<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/NCT02262923</url>
  </required_header>
  <id_info>
    <org_study_id>14-0209-A</org_study_id>
    <nct_id>NCT02262923</nct_id>
  </id_info>
  <brief_title>Dopamine D-2 Antagonist Use in Poor Responders in IVF: a Randomized Controlled Trial</brief_title>
  <official_title>Dopamine D-2 Antagonist Use in Poor Responders in IVF: a Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mount Sinai Hospital, Canada</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mount Sinai Hospital, Canada</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Metoclopramide is a dopamine D2 receptor antagonist with antiemetic and gastrokinetic&#xD;
      properties which has been approved for use in pregnant women. Women with polycystic ovary&#xD;
      syndrome (PCOS) have been found to have lower dopaminergic tone and increased ovarian&#xD;
      vascularity and vascular endothelial growth factor (VEGF) levels compared to controls. During&#xD;
      ovarian stimulation, PCOS patients exhibit greater sensitivity to gonadotropins and increased&#xD;
      follicular development. Administration of dopamine D2 antagonists may mimic the low&#xD;
      dopaminergic tone noted in PCOS patients, increase VEGF levels, angiogenesis, and&#xD;
      subsequently improve follicular growth during ovarian stimulation. This strategy could be&#xD;
      used to improve IVF outcomes in poor responders.&#xD;
&#xD;
      The investigators hypothesize that, compared to gonadotropin use alone, the use of&#xD;
      metoclopramide in combination with gonadotropins in poor responders undergoing IVF will&#xD;
      result in an increased number of mature oocytes obtained at oocyte retrieval and improved IVF&#xD;
      outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Poor responders constitute a significant and challenging population of women to treat with in&#xD;
      vitro fertilization (IVF). This population includes women who respond sub-optimally to&#xD;
      conventional ovarian stimulation with poor follicular recruitment. The estimated incidence of&#xD;
      poor ovarian response ranges from 9-26%. Patients with PCOS are on the opposite end of the&#xD;
      spectrum from poor responders. They are often exquisitely sensitive to ovarian stimulation&#xD;
      and are predisposed to over-respond with the development of ovarian hyperstimulation syndrome&#xD;
      (OHSS). Understanding the underlying mechanisms that enhance their sensitivity may provide&#xD;
      insight into the treatment of poor responders. VEGF is a glycoprotein produced by ovarian&#xD;
      granulosa cells that enhances vascular permeability and angiogenesis, and has been implicated&#xD;
      in the pathogenesis of OHSS. After ovulation is triggered by LH or hCG, follicular expression&#xD;
      of VEGF increases, which is crucial for corpus luteum function and steroidogenesis. However,&#xD;
      excessive VEGF production can lead to third-space shifts of fluids, ascites, and other&#xD;
      life-threatening features of OHSS. Serum concentrations and granulosa cell expression of VEGF&#xD;
      have been shown to be higher in women with PCOS than in controls. Interestingly, compared&#xD;
      with controls, patients with PCOS have also been shown to have lower levels of the&#xD;
      neurotransmitter dopamine and dopamine D2 receptor levels in the ovary. Administration of&#xD;
      dopamine D2 agonists has been shown in animal and human studies to decrease ovarian VEGF&#xD;
      production and reduce the risk of OHSS. In this study, the investigators propose a novel&#xD;
      approach of administering a dopamine D2 antagonist to poor responders to mimic the low&#xD;
      dopaminergic tone of PCOS patients, with the goal of increasing VEGF production and&#xD;
      follicular development during ovarian stimulation. Metoclopramide is a dopamine D2 antagonist&#xD;
      with antiemetic and prokinetic properties and an established safety profile in pregnancy. The&#xD;
      investigators hypothesis is that metoclopramide use prior to, and in conjunction with,&#xD;
      conventional gonadotropin stimulation can improve IVF outcomes in poor responders.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <start_date type="Actual">March 2016</start_date>
  <completion_date type="Actual">March 2018</completion_date>
  <primary_completion_date type="Actual">March 2018</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of oocytes retrieved</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of mature follicles (≥1.5cm) seen on transvaginal ultrasound at the time of ovulation trigger</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak serum estradiol levels measured at the time of ovulation trigger shot</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ratio of mature/ immature oocytes obtained at oocyte retrieval</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Follicular fluid levels of VEGF, VEGFR-1 and VEGFR-2</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total dose of gonadotropins used and number of days of stimulation</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fertilization rates</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of embryos on day 3 and 5</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pregnancy and implantation rates</measure>
