<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/NCT01668056</url>
  </required_header>
  <id_info>
    <org_study_id>1099/09</org_study_id>
    <nct_id>NCT01668056</nct_id>
  </id_info>
  <brief_title>Synchronization of Ovarian Stimulation for in Vitro Fertilization With Follicular Wave Emergence</brief_title>
  <official_title>The Role of Controlling Follicular Wave Emergence to Synchronize Ovarian Stimulation for in Vitro Fertilization</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Sao Paulo General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Sao Paulo General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Ovarian stimulation is an important phase of in vitro fertilization (IVF) treatments. The&#xD;
      harvest of a larger number of viable eggs per cycle compensate eventual laboratory&#xD;
      difficulties and allow for the selection of embryos with higher implantation potential. In&#xD;
      the current protocols, based on the most prevailing theory of ovarian follicular development,&#xD;
      stimulation drugs are usually started on the second or third day after the beginning of&#xD;
      menses. The follicular phase of the menstrual cycle is believed to be the only favorable&#xD;
      moment for follicular development.&#xD;
&#xD;
      In the early 2000's a new model of human ovarian follicular development (follicular waves)&#xD;
      has been proposed based on frequent transvaginal ultrasound observations between two&#xD;
      ovulations. It has been shown that ovarian antral follicles develop in synchronous groups,&#xD;
      two to three times in a cycle. In fact the follicular wave phenomenon has been initially&#xD;
      described in the 80's on domestic animals, like the mare and the cow. Moreover, studies in&#xD;
      these animals have shown that synchronizing the start of the ovarian stimulation drugs with&#xD;
      the beginning of a follicular wave yields better results for assisted reproductive&#xD;
      treatments. Consequently in ovarian stimulation protocols for animal assisted reproduction it&#xD;
      is important to control the initiation of a follicular wave.&#xD;
&#xD;
      Current protocols of ovarian stimulation for IVF in women do not consider the start of a&#xD;
      follicular wave to begin drug administration. Therefore the purpose of this study is to&#xD;
      evaluate two methods to control the emergence of a follicular wave (ovulation induction and&#xD;
      dominant follicle aspiration) and to investigate the effects of synchronizing ovarian&#xD;
      stimulation for IVF with follicular wave emergence in women compared to one of the current&#xD;
      stimulation protocols (flexible GnRH protocol).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>January 2012</start_date>
  <completion_date type="Anticipated">December 2014</completion_date>
  <primary_completion_date type="Anticipated">December 2014</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Emergence of an ovarian follicular wave after dominant follicle aspiration or hCG administration</measure>
    <time_frame>One year</time_frame>
    <description>Evaluate if the aspiration of the dominant follicle is able to induce a follicular wave to emerge.&#xD;
Evaluate if administration of hCG is able to induce ovulation of a dominant follicle larger than 16mm and to induce a follicular wave to emerge.&#xD;
A follicular wave emergence is defined as an increase in the number of ovarian follicles smaller than 10mm seen at the transvaginal ultrasound scan after the interventions</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Follicular growth pattern on ultrasound scan</measure>
    <time_frame>One year</time_frame>
    <description>Evaluate with periodic transvaginal ultrasound scan the size (mm), number and growth rate (mm/day) of ovarian follicles in each of the three groups</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Estradiol and progesterone levels during ovarian stimulation</measure>
    <time_frame>One year</time_frame>
    <description>Evaluate blood levels of estradiol (pg/mL) and progesterone (ng/mL) during ovarian stimulation in each of the three groups at each visit to evaluate the progress of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of mature oocytes retrieved</measure>
    <time_frame>One year</time_frame>
    <description>Evaluate the number of metaphase II oocytes retrieved in each of the three groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total dose of gonadotrophins used</measure>
    <time_frame>One year</time_frame>
