<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/NCT03764865</url>
  </required_header>
  <id_info>
    <org_study_id>2018P000530</org_study_id>
    <nct_id>NCT03764865</nct_id>
  </id_info>
  <brief_title>PooR Embryo Yield Cleavage Stage Versus blaStocyst Embryo Transfer (Pilot)</brief_title>
  <acronym>PRECiSE</acronym>
  <official_title>Day 3 vs Day 5 Embryo Transfer for Patients With Low Embryo Numbers Going Through in Vitro Fertilization</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beth Israel Deaconess Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Boston IVF</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Beth Israel Deaconess Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this pilot study is to test the study protocol for an RCT comparing IVF&#xD;
      outcomes between day 3 and day 5 embryo transfer in patients with five or fewer embryos in a&#xD;
      fresh embryo transfer in vitro fertilization (IVF) cycle. Information derived from this&#xD;
      RCTwould allow us to maximize the chances of success for these patients undergoing IVF.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Embryos created with assisted reproductive technology (ART, e.g. in vitro fertilization&#xD;
      (IVF)) are commonly transferred into a woman's uterus at either the cleavage stage (day 3&#xD;
      after egg retrieval) or blastocyst stage (day 5 after egg retrieval). Until recently, most&#xD;
      IVF cycles transferred embryos at the cleavage stage. However, with improvements in in vitro&#xD;
      culture technique there has been a steady shift in practice to transfer embryos at the&#xD;
      blastocyst stage (day 5 after egg retrieval) as this timing is about the same as when embryos&#xD;
      reach the endometrial cavity in natural conception.&#xD;
&#xD;
      There now is a general consensus that, for good prognosis patients, those with a high embryo&#xD;
      from the IVF cycle, it is beneficial to transfer the embryo on day 5 rather than day 3. The&#xD;
      rationale for this is to allow for self-selection of embryos, meaning those that develop to&#xD;
      blastocyst in vitro are more likely to be viable in vivo and result in a viable pregnancy. In&#xD;
      addition, transferring an embryo on day 5 improves uterine/embryonic synchronicity and&#xD;
      thereby improves outcomes. This allows the transfer of fewer embryos and decreases the&#xD;
      likelihood of multiples (twins, triplets, etc.).&#xD;
&#xD;
      As a result, day 5 transfer has become standard of care for good prognosis patients in the&#xD;
      United States. The American Society of Reproductive Medicine1 issued a committee opinion in&#xD;
      2013 to this effect stating that in &quot;good prognosis&quot; patients, blastocyst transfer results in&#xD;
      a significant increase in live birth rates compared to transfer of an equal number of&#xD;
      cleavage stage embryos (50.5% vs. 30.1%, P&lt; .01)2-5. In addition, for unselected and poor&#xD;
      prognosis patients, no high-quality studies have evaluated whether blastocyst transfer&#xD;
      increases live birth rates when compared to cleavage stage transfer.&#xD;
&#xD;
      It is possible that the attrition of day 3 embryos in vivo is lower than the attrition in&#xD;
      vitro and that day 5 transfer leads to loss of embryos that may have survived in vivo. In&#xD;
      addition, women undergoing blastocyst culture are expected to have a higher incidence of&#xD;
      cycle cancellation due to failure of the embryo to develop to a blastocyst6 and of having&#xD;
      fewer embryos cryopreserved (frozen)7. Because of this, in Europe and Asia, day 3 transfer is&#xD;
      the most common practice.&#xD;
&#xD;
      On the other hand, transferring embryos on day 3 decreases our ability to select the best&#xD;
      embryo, increases laboratory costs and may increase multiple pregnancy rates as, typically,&#xD;
      more embryos are transferred at this time. In addition, in vivo, day 3 embryos are in transit&#xD;
      through the fallopian tube during natural conception and are exposed to a different&#xD;
      developmental and nutritional environment than day 3 IVF embryos transferred into the uterine&#xD;
      cavity. Thus, it is possible that exposing day 3 embryos to the physiologically premature&#xD;
      uterine environment (particularly one that has been subjected to superovulation and thus high&#xD;
      levels of estrogen) increases embryo attrition compared to day 5 transfer, particularly in&#xD;
      poor prognosis patients.&#xD;
&#xD;
      Therefore, a clinical dilemma exists for poor prognosis patients (those with ≤5 embryos&#xD;
      available on day 1 after egg retrieval). Currently, many practices in the United States&#xD;
      transfer embryos from these patients on day 3 due to the risk of not having embryos available&#xD;
      to transfer on day 5. Any remaining embryos are then frozen if they meet criteria on day 5/6.&#xD;
&#xD;
      Retrospective data from Boston IVF, BIDMC's affiliated infertility treatment center,&#xD;
      demonstrates that the live birth rate per transfer among poor prognosis patients is 18% among&#xD;
      those who have a cleavage stage transfer and 38% among those who have a blastocyst transfer.&#xD;
&#xD;
      At Boston IVF, about 35% of patients have a day 3 embryo transfer, which is consistent with&#xD;
      national trends. For a patient undergoing an IVF cycle at Boston IVF, a physician may choose&#xD;
      to transfer an embryo on day 3 or day 5 or allow the laboratory to make that decision, based&#xD;
      on the number of embryos the patient has on day 1 after egg retrieval and the patient's age.&#xD;
      This decision typically is made prior to the IVF cycle. As demonstrated above, pregnancy&#xD;
      rates are far lower in the cleavage stage transfer group and there is the possibility that,&#xD;
      within a select cohort of these patients, we are unrealistically raising patient's&#xD;
      expectations of a live birth.&#xD;
&#xD;
      The purpose of this study is to compare IVF outcomes among poor prognosis patients (≤5&#xD;
      embryos with two pronuclei) who have a day 3 transfer to those who have a day 5 transfer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 1, 2021</start_date>
  <completion_date type="Actual">February 28, 2022</completion_date>
  <primary_completion_date type="Actual">February 28, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>non-inferiority</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>live birth</measure>
    <time_frame>9 months</time_frame>