    <time_frame>1-2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum prolactin levels on cycle day 3,7 and at the time of ovulation trigger</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>in Vitro Fertilization</condition>
  <condition>Poor Responder</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Poor responders will be defined as women who have undergone a previous IVF cycle with fewer than 4 oocytes retrieved and at least one of the following two criteria: (1) advanced age (≥40 years) or any other risk factor for poor ovarian response and (2) abnormal ovarian reserve testing (antral follicle count (AFC) &lt; 5-7 or anti-mullerian hormone (AMH) level &lt; 3.6-7.9 pmol/L). Poor responders who will be undergoing a repeat IVF cycle will be recruited for the study with informed consent.&#xD;
In the control arm, patients will undergo the same ovarian stimulation protocol as the previous IVF cycle in which they experienced a poor response. Starting 3 weeks prior to the first day of stimulation until the time of ovulation trigger (approximately 5 weeks overall), these patients will receive an oral placebo three times daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Experimental</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Poor responders will be defined as women who have undergone a previous IVF cycle with fewer than 4 oocytes retrieved and at least one of the following two criteria: (1) advanced age (≥40 years) or any other risk factor for poor ovarian response and (2) abnormal ovarian reserve testing (antral follicle count (AFC) &lt; 5-7 or anti-mullerian hormone (AMH) level &lt; 3.6-7.9 pmol/L). Poor responders who will be undergoing a repeat IVF cycle will be recruited for the study with informed consent.&#xD;
In the experimental arm, patients will undergo the same ovarian stimulation protocol as the previous IVF cycle in which they experienced a poor response. Starting 3 weeks prior to the first day of stimulation until the time of ovulation trigger (approximately 5 weeks in total), these patients will receive oral metoclopramide 5mg three times daily..</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>metoclopramide</intervention_name>
    <arm_group_label>Experimental</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Poor responders undergoing a repeat IVF cycle defined as women who have undergone at&#xD;
             least one previous IVF cycle with fewer than 4 oocytes retrieved and at least one of&#xD;
             the following:&#xD;
&#xD;
               -  Advanced age (≥40 years) or any other risk factor for poor ovarian response&#xD;
&#xD;
               -  Abnormal ovarian reserve testing (antral follicle count (AFC) &lt; 5-7 or&#xD;
                  anti-mullerian hormone (AMH) level &lt; 3.6-7.9 pmol/L)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects who have previously been recruited into this study and either had cycle&#xD;
             cancellation, underwent retrieval or dropped out of the study.&#xD;
&#xD;
          -  Women with contraindications or allergies to metoclopramide.&#xD;
&#xD;
          -  Women with elevated prolactin levels or known to have pituitary microadenomas or&#xD;
             macroadenoma.&#xD;
&#xD;
          -  Women who are taking dopamine agonist medications.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>43 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Mount Sinai Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5T 3H7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>October 8, 2014</study_first_submitted>
  <study_first_submitted_qc>October 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 13, 2014</study_first_posted>
  <last_update_submitted>April 7, 2022</last_update_submitted>
  <last_update_submitted_qc>April 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 11, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metoclopramide</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/NCT02262923
org study id: 14-0209-A
nct id: NCT02262923
lead sponsor: 
has dmc: No
Metoclopramide is a dopamine D2 receptor antagonist with antiemetic and gastrokinetic
      properties which has been approved for use in pregnant women. Women with polycystic ovary
      syndrome (PCOS) have been found to have lower dopaminergic tone and increased ovarian
      vascularity and vascular endothelial growth factor (VEGF) levels compared to controls. During
      ovarian stimulation, PCOS patients exhibit greater sensitivity to gonadotropins and increased
      follicular development. Administration of dopamine D2 antagonists may mimic the low
      dopaminergic tone noted in PCOS patients, increase VEGF levels, angiogenesis, and
      subsequently improve follicular growth during ovarian stimulation. This strategy could be
      used to improve IVF outcomes in poor responders.

      The investigators hypothesize that, compared to gonadotropin use alone, the use of
      metoclopramide in combination with gonadotropins in poor responders undergoing IVF will
      result in an increased number of mature oocytes obtained at oocyte retrieval and improved IVF
      outcomes.
