<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/NCT03294538</url>
  </required_header>
  <id_info>
    <org_study_id>71436001</org_study_id>
    <nct_id>NCT03294538</nct_id>
  </id_info>
  <brief_title>Study to Evaluate Equivalence of Estradiol Vaginal Cream 0.01% to Estrace® Cream 0.01% in Atrophic Vaginitis</brief_title>
  <official_title>A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Multiple-Site Study to Evaluate the Therapeutic Equivalence of Estradiol Vaginal Cream USP, 0.01% (Teva Pharmaceuticals, USA) to Estrace® Estradiol Vaginal Cream, USP, 0.01% (Warner Chilcott) in the Treatment of Atrophic Vaginitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Actavis Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Teva Pharmaceuticals USA</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Actavis Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objectives of this study were to evaluate the therapeutic equivalence of the Test&#xD;
      formulation, generic Estradiol Vaginal Cream United States Pharmacopoeia (USP), 0.01% (Teva&#xD;
      Pharmaceuticals, United States of America) to the marketed product, Estrace® Cream estradiol&#xD;
      vaginal cream USP, 0.01% (Warner Chilcott) in participants with atrophic vaginitis; to&#xD;
      demonstrate the superiority of the Test and Reference (active) treatments over Placebo&#xD;
      (vehicle) cream in participants with atrophic vaginitis; and to compare the safety of Test,&#xD;
      Reference, and Placebo treatments in participants with atrophic vaginitis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Systemic (oral or transdermal patch administration) estrogen therapies have been shown to&#xD;
      effectively treat symptoms of atrophic vaginitis but bear undesirable side effects including&#xD;
      increased risk of heart attacks, stroke, endometrial cancer, and breast cancer. Topical&#xD;
      therapies (creams and transvaginal delivery systems) provide low doses of estrogen to the&#xD;
      vaginal mucosa to provide local relief for the symptoms of atrophic vaginitis, while reducing&#xD;
      the unwanted side effects associated with systemic delivery systems. Low dose, topical&#xD;
      estrogen therapy is considered most appropriate and convenient for the treatment of vaginal&#xD;
      symptoms associated with menopause, particularly when other symptoms including bone loss or&#xD;
      vasomotor dysfunction do not need to be targeted.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 18, 2016</start_date>
  <completion_date type="Actual">February 15, 2017</completion_date>
  <primary_completion_date type="Actual">February 15, 2017</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups</measure>
    <time_frame>Up to Day 9</time_frame>
    <description>Treatment comparison of the number of participants in the PP population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups</measure>
    <time_frame>Up to Day 9</time_frame>
    <description>Treatment comparison of the number of participants in the mITT population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups</measure>
    <time_frame>Up to Day 9</time_frame>
    <description>The number of participants in the PP population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation was based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups</measure>
    <time_frame>Up to 9 months</time_frame>
    <description>The number of participants in the mITT Population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation is to be based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">663</enrollment>
  <condition>Atrophic Vaginitis</condition>
  <arm_group>
    <arm_group_label>Generic Estradiol Vaginal Cream USP, 0.01%</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants were to self-administer 2 grams (g) of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Estrace Vaginal Cream USP, 0.01%</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vehicle Vaginal Cream</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants were to self-administer 2 g of vehicle vaginal cream once daily at approximately the same time of the day for 7 consecutive days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Generic Estradiol Vaginal Cream USP, 0.01%</intervention_name>
    <description>Vaginal cream, generic formulation of the brand product.</description>
    <arm_group_label>Generic Estradiol Vaginal Cream USP, 0.01%</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Estrace® Vaginal Cream USP, 0.01%</intervention_name>
    <description>Vaginal cream, brand product.</description>
    <arm_group_label>Estrace Vaginal Cream USP, 0.01%</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vehicle Vaginal Cream</intervention_name>
    <description>Vaginal cream, placebo. Has no active ingredient</description>
    <arm_group_label>Vehicle Vaginal Cream</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed Informed Consent Form (ICF) that meets all criteria of current Food and Drug&#xD;
             Administration (FDA) regulations.&#xD;
&#xD;
          -  Females aged 30-75 years inclusive who are postmenopausal, defined as follows:&#xD;
&#xD;
          -  At least 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea&#xD;
             with serum follicle-stimulating hormone (FSH) level of &gt;40 milli-international units&#xD;
             per milliliter (mIU/mL); at least 6 weeks post-surgical bilateral oophorectomy, with&#xD;
             or without hysterectomy; or hysterectomy without oophorectomy if of age that the&#xD;
             Investigator believes would have been naturally reached 12 months of spontaneous&#xD;
             amenorrhea.&#xD;
&#xD;
          -  Vaginal pH &gt;5.0.&#xD;
&#xD;
          -  At least 1 of the following participant self-assessed moderate to severe symptoms of&#xD;
             vulvar and vaginal atrophy (VVA) from the following list that is identified by the&#xD;
             participant as being most bothersome to her:&#xD;
&#xD;
               1. Vaginal Dryness&#xD;
&#xD;
               2. Vaginal and/or vulvar irritation/itching&#xD;
&#xD;
               3. Dysuria&#xD;
&#xD;
               4. Vaginal pain or bleeding associated with sexual activity, provided that&#xD;
                  participant is currently sexually active and plans to remain so throughout study.&#xD;
&#xD;
          -  &quot;Normal&quot; Screening mammogram completed within 9 months prior to Screening in all&#xD;
             participants &gt;40 years old.&#xD;
