>Spontaneous Abortions</condition>
  <condition>Stillbirth</condition>
  <arm_group>
    <arm_group_label>Molecular blastocyst karyotype</arm_group_label>
    <description>Trophectoderm biopsy for genetic study by aCGH</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Trophectoderm biopsy</intervention_name>
    <arm_group_label>Molecular blastocyst karyotype</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Removed cells from human trophectoderm&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Adult patients who require IVF/ICSI procedure to achieve pregnancy&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:Each patient should apply the criteria in a period not exceeding 6&#xD;
        months prior to aspiration. The criteria are:&#xD;
&#xD;
          1. Patients who have indicated an IVF&#xD;
&#xD;
          2. ≥ 21 years of age&#xD;
&#xD;
          3. Regular menstrual cycles every 27-35 days&#xD;
&#xD;
          4. BMI less than 35&#xD;
&#xD;
          5. Normal levels of FSH, LH and E2 in early follicular phase&#xD;
&#xD;
          6. Antral follicles count ≥ 6&#xD;
&#xD;
          7. Couple Normal karyotype&#xD;
&#xD;
          8. Expansion of the triplet CGG of FMR1 gene ≤ 45 repetitions&#xD;
&#xD;
          9. Pelvic transvaginal ultrasound no more than one year prior to oocyte retrieval&#xD;
&#xD;
         10. Normal Hysterosalpingography made not more than 3 years prior to oocyte retrieval&#xD;
&#xD;
         11. Normal Pap and breast exam no more than one year old&#xD;
&#xD;
         12. Negative serology for HIV, hepatitis B and C&#xD;
&#xD;
         13. Positive serology for Rubella and Varicella&#xD;
&#xD;
         14. Administration of 1 mg folic acid / d in both partners from two to three months prior&#xD;
             to the procedure&#xD;
&#xD;
         15. Woman has had previous cycles of ovarian stimulation, requires a wash out period of 30&#xD;
             days.&#xD;
&#xD;
         16. Patients must agree with the clinical trial and sign the informed consent which&#xD;
             explains free participation in the project&#xD;
&#xD;
         17. Patients can abandon participation in the project at any time.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Existence of a disease or condition that discourages achievement pregnancy&#xD;
&#xD;
          2. Endometriosis grade III and IV&#xD;
&#xD;
          3. Unilateral or bilateral Hydrosalpinx&#xD;
&#xD;
          4. Previous cycles of IVF with poor response to ovarian stimulation (≤ 5 oocytes) or&#xD;
             excessive response (OHSS)&#xD;
&#xD;
          5. Azoospermia with TESA or TESE requiring&#xD;
&#xD;
          6. Allergy to any of the drugs used in the procedure&#xD;
&#xD;
          7. Carriers of genetic or chromosomal diseases&#xD;
&#xD;
          8. Repeated IVF failures (≥ 5 cycles)&#xD;
&#xD;
          9. Simultaneous participation in another clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Roberto Coco, PhD</last_name>
    <role>Study Director</role>
    <affiliation>UBA</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Roberto Coco, PhD</last_name>
    <phone>541149613091</phone>
    <email>robertococo@fecunditas.com.ar</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Maria E Ducatelli, PhD</last_name>
    <phone>541149626309</phone>
    <email>mariaducatelli@yahoo.com.ar</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Fecunditas Reproductive Medicine Institute</name>
      <address>
        <city>Buenos Aires</city>
        <zip>1030</zip>
        <country>Argentina</country>
      </address>
    </facility>
    <contact>
      <last_name>Roberto Coco, PhD</last_name>
      <phone>54119613091</phone>
      <email>robertococo@fecunditas.com.ar</email>
    </contact>
    <contact_backup>
      <last_name>Maria E Ducatelli, PhD</last_name>
      <phone>54119626309</phone>
      <email>mariaducatelli@yahoo.com.ar</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Argentina</country>
  </location_countries>
  <verification_date>August 2012</verification_date>
  <study_first_submitted>August 3, 2012</study_first_submitted>
  <study_first_submitted_qc>August 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 14, 2012</study_first_posted>
  <last_update_submitted>August 14, 2012</last_update_submitted>
  <last_update_submitted_qc>August 14, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 15, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Buenos Aires</investigator_affiliation>
    <investigator_full_name>Roberto Coco</investigator_full_name>
    <investigator_title>Director</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stillbirth</mesh_term>
    <mesh_term>Abortion, Spontaneous</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01664546
org study id: Funsare - 001
nct id: NCT01664546
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
An Observational, blind and prospective study of Preimplantational Aneuploidy Screening by
      aCGH in Trophectoderm Biopsy
The hypothesis that preimplantational aneuploidy screening could improve the pregnancy rate
      post procedures IVF/ICSI is based on two main reasons: 1)50% chromosomal risk that exists
      during fertilization in reproductive age, increases with the age and 2)the evidence that most
      chromosome abnormalities are spontaneously aborted. Therefore, to encourage the establishment
      of the pregnancy, the majority of the reproductive centers transfer at least two embryos.
      However this attitude is risky because it increases multiple pregnancies with medical and
      social disadvantages.

