<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/NCT03301233</url>
  </required_header>
  <id_info>
    <org_study_id>2</org_study_id>
    <nct_id>NCT03301233</nct_id>
  </id_info>
  <brief_title>Effect Sildenafil and Estradiiol Valerate on Endometrial Thickness in Infertile Women</brief_title>
  <official_title>The Effect of Estradiol Valerate With and Without Oral Sildenafil on Endometrial Thickness and Pregnancy Rates in Infertile Women: A R.C.T</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ain Shams University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ain Shams University</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The endometrium is a dynamic tissue that responds to changing hormonal signals throughout the&#xD;
      cycle. The changes in the endometrial composition are expressed in alteration in gene&#xD;
      expression, micro architectural morphological changes as well as in protein and hormone&#xD;
      secretion. These factors combine together to construct the &quot;window of implantation&quot; a short&#xD;
      period of time during the luteal phase in which the endometrium is receptive.&#xD;
&#xD;
      Thin endometrium is associated with a low pregnancy rate. Endometrial thickness 7 mm in the&#xD;
      pre-ovulatory phase is widely accepted to be cut-off of thin endometrium.&#xD;
&#xD;
      for that the aim of this study is to compare the effect of sildenafil-estrogen combination to&#xD;
      estrogen alone on endometrium thickness in infertile women. Half of the patients will receive&#xD;
      estrogen ( estradiol valerate ) and the other half will receive combination of&#xD;
      sildenafil-estrogen .&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Being a hormone dependent tissue, the endometrium proliferates in response to estrogen, which&#xD;
      further induces the production of progesterone receptors. As a result, infertile patients who&#xD;
      demonstrated thin endometrium, were offered estradiol (E2) remedies, in an attempt to improve&#xD;
      endometrial proliferation. Most of the studies regarding E2 treatment in patients with thin&#xD;
      endometrium dealt with frozen-thawed embryo transfer cycles. Moreover, while there are&#xD;
      several routes and duration of administration of E2, including per Os, transdermal,&#xD;
      Intramuscular and vaginal, no compelling advantage for one protocol for endometrial&#xD;
      preparation over another, with regard to pregnancy rates, has been established.&#xD;
&#xD;
      Sildenafil acts as a type 5-specific phosphodiesterase inhibitor hence augments the&#xD;
      vasodilatory effects of nitric oxide by preventing the degradation of cGMP. Nitric oxide (NO)&#xD;
      relaxes vascular smooth muscle through a cGMP-mediated pathway and NO synthase isoforms have&#xD;
      been identified in the uterus. A decade ago, Sher and Fisch studied the effect of vaginal&#xD;
      sildenafil on the endometrial thickness of infertile patients with poor endometrial&#xD;
      development, who underwent IVF treatment. They have demonstrated improved uterine artery&#xD;
      blood flow and endometrial growth, with higher implantation and ongoing pregnancy rates&#xD;
      following vaginal sildenafil administration.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 1, 2017</start_date>
  <completion_date type="Actual">July 30, 2018</completion_date>
  <primary_completion_date type="Actual">July 1, 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>Diagnostic</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>Ninety opaque envelopes will be numbered serially and in each envelope the corresponding letter which denotes the allocated group will be put according to randomization table. Then all envelopes will be closed and put in one box. When the first patient arrives, the first envelope will be opened and the patient will be allocated according to the letter inside.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>endometrial line thickness</measure>
    <time_frame>9 days</time_frame>
    <description>The thickness of the endometrium will be measured (maximum distance between each myometrial/endometrial interface through the longitudinal axis of the uterus) using two dimensional transvaginal ultrasound.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>positive pregnancy test</measure>
    <time_frame>14 days after triggering of ovulation</time_frame>
    <description>Serum B-HCG</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>sub endometrial blood flow</measure>
    <time_frame>9 days</time_frame>
    <description>Using two dimensional (2D) transvaginal Doppler, flow velocity wave forms will be obtained from the ascending main branch of the uterine artery on the right and left side of the cervix before it enters the uterus.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Endometrial Thickness</condition>
  <arm_group>
    <arm_group_label>estradiol valerate</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma). One tablet every 12 hour from 2nd day of the cycle till the day of trigger of ovulation).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>estradiol valerate and sildenafil</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma), one tablet every 12 hour from 2nd day of the cycle + sildenafil (silden® 25 mg, E.I.P.I.CO.) every 8 hour from 2nd day of the cycle till the day of trigger of ovulation).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>estradiol valerate and sildenafil</intervention_name>
    <description>(45 women will receive clomiphene citrate (clomid 50mg ®, Sanofi aventis) 2 tab. single dose orally from the 2nd day of the cycle for 5 days with oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma), one tablet every 12 hour from 2nd day of the cycle + sildenafil (silden® 25, E.I.P.I.CO.) every 8 hour from 2nd day of the cycle till the day of trigger of ovulation).</description>
    <arm_group_label>estradiol valerate</arm_group_label>
    <arm_group_label>estradiol valerate and sildenafil</arm_group_label>
    <other_name>cycloprogenova and silden</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients having ovulatory infertility.&#xD;
&#xD;
          2. Age: 20-35 years old.&#xD;
&#xD;
          3. BMI less than 30 kg/m2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Women who have any congenital uterine anomaly (e.g., unicornuate uterus or infantile&#xD;
             uterus) or acquired deformities of the uterine cavity that interfere with embryo&#xD;
             implantation (as Asherman Syndrome).&#xD;
&#xD;
          2. Women who have any tubal factor that relates to infertility (e.g., tubal adhesion or&#xD;
             previous ectopic pregnancy).&#xD;
&#xD;
          3. Women who have contraindication for estrogen treatment (e.g., history of stroke, DVT&#xD;
             and Benign liver disease).&#xD;
&#xD;
          4. Women who have male factor for infertility (e.g., azoospermia, teratospermia).&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hayam F Mohammad, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ain Shams University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ain Shams University</name>
      <address>
        <city>Cairo</city>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>September 24, 2017</study_first_submitted>
  <study_first_submitted_qc>September 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 4, 2017</study_first_posted>
  <last_update_submitted>August 13, 2018</last_update_submitted>
  <last_update_submitted_qc>August 13, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 14, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Ain Shams University</investigator_affiliation>
    <investigator_full_name>Hayam Fathy Mohammad</investigator_full_name>
    <investigator_title>Assistant Professor of Obstetrics and Gynecology , Ain Shams University</investigator_title>
  </responsible_party>
  <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>Sildenafil Citrate</mesh_term>
    <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>
  </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/NCT03301233
org study id: 2
nct id: NCT03301233
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
The endometrium is a dynamic tissue that responds to changing hormonal signals throughout the
      cycle. The changes in the endometrial composition are expressed in alteration in gene
      expression, micro architectural morphological changes as well as in protein and hormone
      secretion. These factors combine together to construct the "window of implantation" a short
      period of time during the luteal phase in which the endometrium is receptive.