    <description>defined as delivery of a live born infant ≥22 weeks of gestation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical pregnancy</measure>
    <time_frame>14 days</time_frame>
    <description>defined by confirmation of a gestational sac on ultrasound</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ongoing pregnancy</measure>
    <time_frame>9 months</time_frame>
    <description>defined by ultrasound confirmation of a gestational sac with at least one fetal pole with a fetal heartbeat</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Multiple pregnancy</measure>
    <time_frame>9 months</time_frame>
    <description>defined as twins or higher-order gestations</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to pregnancy/live birth</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Infertility</condition>
  <arm_group>
    <arm_group_label>day 3 embryo transfer</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>embryo transfer 3 days after fertilization</description>
  </arm_group>
  <arm_group>
    <arm_group_label>day 5 embryo transfer</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>embryo transfer 5 days after fertilization</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>day 3 uterine transfer</intervention_name>
    <description>uterine transfer of embryo on day 3 after fertilization (cleavage stage)</description>
    <arm_group_label>day 3 embryo transfer</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>day 5 uterine transfer</intervention_name>
    <description>uterine transfer of embryo on day 5 after fertilization (blastocyst stage)</description>
    <arm_group_label>day 5 embryo transfer</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  First autologous IVF cycle&#xD;
&#xD;
          -  Written, informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Planned gestational carrier&#xD;
&#xD;
          -  Planned donor egg&#xD;
&#xD;
          -  Morbid obesity: BMI &gt;40&#xD;
&#xD;
          -  History of recurrent pregnancy loss (≥2 spontaneous abortions)&#xD;
&#xD;
          -  Presence of uterine factor infertility&#xD;
&#xD;
          -  Treatment plan includes embryos cultured 'out of protocol'&#xD;
&#xD;
          -  Planned preimplantation genetic testing&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>44 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Werner Neuhausser, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Beth Israel Deaconess Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Boston IVF</name>
      <address>
        <city>Waltham</city>
        <state>Massachusetts</state>
        <zip>02451</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Blastocyst culture and transfer in clinical-assisted reproduction: a committee opinion. Fertil Steril. 2013 Mar 1;99(3):667-72. doi: 10.1016/j.fertnstert.2013.01.087.</citation>
    <PMID>23714439</PMID>
  </reference>
  <reference>
    <citation>Gardner DK, Schoolcraft WB, Wagley L, Schlenker T, Stevens J, Hesla J. A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Hum Reprod. 1998 Dec;13(12):3434-40. doi: 10.1093/humrep/13.12.3434.</citation>
    <PMID>9886530</PMID>
  </reference>
  <reference>
    <citation>Glujovsky D, Farquhar C, Quinteiro Retamar AM, Alvarez Sedo CR, Blake D. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev. 2016 Jun 30;(6):CD002118. doi: 10.1002/14651858.CD002118.pub5.</citation>
    <PMID>27357126</PMID>
  </reference>
  <reference>
    <citation>Papanikolaou EG, D'haeseleer E, Verheyen G, Van de Velde H, Camus M, Van Steirteghem A, Devroey P, Tournaye H. Live birth rate is significantly higher after blastocyst transfer than after cleavage-stage embryo transfer when at least four embryos are available on day 3 of embryo culture. A randomized prospective study. Hum Reprod. 2005 Nov;20(11):3198-203. doi: 10.1093/humrep/dei217. Epub 2005 Jul 29.</citation>
    <PMID>16055454</PMID>
  </reference>
  <reference>
    <citation>Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med. 2006 Mar 16;354(11):1139-46. doi: 10.1056/NEJMoa053524.</citation>
    <PMID>16540614</PMID>
  </reference>
  <reference>
    <citation>Marek D, Langley M, Gardner DK, Confer N, Doody KM, Doody KJ. Introduction of blastocyst culture and transfer for all patients in an in vitro fertilization program. Fertil Steril. 1999 Dec;72(6):1035-40. doi: 10.1016/s0015-0282(99)00409-4.</citation>
    <PMID>10593377</PMID>
  </reference>
  <reference>
    <citation>Tsirigotis M. Blastocyst stage transfer: pitfalls and benefits. Too soon to abandon current practice? Hum Reprod. 1998 Dec;13(12):3285-9. doi: 10.1093/humrep/13.12.3285. No abstract available.</citation>
    <PMID>9886498</PMID>
  </reference>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>December 4, 2018</study_first_submitted>
  <study_first_submitted_qc>December 4, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 5, 2018</study_first_posted>
  <last_update_submitted>January 3, 2023</last_update_submitted>
  <last_update_submitted_qc>January 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 4, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Beth Israel Deaconess Medical Center</investigator_affiliation>
    <investigator_full_name>Werner Neuhausser</investigator_full_name>
    <investigator_title>Instructor in Obstetrics, Gynecology and Reproductive Biology</investigator_title>
  </responsible_party>
  <keyword>cleavage embryo</keyword>
  <keyword>blastocyst</keyword>
  <keyword>embryo transfer</keyword>
  <keyword>in vitro fertilization</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03764865
org study id: 2018P000530
nct id: NCT03764865
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this pilot study is to test the study protocol for an RCT comparing IVF
      outcomes between day 3 and day 5 embryo transfer in patients with five or fewer embryos in a
      fresh embryo transfer in vitro fertilization (IVF) cycle. Information derived from this
      RCTwould allow us to maximize the chances of success for these patients undergoing IVF.
Embryos created with assisted reproductive technology (ART, e.g. in vitro fertilization
      (IVF)) are commonly transferred into a woman's uterus at either the cleavage stage (day 3
      after egg retrieval) or blastocyst stage (day 5 after egg retrieval). Until recently, most
      IVF cycles transferred embryos at the cleavage stage. However, with improvements in in vitro
      culture technique there has been a steady shift in practice to transfer embryos at the
      blastocyst stage (day 5 after egg retrieval) as this timing is about the same as when embryos
      reach the endometrial cavity in natural conception.