    <description>Total dose of gonadotrophins (in international units) necessary to stimulate the ovaries (from the first day of stimulation until the last dose of recombinant FSH administered before the oocyte retrieval)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fertilization rate</measure>
    <time_frame>One year</time_frame>
    <description>Number of embryos formed in relation with the number of oocytes inseminated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pregnancy rate</measure>
    <time_frame>One year</time_frame>
    <description>Positive beta hCG determination on blood 10 days after embryo transfer</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Infertility</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will be stimulated according to the conventional flexible GnRH antagonist protocol for IVF. Alfa follitropin (150IU a day) will be started on the third day of the menstrual cycle. Treatment monitoring will be done with transvaginal ultrasound scans and serum determinations of estradiol and progesterone 5 days after the start of gonadotropins and every each day thereafter. Once the leading follicle reaches 13 mm in mean diameter 0,25mg of cetrorelix acetate will be administered daily. Once at least two follicles reach 18mm or more in mean diameter 250 micrograms of choriogonadotropin alfa will be administered and 36 hours latter patients will undergo follicle aspiration for IVF. Embryos will be cryopreserved (vitrification) on the third or fifth day of development. Two months after women will undergo uterine preparation for embryo transfer.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ovulation induction</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be monitored with daily transvaginal ultrasound scans from the tenth day of the menstrual cycle on. When the dominant follicle reaches a mean diameter of 16mm or more, patients will receive 250 micrograms of choriogonadotropin alfa subcutaneously. Daily transvaginal ultrasound scans will be done starting two days after the administration of the medication until a cohort of ovarian follicles between 4-6 mm is seen (follicular wave emergence). From this point on patients will undergo the same stimulation protocol as Controls, i.e., flexible GnRH antagonist protocol.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dominant follicle aspiration</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be monitored with daily transvaginal ultrasound scans from the tenth day of the menstrual cycle on. When the dominant follicle reaches a mean diameter of 16mm or more, patients will then undergo aspiration of the dominant and all follicles greater than 10mm in mean diameter. aspiration will be transvaginal ultrasound guided and under sedation, as for oocyte retrieval. Oocytes eventually obtained at this first aspiration will not be used for IVF. Daily transvaginal ultrasound scans will be done starting the day after the follicular aspiration until a cohort of follicles between 4-6 mm is seen (follicular wave emergence). From this point on patients will undergo the same stimulation protocol as Controls, i.e., flexible GnRH antagonist protocol.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ovulation induction with choriogonadotropin alfa</intervention_name>
    <description>Administration of 250 micrograms of choriogonadotropin alfa subcutaneously when the dominant follicle of a natural menstrual cycle reaches 16mm or more of mean diameter. Verify if this intervention is able to induce follicular wave emergence and synchronize the start of the flexible GnRH antagonist protocol of ovarian stimulation with the start of a follicular wave.</description>
    <arm_group_label>Ovulation induction</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Aspiration of the dominant follicle</intervention_name>
    <description>Aspiration of all follicles greater than 10mm in mean diameter when the dominant follicle of a natural menstrual cycle reaches 16mm or more of mean diameter. Aspiration will be guided by transvaginal ultrasound. Verify if this intervention is able to induce follicular wave emergence and synchronize the start of the flexible GnRH antagonist protocol of ovarian stimulation with the start of a follicular wave.</description>
    <arm_group_label>Dominant follicle aspiration</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Control</intervention_name>
    <description>Conventional flexible GnRH antagonist protocol of ovarian stimulation for in vitro fertilization, with gonadotropin star at the third day of a natural menstrual cycle.</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age &lt; 35 years old&#xD;
&#xD;
          -  body mass index: 19-30 kg/m2&#xD;
&#xD;
