<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/NCT03238092</url>
  </required_header>
  <id_info>
    <org_study_id>67491417800005327</org_study_id>
    <nct_id>NCT03238092</nct_id>
  </id_info>
  <brief_title>Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort</brief_title>
  <official_title>Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort: a Randomized Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital de Clinicas de Porto Alegre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital de Clinicas de Porto Alegre</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>
      In vitro fertilization(IVF) with Gonadotropin-releasing hormone (GnRH) antagonist is one of&#xD;
      the most used protocol for the treatment of infertile couples nowadays. Despite several&#xD;
      advantages over GnRH agonist, the antagonist may be associated with a slightly reduction in&#xD;
      pregnancy rates.&#xD;
&#xD;
      Several medications have been tested in order to increase ovarian response to ovulation&#xD;
      induction, including estradiol and testosterone. A clinical trial in women with IVF&#xD;
      indication will be performed and this women will be randomly assigned to receive topic&#xD;
      testosterone, oral estradiol or no pre-treatment prior to IVF with human Chorionic&#xD;
      Gonadotropin (hMG) and GnRH antagonist. The primary endpoint will be the size and number of&#xD;
      follicles on the beginning of the cycle, after pre-treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      One of the key-words to a successful IVF it is the response to the ovarian controlled&#xD;
      stimulation. Nowadays, one of the most common protocols includes exogenous gonadotropins and&#xD;
      GnRH antagonist, followed by IVF. The GnRH antagonist avoids the premature peak of LH and has&#xD;
      advantages in relation to the GnRH agonist; however it might have a negative effect over the&#xD;
      pregnancy rate. One possible explanation is the heterogeneity of the follicular cohort at the&#xD;
      moment of ovarian puncture, due to the rise of FSH at luteal-follicular transition. The&#xD;
      estrogen can inhibits this rise of Follicle-Stimulating Hormone (FSH), resulting in a more&#xD;
      synchronic cohort. Previous studies have demonstrated a reduction in the cancellation rates&#xD;
      with estradiol in the luteal phase of the cycle prior to the beginning of IVF using GnRH&#xD;
      antagonist protocol, with a trend towards better quality of transferred embryos and better&#xD;
      implantation rates when compared to the standard protocol with antagonist. The use of&#xD;
      androgens is based on the assumption that they generate an increase in FSH receptors in the&#xD;
      granulosa cells, increase in follicular growth and estrogen production, according to animal&#xD;
      and human studies. Despite promising initial results, further studies are needed to evaluate&#xD;
      the benefit of testosterone as a pretreatment in women undergoing IVF.&#xD;
&#xD;
      The study protocol is the following: Around the 20th day of the cycle prior to the choice of&#xD;
      IVF, transvaginal pelvic ultrasound and serum progesterone dosage will be performed in all&#xD;
      patients. After confirmation of ovulation and no contraindications for the continuation of&#xD;
      the study, according to the randomization, testosterone gel, estradiol oral or no treatment&#xD;
      will be initiated. Both medications will be continued until the first day of subsequent&#xD;
      menstruation. After the menses, between the second and third day of the cycle, a new&#xD;
      transvaginal ultrasound will be performed and blood tests will be collected for the dosage of&#xD;
      FSH, Luteinizing Hormone (LH), progesterone and estradiol. On the same day, subcutaneous hMG&#xD;
      (Menopur®) will be started at a dose between 150 and 300 IU / day, according to age and HAM,&#xD;
      which will be subsequently adjusted according to the ovarian response on serial&#xD;
      ultrasonography. When the largest follicle reaches a mean diameter of 14 mm, the GnRH&#xD;
      antagonist (Orgalutran ®) will be initiated to prevent early LH peak, and monitored&#xD;
      follicular growth with echography every 1-2 days. HCG will be administered at a dose of&#xD;
      10,000 IU (Choriomon®) when three or more follicles reach a mean diameter of 17 mm. After&#xD;
      36h, follicular puncture will be performed transvaginally, under general anesthesia. Embryo&#xD;
      transfer will occur between the third and fifth day after in vitro fertilization. Luteal&#xD;
      support will be given with administration of progesterone 600 mg / day vaginally, initiated&#xD;
      after the transfer and maintained until the first trimester of pregnancy if it occurs. Serum&#xD;
      beta-HCG measurement will be performed on the 12th day after transfer, for evaluation of&#xD;
      pregnancy implantation. Clinical gestation will be considered when there is evidence of&#xD;
      intrauterine embryo with cardiac beats present on the ultrasound, after 6 weeks of transfer&#xD;
      of the embryo (s).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">August 2017</start_date>
  <completion_date type="Anticipated">March 2018</completion_date>
  <primary_completion_date type="Anticipated">January 2018</primary_completion_date>
