<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/NCT03300518</url>
  </required_header>
  <id_info>
    <org_study_id>MSD-MISP-ZX-01</org_study_id>
    <nct_id>NCT03300518</nct_id>
  </id_info>
  <brief_title>Effectiveness of Estradiol Valerate Pretreatment in Antagonist Protocol for Poor Ovarian Response Patient</brief_title>
  <official_title>A Randomized Study to Analysis the Effectiveness of Estradiol Valerate Pretreatment in Antagonist Protocol for Poor Ovarian Response Patient</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Reproductive &amp; Genetic Hospital of CITIC-Xiangya</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Reproductive &amp; Genetic Hospital of CITIC-Xiangya</source>
  <oversight_info>
    <has_dmc>Yes</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 study is to assess the efficacy of add-on estrogen pretreatment in GnRH&#xD;
      antagonist protocol on oocyte retrieval as compared with GnRH antagonist protocol for&#xD;
      patients with poor ovarian response Add-on estrogen pretreatment protocol is superior to none&#xD;
      pretreatment GnRH antagonist protocol for the number of oocytes retrieval&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Women of advanced maternal age seeking ART treatment are characterized as poor ovarian&#xD;
      responders in the process of ovarian simulation. Poor response to ovarian stimulation causes&#xD;
      high cycle cancellation rate and extremely low pregnancy rate.&#xD;
&#xD;
      More attention has been paid to the potential interest of steroid pretreatments in GnRH&#xD;
      antagonist cycles; not only for scheduling the GnRH antagonist cycles, but also for&#xD;
      synchronizing the follicular growth which may result in more oocytes retrieved. But available&#xD;
      clinical results are controversial.&#xD;
&#xD;
      Previous studies have shown that utilizing the natural negative feedback of the&#xD;
      hypothalamus-pituitary-ovary axis induced by estradiol valerate pretreatment effectively&#xD;
      prevented inter-cycle increases in follicle-stimulating hormone, improved follicle&#xD;
      synchronization, and resulted in a more coordinated follicular development, leading to the&#xD;
      recovery of more mature oocytes. However none of the randomized controlled studies compared&#xD;
      estradiol valerate pretreatment or not on treatment outcomes, ongoing pregnancy rate,&#xD;
      directly on poor response patients using estradiol valerate pretreatment in GnRH antagonist&#xD;
      protocol.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 15, 2017</start_date>
  <completion_date type="Actual">August 18, 2021</completion_date>
  <primary_completion_date type="Actual">June 18, 2021</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>The number of oocytes retrieved by the IVG 36 hours after hCG administration</measure>
    <time_frame>36 hours after hCG administration</time_frame>
    <description>The total MII oocytes retrievedd</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical pregnancy rate</measure>
    <time_frame>6weeks</time_frame>
    <description>clinical pregnancy, defined as intrauterine pregnancy with a positive heartbeat at 6 weeks of gestation.Clinical pregnancy rate:Number of clinical pregnancies expressed per 100 initiated cycles, aspiration cycles, or embryo transfer cycles. When clinical pregnancy rates are given, the denominator must be specified.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ongoing pregnancy rate</measure>
    <time_frame>12weeks</time_frame>
    <description>ongoing pregnancy defined as an intact pregnancy at 12 weeks of gestation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Optimal number of embryo</measure>
    <time_frame>1 week</time_frame>
    <description>According to the embryonic developmental rate and morphology, the high quality embryos were defined as the next day (D2) transplanted embryos reached 3 or 4 cells and the third day (D3) transplanted embryos reached 6 to 8 cells with morphological grade 1 or 2</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">552</enrollment>
  <condition>Infertility</condition>
  <arm_group>
    <arm_group_label>pretreatment group</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>the pretreatment group underwent a modified treatment protocol with pretreatment with estogen administering during the cycle preceding the IVF/ICSI cycle. daily dose of 4 mg (2 mg twice a day) estradiol valerate was given orally in the middle luteal phase which is confirmed seven days after ovulation monitoring by the ultrasound up to 2 days of the next menstrual cycle.Recombinant FSH (Puregon) was initiated on menstrual cycle day 2- 3 at an initial dose of 300 IU/day.A daily administration of ganirelix (0.25 mg Orgalutran; Organon) was introduced when the leading follicle is near 13mm, and was repeated up to the time of hCG administration.Ovulation was triggered when the leading follicles reach 18-20mm and at least two follicles 17-18mm , HCG 10000 IU is used to trigger.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>control groups</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>In the control groups standard GnRH-antagonist protocol was applied.Recombinant FSH (Puregon) was initiated on menstrual cycle day 2- 3 at an initial dose of 300 IU/day.A daily administration of ganirelix (0.25 mg Orgalutran; Organon) was introduced when the leading follicle is near 13mm, and was repeated up to the time of hCG administration.Ovulation was triggered when the leading follicles reach 18-20mm and at least two follicles 17-18mm , HCG 10000 IU is used to trigger.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Follitropin Beta;MSD</intervention_name>