      Thin endometrium is associated with a low pregnancy rate. Endometrial thickness 7 mm in the
      pre-ovulatory phase is widely accepted to be cut-off of thin endometrium.

      for that the aim of this study is to compare the effect of sildenafil-estrogen combination to
      estrogen alone on endometrium thickness in infertile women. Half of the patients will receive
      estrogen ( estradiol valerate ) and the other half will receive combination of
      sildenafil-estrogen .
Being a hormone dependent tissue, the endometrium proliferates in response to estrogen, which
      further induces the production of progesterone receptors. As a result, infertile patients who
      demonstrated thin endometrium, were offered estradiol (E2) remedies, in an attempt to improve
      endometrial proliferation. Most of the studies regarding E2 treatment in patients with thin
      endometrium dealt with frozen-thawed embryo transfer cycles. Moreover, while there are
      several routes and duration of administration of E2, including per Os, transdermal,
      Intramuscular and vaginal, no compelling advantage for one protocol for endometrial
      preparation over another, with regard to pregnancy rates, has been established.

      Sildenafil acts as a type 5-specific phosphodiesterase inhibitor hence augments the
      vasodilatory effects of nitric oxide by preventing the degradation of cGMP. Nitric oxide (NO)
      relaxes vascular smooth muscle through a cGMP-mediated pathway and NO synthase isoforms have
      been identified in the uterus. A decade ago, Sher and Fisch studied the effect of vaginal
      sildenafil on the endometrial thickness of infertile patients with poor endometrial
      development, who underwent IVF treatment. They have demonstrated improved uterine artery
      blood flow and endometrial growth, with higher implantation and ongoing pregnancy rates
      following vaginal sildenafil administration.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: Single (Participant)
masking description: Ninety opaque envelopes will be numbered serially and in each envelope the corresponding letter which denotes the allocated group will be put according to randomization table. Then all envelopes will be closed and put in one box. When the first patient arrives, the first envelope will be opened and the patient will be allocated according to the letter inside.
measure: endometrial line thickness
time frame: 9 days
description: The thickness of the endometrium will be measured (maximum distance between each myometrial/endometrial interface through the longitudinal axis of the uterus) using two dimensional transvaginal ultrasound.
measure: positive pregnancy test
time frame: 14 days after triggering of ovulation
description: Serum B-HCG
measure: sub endometrial blood flow
time frame: 9 days
description: Using two dimensional (2D) transvaginal Doppler, flow velocity wave forms will be obtained from the ascending main branch of the uterine artery on the right and left side of the cervix before it enters the uterus.
arm group label: estradiol valerate
arm group type: Active Comparator
description: oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma). One tablet every 12 hour from 2nd day of the cycle till the day of trigger of ovulation).
arm group label: estradiol valerate and sildenafil
arm group type: Experimental
description: oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma), one tablet every 12 hour from 2nd day of the cycle + sildenafil (silden® 25 mg, E.I.P.I.CO.) every 8 hour from 2nd day of the cycle till the day of trigger of ovulation).
intervention type: Drug
intervention name: estradiol valerate and sildenafil
description: (45 women will receive clomiphene citrate (clomid 50mg ®, Sanofi aventis) 2 tab. single dose orally from the 2nd day of the cycle for 5 days with oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma), one tablet every 12 hour from 2nd day of the cycle + sildenafil (silden® 25, E.I.P.I.CO.) every 8 hour from 2nd day of the cycle till the day of trigger of ovulation).
arm group label: estradiol valerate
arm group label: estradiol valerate and sildenafil
other name: cycloprogenova and silden
criteria: 
gender: Female
minimum age: 20 Years
maximum age: 35 Years
healthy volunteers: No
last name: Hayam F Mohammad, MD
role: Principal Investigator
affiliation: Ain Shams University
facility: 
country: Egypt
responsible party type: Principal Investigator
investigator affiliation: Ain Shams University
investigator full name: Hayam Fathy Mohammad
investigator title: Assistant Professor of Obstetrics and Gynecology , Ain Shams University
mesh term: Infertility
mesh term: Sildenafil Citrate
mesh term: Estradiol 17 beta-cypionate
mesh term: Estradiol 3-benzoate
mesh term: Estradiol
mesh term: Polyestradiol phosphate