<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/NCT02201914</url>
  </required_header>
  <id_info>
    <org_study_id>BRM003</org_study_id>
    <nct_id>NCT02201914</nct_id>
  </id_info>
  <brief_title>Clomiphene Citrate Plus Gonadotropins and GnRH Antagonist Versus Flexible GnRH Antagonist Protocol Versus Microdose GnRH Agonist Protocol in Poor Responders Undergoing IVF</brief_title>
  <official_title>Clomiphene Citrate Plus Gonadotropins and GnRH Antagonist Versus Flexible GnRH Antagonist Protocol Versus Microdose GnRH Agonist Protocol in Poor Responders Undergoing IVF: a Randomized Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bioroma</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Bioroma</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Poor ovarian response to stimulation in IVF cycles is a challenging and frustrating&#xD;
      condition, due to its poor prognosis in terms of chances of pregnancy and live births.&#xD;
      Various ovarian stimulation regimens have been tried to overcome these obstacles. A simple&#xD;
      approach is increase the dose of the gonadotropin administration, but the results in terms of&#xD;
      pregnancy rate are very low Another commonly used stimulation regimen is the microdose GnRH&#xD;
      agonist protocol, which takes advantage of the initial rise in endogenous gonadotropins that&#xD;
      follows the agonist administration in the early follicular phase and subsequently prevents a&#xD;
      premature LH surge, with fewer cycle cancellations. However, their application in poor&#xD;
      responders, even if in small doses and for a limited period, has been questioned as they may&#xD;
      cause oversuppression of ovarian function, leading to a prolonged cycle and increased&#xD;
      treatment costs without improving the outcomes.&#xD;
&#xD;
      Recently, GnRH antagonists were introduced in ART treatment. They are effective in preventing&#xD;
      a premature LH surge and allow for a more natural recruitment of follicles in the follicular&#xD;
      phase in a non-suppressed ovary, offering a potential alternative in the treatment of these&#xD;
      patients. However, randomized studies evaluating the efficacy of this regimen in poor&#xD;
      responders did not show any improvements in pregnancy rates. Current approach have included&#xD;
      the addition of oral agents such us clomiphene citrate (CC) to gonadotropins. Some authors&#xD;
      have investigated the role of CC in addition to low dose of gonadotropins in mild stimulation&#xD;
      regimen, demonstrating that, despite a small number of retrieved oocytes, good quality&#xD;
      embryos were produced with a subsequent improvement in the fertilization rate, clinical&#xD;
      pregnancy rate and live birth rate. The only study that evaluate the efficacy of CC in&#xD;
      addition to high doses of gonadotropins in poor responders showed improving in number of&#xD;
      retrieved oocytes, transferred embryos and biochemical pregnancy; however, clinical pregnancy&#xD;
      rate and live birth rate remained low and showed no measurable increase.&#xD;
&#xD;
      The aim of this study was to compare the efficacy of the CC as an adjunctive to a high dose&#xD;
      of gonadotropins in cycles with antagonist protocols with the microdose GnRH agonist and&#xD;
      flexible antagonist protocols in women who responded poorly to ovarian stimulation, to&#xD;
      determine whether this protocol may improve IVF outcomes, offering a valid alternative in&#xD;
      poor responder patients treatment.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>January 2014</start_date>
  <completion_date type="Anticipated">November 2014</completion_date>
  <primary_completion_date type="Anticipated">October 2014</primary_completion_date>
  <phase>Phase 4</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>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical pregnancy rate</measure>
    <time_frame>Time Frame: until 12th gestational week</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>implantation rate</measure>
    <time_frame>Time Frame: until 12th gestational week</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">250</enrollment>
  <condition>Poor Responders</condition>
  <condition>IVF</condition>
  <condition>Clomiphene Citrate</condition>
  <condition>GnRH Agonist</condition>
  <condition>GnRH Antagonist</condition>
  <arm_group>
    <arm_group_label>Clomiphene citrate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Daily FSH and LH plus Cetrorelix</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Triptorelin plus daily FSH and LH</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clomiphene citrate</intervention_name>
    <description>patients receive clomiphene citrate 100 mg daily starting on day 2 for 5 days and 450 IU recombinant FSH and 225 IU recombinant LH daily starting on day 5; Cetrorelix 0,25 mg was administered daily when one or more follicle reached 13-14 mm in diameter until the hCG injection</description>
    <arm_group_label>Clomiphene citrate</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Daily FSH and LH plus Cetrorelix</intervention_name>
    <description>Women receive an initial daily dose of 450 IU recombinant FSH and 225 IU recombinant LH starting on day 3; Cetrorelix 0,25 mg was administered daily when one or more follicle reached 13-14 mm in diameter until the hCG injection.</description>
    <arm_group_label>Daily FSH and LH plus Cetrorelix</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Triptorelin plus daily FSH anh LH</intervention_name>
    <description>women receive short-acting Triptorelin 0,05 mg daily starting on day 1 until the hCG injection and 450 IU recombinant FSH and 225 IU recombinant LH daily starting on day 2.</description>
    <arm_group_label>Triptorelin plus daily FSH and LH</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  poor responders in a previous IVF cycle at least 3 months before at our center and&#xD;
             undergoing a new IVF attempt with at least two of the following criteria : I) age &gt; 40&#xD;
             years old; II) basal follicular stimulation hormone (FSH) &gt; 12 mIU/ml; III) three or&#xD;
             fewer oocytes retrieved in the previous IVF cycle; IV) low estradiol levels on the day&#xD;
             of human chorionic gonadotropin (hCG) administration (&lt; 1500 pmol/ml).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  body mass index &gt; 30&#xD;
&#xD;
          -  biochemical and ultrasound evidence of polycystic ovary syndrome&#xD;
&#xD;
          -  stage III-IV endometriosis&#xD;
&#xD;
          -  inflammatory or autoimmune disorders&#xD;
&#xD;
          -  metabolic disease&#xD;
&#xD;
          -  infertility medications within the past two months&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>25 Years</minimum_age>
    <maximum_age>44 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Mauro Schimberni, MD</last_name>
    <phone>+39063334266</phone>
    <email>bioroma@bioroma.net</email>
  </overall_contact>
  <location>
    <facility>
      <name>Bioroma</name>
      <address>
        <city>Rome</city>
        <zip>00197</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mauro Schimberni, MD</last_name>
      <phone>+39063334266</phone>
      <email>bioroma@bioroma.net</email>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>July 22, 2014</study_first_submitted>
  <study_first_submitted_qc>July 24, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 28, 2014</study_first_posted>
  <last_update_submitted>July 24, 2014</last_update_submitted>
  <last_update_submitted_qc>July 24, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 28, 2014</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>Triptorelin Pamoate</mesh_term>
    <mesh_term>Clomiphene</mesh_term>
    <mesh_term>Enclomiphene</mesh_term>
    <mesh_term>Zuclomiphene</mesh_term>
    <mesh_term>Cetrorelix</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/NCT02201914
org study id: BRM003
nct id: NCT02201914
lead sponsor: 
has dmc: Yes
Poor ovarian response to stimulation in IVF cycles is a challenging and frustrating
      condition, due to its poor prognosis in terms of chances of pregnancy and live births.