    <description>Patients will start stimulation with a daily s.c. injection of follitropin beta( 300IU Puregonon;MSD) menstrual cycle day 2 or 3.</description>
    <arm_group_label>control groups</arm_group_label>
    <arm_group_label>pretreatment group</arm_group_label>
    <other_name>Puregon</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ganirelix</intervention_name>
    <description>A daily administration of ganirelix (0.25 mg Orgalutran; MSD) was introduced when the leading follicle is near 13mm, and was repeated up to the time of hCG administration.</description>
    <arm_group_label>control groups</arm_group_label>
    <arm_group_label>pretreatment group</arm_group_label>
    <other_name>Orgalutran</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>hCG</intervention_name>
    <description>Ovulation was triggered when the leading follicles reach 18-20mm and at least two follicles 17-18mm , HCG 10000 IU is used to trigger</description>
    <arm_group_label>control groups</arm_group_label>
    <arm_group_label>pretreatment group</arm_group_label>
    <other_name>Ovidrel</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>estradiol valerate</intervention_name>
    <description>Estradiol valerate (progynova,Schering) daily dose of 4 mg (2 mg twice a day) was given orally, started 7 days before the presumed onset of menses and administered up to 2 days of the next menstrual cycle</description>
    <arm_group_label>pretreatment group</arm_group_label>
    <other_name>progynova</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:Bologna criteria&#xD;
&#xD;
          -  At least two of the following three features must be present:&#xD;
&#xD;
               1. Advanced maternal age (≥40 years) or any other risk factor for POR&#xD;
&#xD;
               2. A previous POR (≤3 oocytes with a conventional stimulation protocol)&#xD;
&#xD;
               3. An abnormal ovarian reserve test (i.e. antral follicle count &lt; 5-7 follicles or&#xD;
                  AMH&lt; 0.5 - 1.1 ng/mL)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age ≥45 years,&#xD;
&#xD;
          2. Patients who conducted PGD/PGS, and donor egg cycles were excluded.&#xD;
&#xD;
          3. Presence of unilateral ovary absence&#xD;
&#xD;
          4. Abnormal uterine deformity or structure.&#xD;
&#xD;
          5. Spontaneous abortion patients with three or more (including biochemical pregnancy&#xD;
             abortion)&#xD;
&#xD;
          6. With other endocrine disease, ovulation disorders such as adrenal cortex function or&#xD;
             thyroid dysfunction&#xD;
&#xD;
          7. Have assisted reproductive technology contraindications or pregnancy contraindication&#xD;
             of patients&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Fei Gong, Doctor</last_name>
    <role>Study Director</role>
    <affiliation>Reproductive &amp; Genetic Hospital of CITIC-Xiangya</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Reproductive &amp; Genetic Hospital of Citic-Xiangya</name>
      <address>
        <city>Changsha</city>
        <state>Hunan</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>September 28, 2017</study_first_submitted>
  <study_first_submitted_qc>September 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 3, 2017</study_first_posted>
  <last_update_submitted>January 9, 2022</last_update_submitted>
  <last_update_submitted_qc>January 9, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">January 11, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>GnRH antagonist</keyword>
  <keyword>Estrogen pretreatment</keyword>
  <keyword>Poor response patient</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>Estradiol 17 beta-cypionate</mesh_term>
    <mesh_term>Estradiol 3-benzoate</mesh_term>
    <mesh_term>Estradiol</mesh_term>
    <mesh_term>Polyestradiol phosphate</mesh_term>
    <mesh_term>Follicle Stimulating Hormone</mesh_term>
    <mesh_term>Ganirelix</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>April 13, 2022</submitted>
    <returned>January 13, 2023</returned>
  </pending_results>
  <!-- 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/NCT03300518
org study id: MSD-MISP-ZX-01
nct id: NCT03300518
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The purpose of study is to assess the efficacy of add-on estrogen pretreatment in GnRH
      antagonist protocol on oocyte retrieval as compared with GnRH antagonist protocol for
      patients with poor ovarian response Add-on estrogen pretreatment protocol is superior to none
      pretreatment GnRH antagonist protocol for the number of oocytes retrieval
Women of advanced maternal age seeking ART treatment are characterized as poor ovarian
      responders in the process of ovarian simulation. Poor response to ovarian stimulation causes
      high cycle cancellation rate and extremely low pregnancy rate.

      More attention has been paid to the potential interest of steroid pretreatments in GnRH
      antagonist cycles; not only for scheduling the GnRH antagonist cycles, but also for
      synchronizing the follicular growth which may result in more oocytes retrieved. But available
      clinical results are controversial.