          -  tubal or male factor infertility with indication of in vitro fertilization&#xD;
&#xD;
          -  antral follicle count: 10-20&#xD;
&#xD;
          -  normal uterus in transvaginal ultrasound scan&#xD;
&#xD;
          -  FSH on the third day of the menstrual cycle below 12mUI/mL and estradiol below 80pg/mL&#xD;
&#xD;
          -  male partner with at least 5 million motile sperm and 1% normal strict morphology on&#xD;
             semen analyses&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  ovarian factor infertility&#xD;
&#xD;
          -  non identification of one or both ovaries in the transvaginal ultrasound scan&#xD;
&#xD;
          -  non treated endocrine disorders&#xD;
&#xD;
          -  smoking habit&#xD;
&#xD;
          -  endometriosis stage III -IV&#xD;
&#xD;
          -  severe male factor infertility (less than one million sperm per mL of semen)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Edmund c Baracat, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>University of Sao Paulo Medical School</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Paulo C Serafini, PhD</last_name>
    <role>Study Director</role>
    <affiliation>University of Sao Paulo Medical School</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Paulo HM Bianchi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Sao Paulo Medical School</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Paulo HM Bianchi, MD</last_name>
    <email>paulobianchi35@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Sao Paulo General Hospital</name>
      <address>
        <city>Sao Paulo</city>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Paulo HM Bianchi, MD</last_name>
      <email>paulobianchi35@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Paulo HM Bianchi, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <reference>
    <citation>Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril. 2003 Jul;80(1):116-22. doi: 10.1016/s0015-0282(03)00544-2.</citation>
    <PMID>12849812</PMID>
  </reference>
  <reference>
    <citation>Baerwald AR, Adams GP, Pierson RA. Characterization of ovarian follicular wave dynamics in women. Biol Reprod. 2003 Sep;69(3):1023-31. doi: 10.1095/biolreprod.103.017772. Epub 2003 May 14.</citation>
    <PMID>12748128</PMID>
  </reference>
  <reference>
    <citation>Baerwald AR, Adams GP, Pierson RA. Ovarian antral folliculogenesis during the human menstrual cycle: a review. Hum Reprod Update. 2012 Jan-Feb;18(1):73-91. doi: 10.1093/humupd/dmr039. Epub 2011 Nov 8.</citation>
    <PMID>22068695</PMID>
  </reference>
  <reference>
    <citation>Adams GP, Singh J, Baerwald AR. Large animal models for the study of ovarian follicular dynamics in women. Theriogenology. 2012 Nov;78(8):1733-48. doi: 10.1016/j.theriogenology.2012.04.010. Epub 2012 May 22.</citation>
    <PMID>22626769</PMID>
  </reference>
  <reference>
    <citation>de Mello Bianchi PH, Serafini P, Monteiro da Rocha A, Assad Hassun P, Alves da Motta EL, Sampaio Baruselli P, Chada Baracat E. Review: follicular waves in the human ovary: a new physiological paradigm for novel ovarian stimulation protocols. Reprod Sci. 2010 Dec;17(12):1067-76. doi: 10.1177/1933719110366483. Epub 2010 May 3.</citation>
    <PMID>20439948</PMID>
  </reference>
  <verification_date>September 2013</verification_date>
  <study_first_submitted>August 6, 2012</study_first_submitted>
  <study_first_submitted_qc>August 15, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 17, 2012</study_first_posted>
  <last_update_submitted>September 9, 2013</last_update_submitted>
  <last_update_submitted_qc>September 9, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 10, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>in vitro fertilization</keyword>
  <keyword>ovarian stimulation</keyword>
  <keyword>follicular waves</keyword>
  <keyword>luteal phase</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chorionic Gonadotropin</mesh_term>
  </intervention_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/NCT01668056
org study id: 1099/09
nct id: NCT01668056
lead sponsor: 
has dmc: Yes
Ovarian stimulation is an important phase of in vitro fertilization (IVF) treatments. The
      harvest of a larger number of viable eggs per cycle compensate eventual laboratory
      difficulties and allow for the selection of embryos with higher implantation potential. In
      the current protocols, based on the most prevailing theory of ovarian follicular development,
      stimulation drugs are usually started on the second or third day after the beginning of
      menses. The follicular phase of the menstrual cycle is believed to be the only favorable
      moment for follicular development.