      Embryo selection based on morphology and degree of development is not sufficient to identify
      chromosomally normal embryo.

      The experience gained in the last 10 years with PGS using FISH technique has concluded that
      it has no clinical value even in selected populations of advanced maternal age, repeated
      failure in IVF/ICSI, recurrent abortion or severe male factor. The three main arguments were:
      1)the limitation of the technique to enumerate the 24 chromosomes, 2)the reduced ability of
      implantation after biopsy performed on the third day of the in vitro development and 3)the
      discarding of embryos that could have been self-corrected.

      The possibility of amplifying the entire genome from one or two cells of the embryo permits
      the use of methodologies for the screening of 24 chromosomes, such as, comparative genomic
      hybridization-performed on metaphase plates (mCGH) or on slides with thousands of probes
      corresponding to human chromosome segments cloned in bacteria (BAC array) or array of single
      nucleotide polymorphisms (aSNP), besides the classic or real time qPCR.

      Other important developments include the culture of pre-embryos to the blastocyst stage. This
      allows more cells to be obtained and studied when hatching the trophectoderm, and the
      efficiency achieved with the vitrification allows the transfer in another cycle,
      unstimulated, with better results than fresh transfer. These last two facts are important,
      the first from a practical point of view because the study is performed on an embryo that has
      reached the highest degree of development in vitro, and the second because the receptivity of
      the endometrium is better in an unstimulated cycle, and also it avoids the potential
      iatrogenic effect of the drugs used in ovarian stimulation cycle. On this last point, it is
      interesting that the finding reported by the last Australian Register about the risk of birth
      defects after reproductive technologies, show that the rate of abnormalities of the thawed
      embryos is not different from those born without reproductive technology, while the rate of
      birth anomalies with fresh embryos transfer is greater than those without assisted
      reproductive technologies. Furthermore, the non embryo transfer in the fresh cycle permits
      more time for study and implementation of different genetic methodologies that previously
      could not be performed due to time constraints. This new option allows us to organize the
      work better and obviously gain greater efficiency. This possibility is very important to
      geneticists who are willing to work every day when necessary. Considering the above mentioned
      arguments, we propose to perform on couples that require IVF/ICSI the embryo biopsy at the
      blastocyst stage, the immediate vitrification thereof, and to transfer the best blastocyst,
      evaluated by its expansion and the quality of the trophectoderm and inner cell mass, in a
      subsequent cycle with physiologically primed endometrium. The molecular karyotype (aCGH) will
      be performed after the embryo transfer. The result of the karyotype of embryos transferred
      will be determined when the patient take the pregnancy test. In this way, we will know the
      proportion and type of chromosomal abnormalities in three groups of patients after blastocyst
      transfer: a) those that could not get pregnant, b) those that got pregnant but miscarried and
      c) those that successfully gave birth. We suggest that this trial design will allow further
      clarification of the biological behavior of preimplantational aneuploidies and to assess
      whether it really has clinical value. If preimplantation chromosome abnormalities have
      clinical value, the proportion and types of aneuploidies should be different in the three
      groups of patients mentioned above.