      Previous studies have shown that utilizing the natural negative feedback of the
      hypothalamus-pituitary-ovary axis induced by estradiol valerate pretreatment effectively
      prevented inter-cycle increases in follicle-stimulating hormone, improved follicle
      synchronization, and resulted in a more coordinated follicular development, leading to the
      recovery of more mature oocytes. However none of the randomized controlled studies compared
      estradiol valerate pretreatment or not on treatment outcomes, ongoing pregnancy rate,
      directly on poor response patients using estradiol valerate pretreatment in GnRH antagonist
      protocol.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The number of oocytes retrieved by the IVG 36 hours after hCG administration
time frame: 36 hours after hCG administration
description: The total MII oocytes retrievedd
measure: Clinical pregnancy rate
time frame: 6weeks
description: clinical pregnancy, defined as intrauterine pregnancy with a positive heartbeat at 6 weeks of gestation.Clinical pregnancy rate:Number of clinical pregnancies expressed per 100 initiated cycles, aspiration cycles, or embryo transfer cycles. When clinical pregnancy rates are given, the denominator must be specified.
measure: ongoing pregnancy rate
time frame: 12weeks
description: ongoing pregnancy defined as an intact pregnancy at 12 weeks of gestation
measure: Optimal number of embryo
time frame: 1 week
description: According to the embryonic developmental rate and morphology, the high quality embryos were defined as the next day (D2) transplanted embryos reached 3 or 4 cells and the third day (D3) transplanted embryos reached 6 to 8 cells with morphological grade 1 or 2
arm group label: pretreatment group
arm group type: Other
description: the pretreatment group underwent a modified treatment protocol with pretreatment with estogen administering during the cycle preceding the IVF/ICSI cycle. daily dose of 4 mg (2 mg twice a day) estradiol valerate was given orally in the middle luteal phase which is confirmed seven days after ovulation monitoring by the ultrasound up to 2 days of the next menstrual cycle.Recombinant FSH (Puregon) was initiated on menstrual cycle day 2- 3 at an initial dose of 300 IU/day.A daily administration of ganirelix (0.25 mg Orgalutran; Organon) was introduced when the leading follicle is near 13mm, and was repeated up to the time of hCG administration.Ovulation was triggered when the leading follicles reach 18-20mm and at least two follicles 17-18mm , HCG 10000 IU is used to trigger.
arm group label: control groups
arm group type: Other
description: In the control groups standard GnRH-antagonist protocol was applied.Recombinant FSH (Puregon) was initiated on menstrual cycle day 2- 3 at an initial dose of 300 IU/day.A daily administration of ganirelix (0.25 mg Orgalutran; Organon) was introduced when the leading follicle is near 13mm, and was repeated up to the time of hCG administration.Ovulation was triggered when the leading follicles reach 18-20mm and at least two follicles 17-18mm , HCG 10000 IU is used to trigger.
intervention type: Drug
intervention name: Follitropin Beta;MSD
description: Patients will start stimulation with a daily s.c. injection of follitropin beta( 300IU Puregonon;MSD) menstrual cycle day 2 or 3.
arm group label: control groups
arm group label: pretreatment group
other name: Puregon
intervention type: Drug
intervention name: Ganirelix
description: A daily administration of ganirelix (0.25 mg Orgalutran; MSD) was introduced when the leading follicle is near 13mm, and was repeated up to the time of hCG administration.
arm group label: control groups
arm group label: pretreatment group
other name: Orgalutran
intervention type: Drug
intervention name: hCG
description: Ovulation was triggered when the leading follicles reach 18-20mm and at least two follicles 17-18mm , HCG 10000 IU is used to trigger
arm group label: control groups
arm group label: pretreatment group
other name: Ovidrel
intervention type: Drug
intervention name: estradiol valerate
description: Estradiol valerate (progynova,Schering) daily dose of 4 mg (2 mg twice a day) was given orally, started 7 days before the presumed onset of menses and administered up to 2 days of the next menstrual cycle
arm group label: pretreatment group
other name: progynova
criteria: 
gender: Female
minimum age: 40 Years
maximum age: 45 Years
healthy volunteers: No
last name: Fei Gong, Doctor
role: Study Director
affiliation: Reproductive & Genetic Hospital of CITIC-Xiangya
facility: 
country: China
responsible party type: Sponsor
mesh term: Infertility
mesh term: Estradiol 17 beta-cypionate
mesh term: Estradiol 3-benzoate
mesh term: Estradiol
mesh term: Polyestradiol phosphate
mesh term: Follicle Stimulating Hormone
mesh term: Ganirelix
sharing ipd: Undecided
submitted: April 13, 2022
returned: January 13, 2023