      In the early 2000's a new model of human ovarian follicular development (follicular waves)
      has been proposed based on frequent transvaginal ultrasound observations between two
      ovulations. It has been shown that ovarian antral follicles develop in synchronous groups,
      two to three times in a cycle. In fact the follicular wave phenomenon has been initially
      described in the 80's on domestic animals, like the mare and the cow. Moreover, studies in
      these animals have shown that synchronizing the start of the ovarian stimulation drugs with
      the beginning of a follicular wave yields better results for assisted reproductive
      treatments. Consequently in ovarian stimulation protocols for animal assisted reproduction it
      is important to control the initiation of a follicular wave.

      Current protocols of ovarian stimulation for IVF in women do not consider the start of a
      follicular wave to begin drug administration. Therefore the purpose of this study is to
      evaluate two methods to control the emergence of a follicular wave (ovulation induction and
      dominant follicle aspiration) and to investigate the effects of synchronizing ovarian
      stimulation for IVF with follicular wave emergence in women compared to one of the current
      stimulation protocols (flexible GnRH protocol).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Emergence of an ovarian follicular wave after dominant follicle aspiration or hCG administration
time frame: One year
description: Evaluate if the aspiration of the dominant follicle is able to induce a follicular wave to emerge.
Evaluate if administration of hCG is able to induce ovulation of a dominant follicle larger than 16mm and to induce a follicular wave to emerge.
A follicular wave emergence is defined as an increase in the number of ovarian follicles smaller than 10mm seen at the transvaginal ultrasound scan after the interventions
measure: Follicular growth pattern on ultrasound scan
time frame: One year
description: Evaluate with periodic transvaginal ultrasound scan the size (mm), number and growth rate (mm/day) of ovarian follicles in each of the three groups
measure: Estradiol and progesterone levels during ovarian stimulation
time frame: One year
description: Evaluate blood levels of estradiol (pg/mL) and progesterone (ng/mL) during ovarian stimulation in each of the three groups at each visit to evaluate the progress of treatment.
measure: Number of mature oocytes retrieved
time frame: One year
description: Evaluate the number of metaphase II oocytes retrieved in each of the three groups
measure: Total dose of gonadotrophins used
time frame: One year
description: Total dose of gonadotrophins (in international units) necessary to stimulate the ovaries (from the first day of stimulation until the last dose of recombinant FSH administered before the oocyte retrieval)
measure: Fertilization rate
time frame: One year
description: Number of embryos formed in relation with the number of oocytes inseminated
measure: Pregnancy rate
time frame: One year
description: Positive beta hCG determination on blood 10 days after embryo transfer
arm group label: Control
arm group type: Active Comparator
description: Patients will be stimulated according to the conventional flexible GnRH antagonist protocol for IVF. Alfa follitropin (150IU a day) will be started on the third day of the menstrual cycle. Treatment monitoring will be done with transvaginal ultrasound scans and serum determinations of estradiol and progesterone 5 days after the start of gonadotropins and every each day thereafter. Once the leading follicle reaches 13 mm in mean diameter 0,25mg of cetrorelix acetate will be administered daily. Once at least two follicles reach 18mm or more in mean diameter 250 micrograms of choriogonadotropin alfa will be administered and 36 hours latter patients will undergo follicle aspiration for IVF. Embryos will be cryopreserved (vitrification) on the third or fifth day of development. Two months after women will undergo uterine preparation for embryo transfer.
arm group label: Ovulation induction
arm group type: Experimental
description: Patients will be monitored with daily transvaginal ultrasound scans from the tenth day of the menstrual cycle on. When the dominant follicle reaches a mean diameter of 16mm or more, patients will receive 250 micrograms of choriogonadotropin alfa subcutaneously. Daily transvaginal ultrasound scans will be done starting two days after the administration of the medication until a cohort of ovarian follicles between 4-6 mm is seen (follicular wave emergence). From this point on patients will undergo the same stimulation protocol as Controls, i.e., flexible GnRH antagonist protocol.
