<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/NCT03755037</url>
  </required_header>
  <id_info>
    <org_study_id>Beni-Suef 16</org_study_id>
    <nct_id>NCT03755037</nct_id>
  </id_info>
  <brief_title>Clomiphene Citrate, Estradiol and Sildenafil for Induction of Ovulation in Unexplained Infertility</brief_title>
  <official_title>Clomiphine Citrate and Estradiol Versus Clomiphine Citrate and Sildenafil in Comparison With Clomiphine Citrate Alone for Induction of Ovulation in Unexplained Infertility: Double Blind Randomised Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nesreen Abdel Fattah Abdullah Shehata</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Beni-Suef University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Beni-Suef University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Diagnosis of unexplained infertility is made after the recommended testing fails to reveal&#xD;
      any abnormality. The treatment for unexplained infertility is empiric because it does not&#xD;
      address a specific defect or functional impairment. The principal treatments for unexplained&#xD;
      infertility include expectant observation with timed intercourse and lifestyle changes,&#xD;
      clomiphene citrate and intrauterine insemination (IUI), controlled ovarian hyperstimulation&#xD;
      (COH) with IUI, and IVF).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Clomiphene citrate has been widely used alone, and in combination with intrauterine&#xD;
      insemination (IUI), for treatment of unexplained subfertility, The mechanism of action is&#xD;
      based on its mixed estrogenic and antiestrogenic properties. Clomiphene is frequently used to&#xD;
      treat unexplained female infertility by inducing multifollicular response and correcting&#xD;
      potential subtle ovulatory dysfunction .,)The American Society for Reproductive&#xD;
      Medicine,2003).&#xD;
&#xD;
      The use of clomiphene citrate decreases the uterine blood flow during the early luteal phase,&#xD;
      a periimplantation stage., )The American College of Obstetricians and Gynecologists,1995).&#xD;
&#xD;
      Although ovulation is found in 80% of women with a cumulative effect in 6-8 months, the&#xD;
      pregnancy rate can still be very low in these women . The possible causes are the&#xD;
      anti-estrogenic effects of CC at the endometrium and cervical mucus level . The endometrial&#xD;
      effect is without doubt one of the most important handicaps in infertility treatment. The&#xD;
      pregnancy rate can be very low, especially if the endometrial thickness (ET) is &lt;6-8 mm ., )J&#xD;
      Turk Ger Gynecol Assoc. ,2012).&#xD;
&#xD;
      Ethinyl E2 reverse the deleterious effect of CC on endometrial development during the&#xD;
      follicular phase. Endometrial thickness was dependent on peak E2 concentrations in&#xD;
      serum.,(Richard P. Dickey, et.al.,2003).&#xD;
&#xD;
      Sildenafil citrate could lead to an improvement in uterine blood flow and, in conjunction&#xD;
      with estrogen, led to the estrogen-induced proliferation of the endometrial lining .&#xD;
&#xD;
      Sildenafil citrate enhances uterine blood flow and increases endometrial thickening . The&#xD;
      achieved implantation depends on the blastocyst's ability to infiltrate the endometrium and&#xD;
      develop a sustaining blood supply, which requires the following genes to produce the&#xD;
      necessary proteins for digesting the endometrial cellular matrix, to regulate cell growth,&#xD;
      and to induce angiogenesis (Razieh Dehghani Firouzabadi,et.al.,2013).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 31, 2017</start_date>
  <completion_date type="Actual">April 30, 2018</completion_date>
  <primary_completion_date type="Actual">April 30, 2018</primary_completion_date>
  <phase>Phase 1</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>Women with unexplained infertility (n=150) were divided into 3 equal groups. Group 1 received estradiol and clomiphine citrate (cc), group 2 received sildenafil and cc and group 3 cc and placebo.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>Double blind randomisation</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Ultrasound parameters</measure>
    <time_frame>at day 14 until day 17 of menstrual cycle</time_frame>
    <description>Number of follicles in each ovary and endometrial thickness</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pregnancy</measure>
    <time_frame>at day 21 and 24 of menstrual cycle</time_frame>
    <description>A serum pregnancy test was done</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">150</enrollment>
  <condition>Female Infertility</condition>
  <arm_group>
    <arm_group_label>Estradiol and cc</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Group 1 received estradiol, cc and placebo simillar to sildenafil for induction of ovulation.&#xD;