      There now is a general consensus that, for good prognosis patients, those with a high embryo
      from the IVF cycle, it is beneficial to transfer the embryo on day 5 rather than day 3. The
      rationale for this is to allow for self-selection of embryos, meaning those that develop to
      blastocyst in vitro are more likely to be viable in vivo and result in a viable pregnancy. In
      addition, transferring an embryo on day 5 improves uterine/embryonic synchronicity and
      thereby improves outcomes. This allows the transfer of fewer embryos and decreases the
      likelihood of multiples (twins, triplets, etc.).

      As a result, day 5 transfer has become standard of care for good prognosis patients in the
      United States. The American Society of Reproductive Medicine1 issued a committee opinion in
      2013 to this effect stating that in "good prognosis" patients, blastocyst transfer results in
      a significant increase in live birth rates compared to transfer of an equal number of
      cleavage stage embryos (50.5% vs. 30.1%, P< .01)2-5. In addition, for unselected and poor
      prognosis patients, no high-quality studies have evaluated whether blastocyst transfer
      increases live birth rates when compared to cleavage stage transfer.

      It is possible that the attrition of day 3 embryos in vivo is lower than the attrition in
      vitro and that day 5 transfer leads to loss of embryos that may have survived in vivo. In
      addition, women undergoing blastocyst culture are expected to have a higher incidence of
      cycle cancellation due to failure of the embryo to develop to a blastocyst6 and of having
      fewer embryos cryopreserved (frozen)7. Because of this, in Europe and Asia, day 3 transfer is
      the most common practice.

      On the other hand, transferring embryos on day 3 decreases our ability to select the best
      embryo, increases laboratory costs and may increase multiple pregnancy rates as, typically,
      more embryos are transferred at this time. In addition, in vivo, day 3 embryos are in transit
      through the fallopian tube during natural conception and are exposed to a different
      developmental and nutritional environment than day 3 IVF embryos transferred into the uterine
      cavity. Thus, it is possible that exposing day 3 embryos to the physiologically premature
      uterine environment (particularly one that has been subjected to superovulation and thus high
      levels of estrogen) increases embryo attrition compared to day 5 transfer, particularly in
      poor prognosis patients.

      Therefore, a clinical dilemma exists for poor prognosis patients (those with ≤5 embryos
      available on day 1 after egg retrieval). Currently, many practices in the United States
      transfer embryos from these patients on day 3 due to the risk of not having embryos available
      to transfer on day 5. Any remaining embryos are then frozen if they meet criteria on day 5/6.