&#xD;
          -  Normal clinical breast examination at the Screening Visit.&#xD;
&#xD;
          -  Documented papanicolaou (PAP) smear conducted within the previous 12 months with no&#xD;
             findings that the Investigator believes would contraindicate the use of topical&#xD;
             vaginal estradiol.&#xD;
&#xD;
          -  Participants with an intact uterus should have vaginal ultrasonography results to&#xD;
             confirm an inactive endometrial lining, defined as endometrial thickness less than 4&#xD;
             millimeters (mm).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Females younger than 30 years of age or older than 75 years of age.&#xD;
&#xD;
          2. Participants with a Serum follicle-stimulating hormone (FSH) level of ≤40 mIU/mL at&#xD;
             Screening.&#xD;
&#xD;
          3. Greater than 5% superficial cells on vaginal cytology.&#xD;
&#xD;
          4. Vaginal pH ≤5.&#xD;
&#xD;
          5. Significant history or current evidence of chronic infectious disease, system&#xD;
             disorder, organ disorder (including significant liver/kidney impairment) or other&#xD;
             medical condition that in the Investigator's opinion would place the study participant&#xD;
             at undue risk by participation or could jeopardize the integrity of the study&#xD;
             evaluations.&#xD;
&#xD;
          6. Participants with an intact uterus should have vaginal ultrasonography results to&#xD;
             confirm an inactive endometrial lining. Participants with an endometrial thickness&#xD;
             equal to or greater than 4 mm.&#xD;
&#xD;
          7. Documented PAP smear conducted within the previous 12 months with findings that the&#xD;
             Investigator believes would contraindicate the use of topical vaginal estradiol.&#xD;
&#xD;
          8. Participants with known concurrent vaginal infections including but not limited to:&#xD;
&#xD;
             Candida albicans, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhea,&#xD;
             or Gardnerella vaginalis.&#xD;
&#xD;
          9. Participants with active vaginal herpes simplex infection or have had an outbreak&#xD;
             within 30 days of the first dosing day.&#xD;
&#xD;
         10. Participants with known, suspected, or current history of carcinoma of the breast. All&#xD;
             participants over the age of 40 must have had a mammogram performed within 9 months of&#xD;
             the study start and all participants will have a physical breast exam performed at&#xD;
             Screening.&#xD;
&#xD;
         11. Participants with known, suspected or current history of hormone dependent tumor.&#xD;
&#xD;
         12. Participants with baseline systolic blood pressure of &gt;150 millimetres of mercury&#xD;
             (mmHg) and/or diastolic pressure &gt;90 mmHg.&#xD;
&#xD;
         13. Any participant with undiagnosed vaginal bleeding or significant risk factors for&#xD;
             endometrial cancer.&#xD;
&#xD;
         14. Any history of estrogen-dependent neoplasia (for example, endometrial cancer).&#xD;
&#xD;
         15. History of acute thrombophlebitis or thromboembolic disorder.&#xD;
&#xD;
         16. Any current or recent (within the previous 6 months) genital bleeding of unknown&#xD;
             etiology.&#xD;
&#xD;
         17. Any prescription treatment or over-the-counter (OTC) or natural remedies for vaginal&#xD;
             dryness/irritation within 28 days of Screening. Products used for lubrication during&#xD;
             sexual intercourse within 7 days of Screening.&#xD;
&#xD;
         18. Participants whose fasting triglyceride levels are greater than 350 mg/dL.&#xD;
&#xD;
         19. Any participant with a history of radiation therapy or recent (within previous 6&#xD;
             weeks) surgical therapy to the vaginal or cervical areas.&#xD;
&#xD;
         20. Any known or suspected allergies that in the Investigator's opinion would compromise&#xD;
             the safety of the participant.&#xD;
&#xD;
         21. Participants who have used vaginal hormonal products (rings, creams, gels) within the&#xD;
             28 days prior to Screening.&#xD;
&#xD;
         22. Any participant who has used transdermal estrogen and/or progestin therapy within the&#xD;
             28 days prior to Screening.&#xD;
&#xD;
         23. Participants who have used oral estrogen and/ or progestin therapy or intrauterine&#xD;
             progestin therapy within the 56 days prior to Screening.&#xD;
&#xD;
         24. Participants who have used progestin implants or estrogen alone injectable drug&#xD;
             therapy within the 3 months before Screening.&#xD;
&#xD;
         25. Participants who have used estrogen pellet therapy or progestin injectable drug&#xD;
             therapy within the 6 months before Screening.&#xD;
&#xD;
         26. Participants who, in the opinion of the Investigator, would be non-compliant with the&#xD;
             requirements of the study protocol.&#xD;
&#xD;
         27. Participants who are unable or unwilling to give informed consent.&#xD;
&#xD;
         28. Receipt of any drug as part of a research study within 30 days prior to Screening.&#xD;
&#xD;
         29. Participants who have participated in this study previously.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Study Director</last_name>
    <role>Study Director</role>
    <affiliation>Teva Pharmaceuticals USA</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Site Number 44</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 17</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85712</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 31</name>
      <address>
        <city>La Mesa</city>
        <state>California</state>
        <zip>91942</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 11</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95821</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 05</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>91208</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 15</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 25</name>
      <address>
        <city>Colorado Springs</city>
        <state>Colorado</state>
        <zip>80923</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 01</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 14</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80220</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 18</name>