CC 50 mg (clomid) orally twice daily from 3rd day to 7th day of menstrual cycle of the patient then ethinyl estradiol 0.05mg orally twice daily on the 8th day of same cycle till 11th day.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sildenafil and cc</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Group 2 received CC 50 mg (clomid) orally twice daily from 3rd day to 7th day of menstrual cycle of the patient, sildenafil citrate (Respatio) 20 mg tab orally 3 times daily from8th day of same cycle till 11th day and placebo simillar to estradiol.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo and cc</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Group 3 received cc and placebo similar to sildenafil and placebo similar to estradiol with the same doses.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clomid, Respatio and Ethinyl estradiol</intervention_name>
    <description>Drugs were received during the menstrual cycle.</description>
    <arm_group_label>Estradiol and cc</arm_group_label>
    <arm_group_label>Placebo and cc</arm_group_label>
    <arm_group_label>Sildenafil and cc</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Women whose infertility tests were normal then diagnosed as unexplained infertility.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any cause of infertility male factor, tubal or ovarian.&#xD;
&#xD;
          -  Chronic illness as cardiac or renal disease&#xD;
&#xD;
          -  Any contraindication for used drugs&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>female unexplained infertility patients</gender_description>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Nesreen Abd El Fattah Abd Allah</name>
      <address>
        <city>Cairo</city>
        <zip>11412</zip>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <reference>
    <citation>1. Alexander Quaas, MD, Ph .D .,and Anuja Dokras, MD . diagnosis and treatment of unexplainrd infertilityRev Obstet Gynecol. 2008 Spring; 1(2): 69-76 2. J Turk Ger Gynecol Assoc.: The effect of administering estrogen to clomiphene citrate stimulated cycles on endometrial thickness and pregnancy rates in unexplained infertility. (2012) . Sep 1;13(3):157-61. 3. Paulus WE, Strehler E, Zhang M, Jelinkova L,El-Danasouri I and Sterzik K. : Benefit of sildenafil citrate in assisted reproductivetherapy. Fertil Steri 2002 Apr;77(4):846-7. 4. Razieh Dehghani Firouzabadi, M.D., Robab Davar, M.D., Farzaneh Hojjat, M.D., and Mohamad Mahdavi, M.D. :effect of sildenafil on endomeerial preparation and outcome of frozen_thawed embryo transfer cycles(. Iran J Reprod Med. 2013 Feb; 11(2): 151-158. 5. Richard P. Dickey, M.D., Ph.D.,):clomiphene citrate for woman with unexplained infertility . pp 261-271 13 May 2015 6. The American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women:. Fertil Steril . Fertil Steril. 2013 Aug;100(2):341-8. doi: 10.1016/j.fertnstert.2013.05.033. Epub 2013 Jun 27.</citation>
  </reference>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>November 25, 2018</study_first_submitted>
  <study_first_submitted_qc>November 25, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 27, 2018</study_first_posted>
  <last_update_submitted>November 25, 2018</last_update_submitted>
  <last_update_submitted_qc>November 25, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Beni-Suef University</investigator_affiliation>
    <investigator_full_name>Nesreen Abdel Fattah Abdullah Shehata</investigator_full_name>
    <investigator_title>Assistant professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
    <mesh_term>Infertility, Female</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ethinyl Estradiol</mesh_term>
    <mesh_term>Estradiol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03755037
org study id: Beni-Suef 16
nct id: NCT03755037
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Diagnosis of unexplained infertility is made after the recommended testing fails to reveal
      any abnormality. The treatment for unexplained infertility is empiric because it does not
      address a specific defect or functional impairment. The principal treatments for unexplained
      infertility include expectant observation with timed intercourse and lifestyle changes,
      clomiphene citrate and intrauterine insemination (IUI), controlled ovarian hyperstimulation
      (COH) with IUI, and IVF).
Clomiphene citrate has been widely used alone, and in combination with intrauterine
      insemination (IUI), for treatment of unexplained subfertility, The mechanism of action is
      based on its mixed estrogenic and antiestrogenic properties. Clomiphene is frequently used to
      treat unexplained female infertility by inducing multifollicular response and correcting
      potential subtle ovulatory dysfunction .,)The American Society for Reproductive
      Medicine,2003).