  <phase>Phase 3</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>As a pre-treatment for in vitro fertilization, one arm will receive transdermic testosterone , one arm will receive oral estradiol and a third arm will be the control group, without pre-treatment</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>number of antral follicles</measure>
    <time_frame>15 days after intervention</time_frame>
    <description>Number of follicles measured by transvaginal ultrasound during the first or second day after menstruation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>follicular cohort homogeneity</measure>
    <time_frame>15 days after intervention</time_frame>
    <description>The comparison of medium follicular diameter (also measured by transvaginal ultrasound) of all the follicles during the first or second day after menstruation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>metaphase II oocytes</measure>
    <time_frame>30 days</time_frame>
    <description>the number of metaphase II oocytes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>gonadotrophin use</measure>
    <time_frame>30 days</time_frame>
    <description>number of units of gonadotrophin used during the in vitro fertilization protocol</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of embryos</measure>
    <time_frame>30 days</time_frame>
    <description>the number of embryos assessed during the in vitro fertilization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>pregnancy</measure>
    <time_frame>6 weeks</time_frame>
    <description>clinical pregnancy, defined by the evidence of intrauterine embryo in the ultrasound</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">26</enrollment>
  <condition>Fertility Disorders</condition>
  <arm_group>
    <arm_group_label>Estradiol group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In the late luteal phase, the participant will receive estradiol 2mg and will take orally a total of 4mg per day (2mg in the morning and 2 mg in the night) until the next menstrual bleeding. After that, the patient will descontinue the medication and proceed to the regular in vitro fertilization protocol.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No pre-treatment will be administrated. The regular in vitro fertilization protocol will be performed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Testosterone group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Testosterone 25mg (10mg/g) transdermal during the late luteal phase, until the next menstrual bleeding.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Testosterone</intervention_name>
    <description>testosterone gel daily during the late luteal phase.</description>
    <arm_group_label>Testosterone group</arm_group_label>
    <other_name>androgel</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Estradiol</intervention_name>
    <description>oral estradiol during the late luteal phase.</description>
    <arm_group_label>Estradiol group</arm_group_label>
    <other_name>estradiol valerato</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Regular cycles (between 25-34 days)&#xD;
&#xD;
          -  In vitro fertilization indication for male cause, unexplained infertility or tubal&#xD;
             factor&#xD;
&#xD;
          -  Both ovaries&#xD;
&#xD;
          -  Thyroid-stimulating hormone(TSH) &lt; 2,5 mU/L&#xD;
&#xD;
          -  Anti-Müllerian hormone (AMH) between 1-5 ng/ml&#xD;
&#xD;
          -  Body Mass Index (BMI) &lt; 30&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Ovarian surgery&#xD;
&#xD;
          -  Endometriosis&#xD;
&#xD;
          -  Endocrinology or metabolic disorder&#xD;
&#xD;
          -  Polycystic ovary syndrome (PCOS)&#xD;
&#xD;
          -  Poor Ovarian Response (according to Bologna criteria)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>39 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>João Sabino, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital de Clinicas de Porto Alegre</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Camila Bessow, MD</last_name>
    <phone>+5551992723620</phone>
    <email>k.bessow@gmail.com</email>
  </overall_contact>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 1, 2017</study_first_submitted>
  <study_first_submitted_qc>August 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>August 1, 2017</last_update_submitted>
  <last_update_submitted_qc>August 1, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>in vitro fertilization</keyword>
  <keyword>estradiol</keyword>
  <keyword>gnrh antagonist</keyword>
  <keyword>testosterone</keyword>
  <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>Testosterone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03238092
org study id: 67491417800005327
nct id: NCT03238092
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In vitro fertilization(IVF) with Gonadotropin-releasing hormone (GnRH) antagonist is one of
      the most used protocol for the treatment of infertile couples nowadays. Despite several
      advantages over GnRH agonist, the antagonist may be associated with a slightly reduction in
      pregnancy rates.

      Several medications have been tested in order to increase ovarian response to ovulation
      induction, including estradiol and testosterone. A clinical trial in women with IVF
      indication will be performed and this women will be randomly assigned to receive topic
      testosterone, oral estradiol or no pre-treatment prior to IVF with human Chorionic
      Gonadotropin (hMG) and GnRH antagonist. The primary endpoint will be the size and number of
      follicles on the beginning of the cycle, after pre-treatment.