arm group label: Dominant follicle aspiration
arm group type: Experimental
description: Patients will be monitored with daily transvaginal ultrasound scans from the tenth day of the menstrual cycle on. When the dominant follicle reaches a mean diameter of 16mm or more, patients will then undergo aspiration of the dominant and all follicles greater than 10mm in mean diameter. aspiration will be transvaginal ultrasound guided and under sedation, as for oocyte retrieval. Oocytes eventually obtained at this first aspiration will not be used for IVF. Daily transvaginal ultrasound scans will be done starting the day after the follicular aspiration until a cohort of follicles between 4-6 mm is seen (follicular wave emergence). From this point on patients will undergo the same stimulation protocol as Controls, i.e., flexible GnRH antagonist protocol.
intervention type: Drug
intervention name: Ovulation induction with choriogonadotropin alfa
description: Administration of 250 micrograms of choriogonadotropin alfa subcutaneously when the dominant follicle of a natural menstrual cycle reaches 16mm or more of mean diameter. Verify if this intervention is able to induce follicular wave emergence and synchronize the start of the flexible GnRH antagonist protocol of ovarian stimulation with the start of a follicular wave.
arm group label: Ovulation induction
intervention type: Procedure
intervention name: Aspiration of the dominant follicle
description: Aspiration of all follicles greater than 10mm in mean diameter when the dominant follicle of a natural menstrual cycle reaches 16mm or more of mean diameter. Aspiration will be guided by transvaginal ultrasound. Verify if this intervention is able to induce follicular wave emergence and synchronize the start of the flexible GnRH antagonist protocol of ovarian stimulation with the start of a follicular wave.
arm group label: Dominant follicle aspiration
intervention type: Other
intervention name: Control
description: Conventional flexible GnRH antagonist protocol of ovarian stimulation for in vitro fertilization, with gonadotropin star at the third day of a natural menstrual cycle.
arm group label: Control
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: No
last name: Edmund c Baracat, PhD
role: Study Chair
affiliation: University of Sao Paulo Medical School
last name: Paulo C Serafini, PhD
role: Study Director
affiliation: University of Sao Paulo Medical School
last name: Paulo HM Bianchi, MD
role: Principal Investigator
affiliation: University of Sao Paulo Medical School
last name: Paulo HM Bianchi, MD
email: paulobianchi35@gmail.com
facility: 
status: Recruiting
contact: 
investigator: 
country: Brazil
citation: Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril. 2003 Jul;80(1):116-22. doi: 10.1016/s0015-0282(03)00544-2.
PMID: 12849812
citation: Baerwald AR, Adams GP, Pierson RA. Characterization of ovarian follicular wave dynamics in women. Biol Reprod. 2003 Sep;69(3):1023-31. doi: 10.1095/biolreprod.103.017772. Epub 2003 May 14.
PMID: 12748128
citation: Baerwald AR, Adams GP, Pierson RA. Ovarian antral folliculogenesis during the human menstrual cycle: a review. Hum Reprod Update. 2012 Jan-Feb;18(1):73-91. doi: 10.1093/humupd/dmr039. Epub 2011 Nov 8.
PMID: 22068695
citation: Adams GP, Singh J, Baerwald AR. Large animal models for the study of ovarian follicular dynamics in women. Theriogenology. 2012 Nov;78(8):1733-48. doi: 10.1016/j.theriogenology.2012.04.010. Epub 2012 May 22.
PMID: 22626769
citation: de Mello Bianchi PH, Serafini P, Monteiro da Rocha A, Assad Hassun P, Alves da Motta EL, Sampaio Baruselli P, Chada Baracat E. Review: follicular waves in the human ovary: a new physiological paradigm for novel ovarian stimulation protocols. Reprod Sci. 2010 Dec;17(12):1067-76. doi: 10.1177/1933719110366483. Epub 2010 May 3.
PMID: 20439948
responsible party type: Sponsor
mesh term: Infertility
mesh term: Chorionic Gonadotropin