<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/NCT03766594</url>
  </required_header>
  <id_info>
    <org_study_id>SURPL</org_study_id>
    <nct_id>NCT03766594</nct_id>
  </id_info>
  <brief_title>Sildenafil Citrate in Early Unexplained Recurrent Pregnancy Loss</brief_title>
  <official_title>Effect of Preconceptional Sildenafil Citrate Treatment in Women With Early Unexplained Recurrent Pregnancy Loss: a Randomized Controlled Trial</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>
      Recurrent unexplained spontaneous miscarriage (RSM) is defined as three consecutive pregnancy&#xD;
      loss prior to 20 weeks from the last menstrual period. 1% to 2% of women experience RSM.&#xD;
      Treatment of URSM is a challenging issue. The currently available lines of treatment&#xD;
      according to simplicity of use, reliability and degree of invasiveness include&#xD;
      corticosteroids, sildenafil citrate, aspirin, heparin and immunoglobulins (besides good&#xD;
      antenatal care), but up to now there are no prospective randomized studies, powerful enough,&#xD;
      to determine a significant difference between these therapeutic protocols, with any of the&#xD;
      above mentioned pharmacological agents.&#xD;
&#xD;
      Sildenafil Citrate (Viagra®), a vasodilator, is also described as an anti-inflammatory agent.&#xD;
      While improving uterine blood flow in the proliferative phase, NO may have detrimental&#xD;
      effects at the level of the endometrium during the implantation window. The NO- mediated&#xD;
      release of cytokines such as tumour necrosis factor- from activated natural killer cells has&#xD;
      been implicated as a cause of implantation failure.&#xD;
&#xD;
      Based on these observations, this study attempts was made to study uterine arteries and&#xD;
      sub-endometrial blood flow during the luteal phase in normal fertile women and in patients&#xD;
      with Unexplained recurrent miscarriage&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2018</start_date>
  <completion_date type="Actual">December 1, 2018</completion_date>
  <primary_completion_date type="Actual">November 20, 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>Patients will be randomized into two groups: Group (A) folic acid and sildenafil citrate and Group (B) folic acid and placebo.&#xD;
Folic acid (0.5 mg) will be started 3 months before conception in the two groups. Sildenafil citrate (dose: 25 mg; oral tablets, 4 times/day) or placebo will be started preconception for 24 days</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
    <masking_description>Patients are randomized to receive either folic acid and sildenafil citrate or folic acid and placebo. Placebo tablets were same size and appearance of the sildenafil citrate tablets.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Miscarriage rate</measure>
    <time_frame>24 gestational weeks</time_frame>
    <description>number of spontaneous/missed miscarriages among the participants in both groups</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Uterine artery resistance index</measure>
    <time_frame>At 24 gestational weeks</time_frame>
    <description>Uterine artery resistance index assessed by uterine artery Doppler study in ongoing pregnancies of both groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Uterine artery pulsatility index</measure>
    <time_frame>At 24 gestational weeks</time_frame>
    <description>Uterine artery pulsatility index assessed by uterine artery Doppler study in ongoing pregnancies of both groups</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Miscarriage, Recurrent</condition>
  <arm_group>
    <arm_group_label>Sildenafil group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Includes 45 women who received Sildenafil citrate (Respatio(R) 25mg tablets four times daily for 24 days preconceptionally starting first day of previous period) and folic acid (Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Includes 45 women who received placebo oral tablets (apparently identical to Respatio(R) 25mg tablets, four times daily for 24 days preconceptionally starting first day of previous period) and folic acid (Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sildenafil Citrate</intervention_name>
    <description>Respatio(R) 25mg tablets four times daily for 24 days preconceptionally starting first day of previous period</description>
    <arm_group_label>Sildenafil group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Folic Acid</intervention_name>
    <description>Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally</description>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Sildenafil group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Placebo tablet apparently identical to Respatio(R) 25mg tablets, taken four times daily for 24 days preconceptionally starting first day of previous period</description>
    <arm_group_label>Control group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age: 20-35 years.&#xD;
&#xD;
          -  BMI (20-30)&#xD;
&#xD;
          -  History of three or more successive unexplained recurrent miscarriage.&#xD;
&#xD;
          -  Normal uterine cavity by hystrography or hysteroscopy.&#xD;
&#xD;
          -  No luteal phase defects by progesterone &gt; 10 ng.&#xD;
&#xD;
          -  Normal thyroid function (TSH, T3, T4)&#xD;
&#xD;
          -  Normal lupus anticoagulant measured by activated partial throbmoplastine time (32-43&#xD;
             seconds).&#xD;
&#xD;
          -  Normal anticardolipin (IgG &lt; 20 gpl and IgM &lt; 15 MPL measured by ELISA).&#xD;
&#xD;
          -  Normal anti thyroid antibodies.&#xD;
&#xD;
          -  Normal glucouse tolerance test.&#xD;
&#xD;
          -  Normal parental karyotyping.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age&lt;20 or&gt;35 year&#xD;
&#xD;
          -  BMI&lt;20 or&gt;30&#xD;
&#xD;
          -  Systemic diseases that might affect pregnancy such as diabetes or thyroid disorders or&#xD;
             hypertension.&#xD;
&#xD;
          -  History of consanguinity.&#xD;
&#xD;
          -  Family history of chromosomal abnormalities (e.g. trisomy 21, trisomy 13, Turner's&#xD;