      Retrospective data from Boston IVF, BIDMC's affiliated infertility treatment center,
      demonstrates that the live birth rate per transfer among poor prognosis patients is 18% among
      those who have a cleavage stage transfer and 38% among those who have a blastocyst transfer.

      At Boston IVF, about 35% of patients have a day 3 embryo transfer, which is consistent with
      national trends. For a patient undergoing an IVF cycle at Boston IVF, a physician may choose
      to transfer an embryo on day 3 or day 5 or allow the laboratory to make that decision, based
      on the number of embryos the patient has on day 1 after egg retrieval and the patient's age.
      This decision typically is made prior to the IVF cycle. As demonstrated above, pregnancy
      rates are far lower in the cleavage stage transfer group and there is the possibility that,
      within a select cohort of these patients, we are unrealistically raising patient's
      expectations of a live birth.

      The purpose of this study is to compare IVF outcomes among poor prognosis patients (≤5
      embryos with two pronuclei) who have a day 3 transfer to those who have a day 5 transfer.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: non-inferiority
primary purpose: Treatment
masking: None (Open Label)
measure: live birth
time frame: 9 months
description: defined as delivery of a live born infant ≥22 weeks of gestation
measure: Clinical pregnancy
time frame: 14 days
description: defined by confirmation of a gestational sac on ultrasound
measure: Ongoing pregnancy
time frame: 9 months
description: defined by ultrasound confirmation of a gestational sac with at least one fetal pole with a fetal heartbeat
measure: Multiple pregnancy
time frame: 9 months
description: defined as twins or higher-order gestations
measure: Time to pregnancy/live birth
time frame: 2 years
arm group label: day 3 embryo transfer
arm group type: Experimental
description: embryo transfer 3 days after fertilization
arm group label: day 5 embryo transfer
arm group type: Experimental
description: embryo transfer 5 days after fertilization
intervention type: Procedure
intervention name: day 3 uterine transfer
description: uterine transfer of embryo on day 3 after fertilization (cleavage stage)
arm group label: day 3 embryo transfer
intervention type: Procedure
intervention name: day 5 uterine transfer
description: uterine transfer of embryo on day 5 after fertilization (blastocyst stage)
arm group label: day 5 embryo transfer
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 44 Years
healthy volunteers: No
last name: Werner Neuhausser, MD PhD
role: Principal Investigator
affiliation: Beth Israel Deaconess Medical Center
facility: 
country: United States
citation: Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Blastocyst culture and transfer in clinical-assisted reproduction: a committee opinion. Fertil Steril. 2013 Mar 1;99(3):667-72. doi: 10.1016/j.fertnstert.2013.01.087.
PMID: 23714439
citation: Gardner DK, Schoolcraft WB, Wagley L, Schlenker T, Stevens J, Hesla J. A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Hum Reprod. 1998 Dec;13(12):3434-40. doi: 10.1093/humrep/13.12.3434.
PMID: 9886530
citation: Glujovsky D, Farquhar C, Quinteiro Retamar AM, Alvarez Sedo CR, Blake D. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev. 2016 Jun 30;(6):CD002118. doi: 10.1002/14651858.CD002118.pub5.
PMID: 27357126
citation: Papanikolaou EG, D'haeseleer E, Verheyen G, Van de Velde H, Camus M, Van Steirteghem A, Devroey P, Tournaye H. Live birth rate is significantly higher after blastocyst transfer than after cleavage-stage embryo transfer when at least four embryos are available on day 3 of embryo culture. A randomized prospective study. Hum Reprod. 2005 Nov;20(11):3198-203. doi: 10.1093/humrep/dei217. Epub 2005 Jul 29.
PMID: 16055454
citation: Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med. 2006 Mar 16;354(11):1139-46. doi: 10.1056/NEJMoa053524.
PMID: 16540614
citation: Marek D, Langley M, Gardner DK, Confer N, Doody KM, Doody KJ. Introduction of blastocyst culture and transfer for all patients in an in vitro fertilization program. Fertil Steril. 1999 Dec;72(6):1035-40. doi: 10.1016/s0015-0282(99)00409-4.
PMID: 10593377
citation: Tsirigotis M. Blastocyst stage transfer: pitfalls and benefits. Too soon to abandon current practice? Hum Reprod. 1998 Dec;13(12):3285-9. doi: 10.1093/humrep/13.12.3285. No abstract available.
PMID: 9886498
responsible party type: Principal Investigator
investigator affiliation: Beth Israel Deaconess Medical Center
investigator full name: Werner Neuhausser
investigator title: Instructor in Obstetrics, Gynecology and Reproductive Biology
mesh term: Infertility
sharing ipd: No