Poor responders constitute a significant and challenging population of women to treat with in
      vitro fertilization (IVF). This population includes women who respond sub-optimally to
      conventional ovarian stimulation with poor follicular recruitment. The estimated incidence of
      poor ovarian response ranges from 9-26%. Patients with PCOS are on the opposite end of the
      spectrum from poor responders. They are often exquisitely sensitive to ovarian stimulation
      and are predisposed to over-respond with the development of ovarian hyperstimulation syndrome
      (OHSS). Understanding the underlying mechanisms that enhance their sensitivity may provide
      insight into the treatment of poor responders. VEGF is a glycoprotein produced by ovarian
      granulosa cells that enhances vascular permeability and angiogenesis, and has been implicated
      in the pathogenesis of OHSS. After ovulation is triggered by LH or hCG, follicular expression
      of VEGF increases, which is crucial for corpus luteum function and steroidogenesis. However,
      excessive VEGF production can lead to third-space shifts of fluids, ascites, and other
      life-threatening features of OHSS. Serum concentrations and granulosa cell expression of VEGF
      have been shown to be higher in women with PCOS than in controls. Interestingly, compared
      with controls, patients with PCOS have also been shown to have lower levels of the
      neurotransmitter dopamine and dopamine D2 receptor levels in the ovary. Administration of
      dopamine D2 agonists has been shown in animal and human studies to decrease ovarian VEGF
      production and reduce the risk of OHSS. In this study, the investigators propose a novel
      approach of administering a dopamine D2 antagonist to poor responders to mimic the low
      dopaminergic tone of PCOS patients, with the goal of increasing VEGF production and
      follicular development during ovarian stimulation. Metoclopramide is a dopamine D2 antagonist
      with antiemetic and prokinetic properties and an established safety profile in pregnancy. The
      investigators hypothesis is that metoclopramide use prior to, and in conjunction with,
      conventional gonadotropin stimulation can improve IVF outcomes in poor responders.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Number of oocytes retrieved
time frame: 1 year
measure: Number of mature follicles (≥1.5cm) seen on transvaginal ultrasound at the time of ovulation trigger
time frame: 1 year
measure: Peak serum estradiol levels measured at the time of ovulation trigger shot
time frame: 1 year
measure: Ratio of mature/ immature oocytes obtained at oocyte retrieval
time frame: 1 year
measure: Follicular fluid levels of VEGF, VEGFR-1 and VEGFR-2
time frame: 1 year
measure: Total dose of gonadotropins used and number of days of stimulation
time frame: 1 year
measure: Fertilization rates
time frame: 1 year
measure: Number of embryos on day 3 and 5
time frame: 1 year
measure: Pregnancy and implantation rates
time frame: 1-2 years
measure: Serum prolactin levels on cycle day 3,7 and at the time of ovulation trigger
time frame: 1 year
arm group label: Control
arm group type: No Intervention
description: Poor responders will be defined as women who have undergone a previous IVF cycle with fewer than 4 oocytes retrieved and at least one of the following two criteria: (1) advanced age (≥40 years) or any other risk factor for poor ovarian response and (2) abnormal ovarian reserve testing (antral follicle count (AFC) < 5-7 or anti-mullerian hormone (AMH) level < 3.6-7.9 pmol/L). Poor responders who will be undergoing a repeat IVF cycle will be recruited for the study with informed consent.
In the control arm, patients will undergo the same ovarian stimulation protocol as the previous IVF cycle in which they experienced a poor response. Starting 3 weeks prior to the first day of stimulation until the time of ovulation trigger (approximately 5 weeks overall), these patients will receive an oral placebo three times daily.
arm group label: Experimental
arm group type: Experimental
description: Poor responders will be defined as women who have undergone a previous IVF cycle with fewer than 4 oocytes retrieved and at least one of the following two criteria: (1) advanced age (≥40 years) or any other risk factor for poor ovarian response and (2) abnormal ovarian reserve testing (antral follicle count (AFC) < 5-7 or anti-mullerian hormone (AMH) level < 3.6-7.9 pmol/L). Poor responders who will be undergoing a repeat IVF cycle will be recruited for the study with informed consent.
In the experimental arm, patients will undergo the same ovarian stimulation protocol as the previous IVF cycle in which they experienced a poor response. Starting 3 weeks prior to the first day of stimulation until the time of ovulation trigger (approximately 5 weeks in total), these patients will receive oral metoclopramide 5mg three times daily..
intervention type: Drug
intervention name: metoclopramide
arm group label: Experimental
criteria: 
gender: Female
minimum age: 21 Years
maximum age: 43 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Metoclopramide