      We will offer free to all pregnant women the amniocentesis to confirm whether the fetal
      karyotype is consistent with the trophectoderm, especially those who have had an aneuploid
      blastocyst transfer. Those who refuse to be assessed prenatally, testing will be made at the
      time of delivery via umbilical cord blood. In contrast, the patients who have miscarried,
      depending on the gestational age, will be offered a study of the aborted product obtained by
      curettage, chorionic villus puncture, amniocentesis or fetal biopsy.

      The patients who did not achieve pregnancy or who lost it spontaneously due to chromosome
      abnormality, can benefit in a subsequent transfer with the remaining vitrified euploid
      embryos or with those obtained during a new stimulation cycle performing the aCGH before
      transfer. Patients who achieved "take home a baby" and who decide to have more children may
      also take advantage of the remaining euploid devitrified blastocyst.

      We prefer in this clinical trial not to transfer during the stimulated cycle because a pilot
      study, with unstimulated cycle transfer, yielded better results in terms of pregnancy rate
      compared to historical data of PGD with fresh transfer. Other recent studies of devitrified
      blastocyst transfer in a natural cycle or with endometrium physiologically prepared also show
      better pregnancy rates and besides, are less iatrogenic than the fresh embryo transfer.

      The hypothesis of embryonic aneuploidy screening for selecting the best embryo is correct and
      is supported by the published data of cytogenetic studies on gametes and/or human embryos.
      When the couple produce enough blastocysts of good quality, the selection of the euploid
      blastocyst for transfer is beneficial, but if the couple produce only one aneuploid
      blastocyst we are not sure of discarding it until we are able to demonstrate the behavior of
      aneuploidies in preimplantational period, especially if the chromosomal abnormality found is
      not part of the pathology of the newborn, otherwise we would be eliminating the last chance
      for the couple to become genetic parents.

      We believe that once demonstrated, the clinical value of the embryo molecular karyotype and
      its application, could be beneficial in achieving a better ongoing pregnancy rate in selected
      patient groups such as women of advanced reproductive age, recurrent abortions and severe
      male factor.
observational model: Case-Only
time perspective: Prospective
measure: Clinical pregnancy
time frame: Five weeks after blastocyst transfer
description: Gestational sac with a heartbeat
measure: Trophectoderm molecular karyotype
time frame: After blastocyst transfer
description: Trophectoderm ploidy Imbalanced chromosome complement
measure: Spontaneous miscarriage
time frame: During pregnancy
description: Absence of vital signs
Abortion product
Stillbirth
measure: Non pregnancy
time frame: Two weeks after transfer
description: Beta hCG
measure: Fetal karyotype
time frame: Sixteenth week of pregnancy
description: Karyotype in amniocytes obtained by amniocentesis
measure: Newborn karyotype
time frame: At delivery
description: Lymphocyte culture of cord blood
arm group label: Molecular blastocyst karyotype
description: Trophectoderm biopsy for genetic study by aCGH
intervention type: Procedure
intervention name: Trophectoderm biopsy
arm group label: Molecular blastocyst karyotype
Removed cells from human trophectoderm
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 21 Years
maximum age: 50 Years
healthy volunteers: No
last name: Roberto Coco, PhD
role: Study Director
affiliation: UBA
last name: Roberto Coco, PhD
phone: 541149613091
email: robertococo@fecunditas.com.ar
last name: Maria E Ducatelli, PhD
phone: 541149626309
email: mariaducatelli@yahoo.com.ar
facility: 
contact: 
contact backup: 
country: Argentina
responsible party type: Principal Investigator
investigator affiliation: University of Buenos Aires
investigator full name: Roberto Coco
investigator title: Director
mesh term: Stillbirth
mesh term: Abortion, Spontaneous