      Various ovarian stimulation regimens have been tried to overcome these obstacles. A simple
      approach is increase the dose of the gonadotropin administration, but the results in terms of
      pregnancy rate are very low Another commonly used stimulation regimen is the microdose GnRH
      agonist protocol, which takes advantage of the initial rise in endogenous gonadotropins that
      follows the agonist administration in the early follicular phase and subsequently prevents a
      premature LH surge, with fewer cycle cancellations. However, their application in poor
      responders, even if in small doses and for a limited period, has been questioned as they may
      cause oversuppression of ovarian function, leading to a prolonged cycle and increased
      treatment costs without improving the outcomes.

      Recently, GnRH antagonists were introduced in ART treatment. They are effective in preventing
      a premature LH surge and allow for a more natural recruitment of follicles in the follicular
      phase in a non-suppressed ovary, offering a potential alternative in the treatment of these
      patients. However, randomized studies evaluating the efficacy of this regimen in poor
      responders did not show any improvements in pregnancy rates. Current approach have included
      the addition of oral agents such us clomiphene citrate (CC) to gonadotropins. Some authors
      have investigated the role of CC in addition to low dose of gonadotropins in mild stimulation
      regimen, demonstrating that, despite a small number of retrieved oocytes, good quality
      embryos were produced with a subsequent improvement in the fertilization rate, clinical
      pregnancy rate and live birth rate. The only study that evaluate the efficacy of CC in
      addition to high doses of gonadotropins in poor responders showed improving in number of
      retrieved oocytes, transferred embryos and biochemical pregnancy; however, clinical pregnancy
      rate and live birth rate remained low and showed no measurable increase.

      The aim of this study was to compare the efficacy of the CC as an adjunctive to a high dose
      of gonadotropins in cycles with antagonist protocols with the microdose GnRH agonist and
      flexible antagonist protocols in women who responded poorly to ovarian stimulation, to
      determine whether this protocol may improve IVF outcomes, offering a valid alternative in
      poor responder patients treatment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Clinical pregnancy rate
time frame: Time Frame: until 12th gestational week
measure: implantation rate
time frame: Time Frame: until 12th gestational week
arm group label: Clomiphene citrate
arm group type: Experimental
arm group label: Daily FSH and LH plus Cetrorelix
arm group type: Experimental
arm group label: Triptorelin plus daily FSH and LH
arm group type: Experimental
intervention type: Drug
intervention name: Clomiphene citrate
description: patients receive clomiphene citrate 100 mg daily starting on day 2 for 5 days and 450 IU recombinant FSH and 225 IU recombinant LH daily starting on day 5; Cetrorelix 0,25 mg was administered daily when one or more follicle reached 13-14 mm in diameter until the hCG injection
arm group label: Clomiphene citrate
intervention type: Drug
intervention name: Daily FSH and LH plus Cetrorelix
description: Women receive an initial daily dose of 450 IU recombinant FSH and 225 IU recombinant LH starting on day 3; Cetrorelix 0,25 mg was administered daily when one or more follicle reached 13-14 mm in diameter until the hCG injection.
arm group label: Daily FSH and LH plus Cetrorelix
intervention type: Drug
intervention name: Triptorelin plus daily FSH anh LH
description: women receive short-acting Triptorelin 0,05 mg daily starting on day 1 until the hCG injection and 450 IU recombinant FSH and 225 IU recombinant LH daily starting on day 2.
arm group label: Triptorelin plus daily FSH and LH
criteria: 
gender: Female
minimum age: 25 Years
maximum age: 44 Years
healthy volunteers: No
last name: Mauro Schimberni, MD
phone: +39063334266
email: bioroma@bioroma.net
facility: 
status: Recruiting
contact: 
country: Italy
responsible party type: Sponsor
mesh term: Triptorelin Pamoate
mesh term: Clomiphene
mesh term: Enclomiphene
mesh term: Zuclomiphene
mesh term: Cetrorelix