      The use of clomiphene citrate decreases the uterine blood flow during the early luteal phase,
      a periimplantation stage., )The American College of Obstetricians and Gynecologists,1995).

      Although ovulation is found in 80% of women with a cumulative effect in 6-8 months, the
      pregnancy rate can still be very low in these women . The possible causes are the
      anti-estrogenic effects of CC at the endometrium and cervical mucus level . The endometrial
      effect is without doubt one of the most important handicaps in infertility treatment. The
      pregnancy rate can be very low, especially if the endometrial thickness (ET) is <6-8 mm ., )J
      Turk Ger Gynecol Assoc. ,2012).

      Ethinyl E2 reverse the deleterious effect of CC on endometrial development during the
      follicular phase. Endometrial thickness was dependent on peak E2 concentrations in
      serum.,(Richard P. Dickey, et.al.,2003).

      Sildenafil citrate could lead to an improvement in uterine blood flow and, in conjunction
      with estrogen, led to the estrogen-induced proliferation of the endometrial lining .

      Sildenafil citrate enhances uterine blood flow and increases endometrial thickening . The
      achieved implantation depends on the blastocyst's ability to infiltrate the endometrium and
      develop a sustaining blood supply, which requires the following genes to produce the
      necessary proteins for digesting the endometrial cellular matrix, to regulate cell growth,
      and to induce angiogenesis (Razieh Dehghani Firouzabadi,et.al.,2013).
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Women with unexplained infertility (n=150) were divided into 3 equal groups. Group 1 received estradiol and clomiphine citrate (cc), group 2 received sildenafil and cc and group 3 cc and placebo.
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: Double blind randomisation
measure: Ultrasound parameters
time frame: at day 14 until day 17 of menstrual cycle
description: Number of follicles in each ovary and endometrial thickness
measure: Pregnancy
time frame: at day 21 and 24 of menstrual cycle
description: A serum pregnancy test was done
arm group label: Estradiol and cc
arm group type: Active Comparator
description: Group 1 received estradiol, cc and placebo simillar to sildenafil for induction of ovulation.
CC 50 mg (clomid) orally twice daily from 3rd day to 7th day of menstrual cycle of the patient then ethinyl estradiol 0.05mg orally twice daily on the 8th day of same cycle till 11th day.
arm group label: Sildenafil and cc
arm group type: Active Comparator
description: Group 2 received CC 50 mg (clomid) orally twice daily from 3rd day to 7th day of menstrual cycle of the patient, sildenafil citrate (Respatio) 20 mg tab orally 3 times daily from8th day of same cycle till 11th day and placebo simillar to estradiol.
arm group label: Placebo and cc
arm group type: Placebo Comparator
description: Group 3 received cc and placebo similar to sildenafil and placebo similar to estradiol with the same doses.
intervention type: Drug
intervention name: Clomid, Respatio and Ethinyl estradiol
description: Drugs were received during the menstrual cycle.
arm group label: Estradiol and cc
arm group label: Placebo and cc
arm group label: Sildenafil and cc
criteria: 
gender: Female
gender based: Yes
gender description: female unexplained infertility patients
minimum age: 20 Years
maximum age: 30 Years
healthy volunteers: No
facility: 
country: Egypt
citation: 1. Alexander Quaas, MD, Ph .D .,and Anuja Dokras, MD . diagnosis and treatment of unexplainrd infertilityRev Obstet Gynecol. 2008 Spring; 1(2): 69-76 2. J Turk Ger Gynecol Assoc.: The effect of administering estrogen to clomiphene citrate stimulated cycles on endometrial thickness and pregnancy rates in unexplained infertility. (2012) . Sep 1;13(3):157-61. 3. Paulus WE, Strehler E, Zhang M, Jelinkova L,El-Danasouri I and Sterzik K. : Benefit of sildenafil citrate in assisted reproductivetherapy. Fertil Steri 2002 Apr;77(4):846-7. 4. Razieh Dehghani Firouzabadi, M.D., Robab Davar, M.D., Farzaneh Hojjat, M.D., and Mohamad Mahdavi, M.D. :effect of sildenafil on endomeerial preparation and outcome of frozen_thawed embryo transfer cycles(. Iran J Reprod Med. 2013 Feb; 11(2): 151-158. 5. Richard P. Dickey, M.D., Ph.D.,):clomiphene citrate for woman with unexplained infertility . pp 261-271 13 May 2015 6. The American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women:. Fertil Steril . Fertil Steril. 2013 Aug;100(2):341-8. doi: 10.1016/j.fertnstert.2013.05.033. Epub 2013 Jun 27.
responsible party type: Sponsor-Investigator
investigator affiliation: Beni-Suef University
investigator full name: Nesreen Abdel Fattah Abdullah Shehata
investigator title: Assistant professor
mesh term: Infertility
mesh term: Infertility, Female
mesh term: Ethinyl Estradiol
mesh term: Estradiol
sharing ipd: No