One of the key-words to a successful IVF it is the response to the ovarian controlled
      stimulation. Nowadays, one of the most common protocols includes exogenous gonadotropins and
      GnRH antagonist, followed by IVF. The GnRH antagonist avoids the premature peak of LH and has
      advantages in relation to the GnRH agonist; however it might have a negative effect over the
      pregnancy rate. One possible explanation is the heterogeneity of the follicular cohort at the
      moment of ovarian puncture, due to the rise of FSH at luteal-follicular transition. The
      estrogen can inhibits this rise of Follicle-Stimulating Hormone (FSH), resulting in a more
      synchronic cohort. Previous studies have demonstrated a reduction in the cancellation rates
      with estradiol in the luteal phase of the cycle prior to the beginning of IVF using GnRH
      antagonist protocol, with a trend towards better quality of transferred embryos and better
      implantation rates when compared to the standard protocol with antagonist. The use of
      androgens is based on the assumption that they generate an increase in FSH receptors in the
      granulosa cells, increase in follicular growth and estrogen production, according to animal
      and human studies. Despite promising initial results, further studies are needed to evaluate
      the benefit of testosterone as a pretreatment in women undergoing IVF.

      The study protocol is the following: Around the 20th day of the cycle prior to the choice of
      IVF, transvaginal pelvic ultrasound and serum progesterone dosage will be performed in all
      patients. After confirmation of ovulation and no contraindications for the continuation of
      the study, according to the randomization, testosterone gel, estradiol oral or no treatment
      will be initiated. Both medications will be continued until the first day of subsequent
      menstruation. After the menses, between the second and third day of the cycle, a new
      transvaginal ultrasound will be performed and blood tests will be collected for the dosage of
      FSH, Luteinizing Hormone (LH), progesterone and estradiol. On the same day, subcutaneous hMG
      (Menopur®) will be started at a dose between 150 and 300 IU / day, according to age and HAM,
      which will be subsequently adjusted according to the ovarian response on serial
      ultrasonography. When the largest follicle reaches a mean diameter of 14 mm, the GnRH
      antagonist (Orgalutran ®) will be initiated to prevent early LH peak, and monitored
      follicular growth with echography every 1-2 days. HCG will be administered at a dose of
      10,000 IU (Choriomon®) when three or more follicles reach a mean diameter of 17 mm. After
      36h, follicular puncture will be performed transvaginally, under general anesthesia. Embryo
      transfer will occur between the third and fifth day after in vitro fertilization. Luteal
      support will be given with administration of progesterone 600 mg / day vaginally, initiated
      after the transfer and maintained until the first trimester of pregnancy if it occurs. Serum
      beta-HCG measurement will be performed on the 12th day after transfer, for evaluation of
      pregnancy implantation. Clinical gestation will be considered when there is evidence of
      intrauterine embryo with cardiac beats present on the ultrasound, after 6 weeks of transfer
      of the embryo (s).
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: As a pre-treatment for in vitro fertilization, one arm will receive transdermic testosterone , one arm will receive oral estradiol and a third arm will be the control group, without pre-treatment
primary purpose: Treatment
masking: None (Open Label)
measure: number of antral follicles
time frame: 15 days after intervention
description: Number of follicles measured by transvaginal ultrasound during the first or second day after menstruation
measure: follicular cohort homogeneity
time frame: 15 days after intervention
description: The comparison of medium follicular diameter (also measured by transvaginal ultrasound) of all the follicles during the first or second day after menstruation
measure: metaphase II oocytes
time frame: 30 days
description: the number of metaphase II oocytes
measure: gonadotrophin use
time frame: 30 days
description: number of units of gonadotrophin used during the in vitro fertilization protocol
measure: number of embryos
time frame: 30 days
description: the number of embryos assessed during the in vitro fertilization
measure: pregnancy
time frame: 6 weeks
description: clinical pregnancy, defined by the evidence of intrauterine embryo in the ultrasound
arm group label: Estradiol group
arm group type: Active Comparator
description: In the late luteal phase, the participant will receive estradiol 2mg and will take orally a total of 4mg per day (2mg in the morning and 2 mg in the night) until the next menstrual bleeding. After that, the patient will descontinue the medication and proceed to the regular in vitro fertilization protocol.
arm group label: Control group
arm group type: No Intervention
description: No pre-treatment will be administrated. The regular in vitro fertilization protocol will be performed.
arm group label: Testosterone group
arm group type: Experimental
description: Testosterone 25mg (10mg/g) transdermal during the late luteal phase, until the next menstrual bleeding.
intervention type: Drug
intervention name: Testosterone
description: testosterone gel daily during the late luteal phase.
arm group label: Testosterone group
other name: androgel
intervention type: Drug
intervention name: Estradiol
description: oral estradiol during the late luteal phase.
arm group label: Estradiol group
other name: estradiol valerato
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 39 Years
healthy volunteers: No
last name: João Sabino, PhD
role: Principal Investigator
affiliation: Hospital de Clinicas de Porto Alegre
last name: Camila Bessow, MD
phone: +5551992723620
email: k.bessow@gmail.com
responsible party type: Sponsor
mesh term: Estradiol 17 beta-cypionate
mesh term: Estradiol 3-benzoate
mesh term: Estradiol
mesh term: Polyestradiol phosphate
mesh term: Testosterone
sharing ipd: Undecided