             disease …etc.).&#xD;
&#xD;
          -  History of autoimmune diseases, eg: systemic lupus.&#xD;
&#xD;
          -  Congenital anomaly in uterine cavity as bicornate or septate uterus.&#xD;
&#xD;
          -  Luteal phase defect and corpus luteum insufficiency.&#xD;
&#xD;
          -  Uterine masses as fibroid or polyps.&#xD;
&#xD;
          -  Patient with patuoles os.&#xD;
&#xD;
          -  patient with antiphosphlipid syndrome.&#xD;
&#xD;
          -  Cigarette smoking and alcohol.&#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>Mohamed Yakout, MBBCh</last_name>
    <role>Principal Investigator</role>
    <affiliation>M Yakout</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ain SHams Maternity Hospital</name>
      <address>
        <city>Cairo</city>
        <state>Abbaseya</state>
        <zip>002</zip>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 5, 2018</study_first_submitted>
  <study_first_submitted_qc>December 5, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 6, 2018</study_first_posted>
  <last_update_submitted>December 5, 2018</last_update_submitted>
  <last_update_submitted_qc>December 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 6, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Ain Shams University</investigator_affiliation>
    <investigator_full_name>Mohamed Yakout Mohamed</investigator_full_name>
    <investigator_title>Resident of O&amp;G</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Abortion, Spontaneous</mesh_term>
    <mesh_term>Abortion, Habitual</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Folic Acid</mesh_term>
    <mesh_term>Sildenafil Citrate</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/NCT03766594
org study id: SURPL
nct id: NCT03766594
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Recurrent unexplained spontaneous miscarriage (RSM) is defined as three consecutive pregnancy
      loss prior to 20 weeks from the last menstrual period. 1% to 2% of women experience RSM.
      Treatment of URSM is a challenging issue. The currently available lines of treatment
      according to simplicity of use, reliability and degree of invasiveness include
      corticosteroids, sildenafil citrate, aspirin, heparin and immunoglobulins (besides good
      antenatal care), but up to now there are no prospective randomized studies, powerful enough,
      to determine a significant difference between these therapeutic protocols, with any of the
      above mentioned pharmacological agents.

      Sildenafil Citrate (Viagra®), a vasodilator, is also described as an anti-inflammatory agent.
      While improving uterine blood flow in the proliferative phase, NO may have detrimental
      effects at the level of the endometrium during the implantation window. The NO- mediated
      release of cytokines such as tumour necrosis factor- from activated natural killer cells has
      been implicated as a cause of implantation failure.

      Based on these observations, this study attempts was made to study uterine arteries and
      sub-endometrial blood flow during the luteal phase in normal fertile women and in patients
      with Unexplained recurrent miscarriage
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will be randomized into two groups: Group (A) folic acid and sildenafil citrate and Group (B) folic acid and placebo.
Folic acid (0.5 mg) will be started 3 months before conception in the two groups. Sildenafil citrate (dose: 25 mg; oral tablets, 4 times/day) or placebo will be started preconception for 24 days
primary purpose: Treatment
masking: Double (Participant, Care Provider)
masking description: Patients are randomized to receive either folic acid and sildenafil citrate or folic acid and placebo. Placebo tablets were same size and appearance of the sildenafil citrate tablets.
measure: Miscarriage rate
time frame: 24 gestational weeks
description: number of spontaneous/missed miscarriages among the participants in both groups
measure: Uterine artery resistance index
time frame: At 24 gestational weeks
description: Uterine artery resistance index assessed by uterine artery Doppler study in ongoing pregnancies of both groups
measure: Uterine artery pulsatility index
time frame: At 24 gestational weeks
description: Uterine artery pulsatility index assessed by uterine artery Doppler study in ongoing pregnancies of both groups
arm group label: Sildenafil group
arm group type: Active Comparator
description: Includes 45 women who received Sildenafil citrate (Respatio(R) 25mg tablets four times daily for 24 days preconceptionally starting first day of previous period) and folic acid (Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally).
arm group label: Control group
arm group type: Active Comparator
description: Includes 45 women who received placebo oral tablets (apparently identical to Respatio(R) 25mg tablets, four times daily for 24 days preconceptionally starting first day of previous period) and folic acid (Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally).
intervention type: Drug
intervention name: Sildenafil Citrate
description: Respatio(R) 25mg tablets four times daily for 24 days preconceptionally starting first day of previous period
arm group label: Sildenafil group
intervention type: Drug
intervention name: Folic Acid
description: Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally
arm group label: Control group
arm group label: Sildenafil group
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Placebo tablet apparently identical to Respatio(R) 25mg tablets, taken four times daily for 24 days preconceptionally starting first day of previous period
arm group label: Control group
criteria: 
gender: Female
minimum age: 20 Years
maximum age: 35 Years
healthy volunteers: No
last name: Mohamed Yakout, MBBCh
role: Principal Investigator
affiliation: M Yakout
facility: 
country: Egypt
responsible party type: Principal Investigator
investigator affiliation: Ain Shams University
investigator full name: Mohamed Yakout Mohamed
investigator title: Resident of O&G
mesh term: Abortion, Spontaneous
mesh term: Abortion, Habitual
mesh term: Recurrence
mesh term: Folic Acid
mesh term: Sildenafil Citrate