      <address>
        <city>New London</city>
        <state>Connecticut</state>
        <zip>06320</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 06</name>
      <address>
        <city>Jupiter</city>
        <state>Florida</state>
        <zip>33458</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 13</name>
      <address>
        <city>Lake Worth</city>
        <state>Florida</state>
        <zip>33461</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 30</name>
      <address>
        <city>Miami Lakes</city>
        <state>Florida</state>
        <zip>33014</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 27</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33015</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 40</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33130</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 20</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 39</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33144</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 38</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33186</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 08</name>
      <address>
        <city>New Port Richey</city>
        <state>Florida</state>
        <zip>34652</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 03</name>
      <address>
        <city>Ormond Beach</city>
        <state>Florida</state>
        <zip>32174</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 45</name>
      <address>
        <city>Port Saint Lucie</city>
        <state>Florida</state>
        <zip>34952</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 19</name>
      <address>
        <city>Saint Petersburg</city>
        <state>Florida</state>
        <zip>33709</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 10</name>
      <address>
        <city>Sarasota</city>
        <state>Florida</state>
        <zip>34239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 02</name>
      <address>
        <city>West Palm Beach</city>
        <state>Florida</state>
        <zip>33409</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 29</name>
      <address>
        <city>Roswell</city>
        <state>Georgia</state>
        <zip>30075</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 22</name>
      <address>
        <city>Savannah</city>
        <state>Georgia</state>
        <zip>31406</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 21</name>
      <address>
        <city>Wichita</city>
        <state>Kansas</state>
        <zip>67226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 33</name>
      <address>
        <city>Metairie</city>
        <state>Louisiana</state>
        <zip>70001</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 16</name>
      <address>
        <city>Kalamazoo</city>
        <state>Michigan</state>
        <zip>49009</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 34</name>
      <address>
        <city>Saginaw</city>
        <state>Michigan</state>
        <zip>48604</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 35</name>
      <address>
        <city>Lincoln</city>
        <state>Nebraska</state>
        <zip>68510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 12</name>
      <address>
        <city>Lawrenceville</city>
        <state>New Jersey</state>
        <zip>08648</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 26</name>
      <address>
        <city>Plainsboro</city>
        <state>New Jersey</state>
        <zip>08536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 36</name>
      <address>
        <city>Raleigh</city>
        <state>North Carolina</state>
        <zip>27607</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 04</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 37</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 07</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 24</name>
      <address>
        <city>Englewood</city>
        <state>Ohio</state>
        <zip>45322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 28</name>
      <address>
        <city>West Chester</city>
        <state>Ohio</state>
        <zip>45069</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 23</name>
      <address>
        <city>Bluffton</city>
        <state>South Carolina</state>
        <zip>29910</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 41</name>
      <address>
        <city>Mount Pleasant</city>
        <state>South Carolina</state>
        <zip>29464</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 43</name>
      <address>
        <city>Myrtle Beach</city>
        <state>South Carolina</state>
        <zip>29572</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 32</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site Number 09</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2019</verification_date>
  <study_first_submitted>September 20, 2017</study_first_submitted>
  <study_first_submitted_qc>September 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 27, 2017</study_first_posted>
  <results_first_submitted>October 15, 2019</results_first_submitted>
  <results_first_submitted_qc>December 11, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">December 26, 2019</results_first_posted>
  <last_update_submitted>December 11, 2019</last_update_submitted>
  <last_update_submitted_qc>December 11, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 26, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vaginitis</mesh_term>
    <mesh_term>Atrophic Vaginitis</mesh_term>
    <mesh_term>Atrophy</mesh_term>
  </condition_browse>
  <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>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 4, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/38/NCT03294538/SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 18, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/38/NCT03294538/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The populations for this study included the Safety Population, the modified Intent-to-Treat (mITT) population, and the Per-Protocol (PP) Population.</recruitment_details>
      <pre_assignment_details>Following the 14-day screening period, participants who continued to meet the inclusion/exclusion (I/E) criteria were randomly assigned to treatment on a 2:2:1 ratio of generic Estradiol Vaginal Cream United States Pharmacopoeia (USP), 0.01%; Estrace Vaginal Cream USP, 0.01%; or vehicle vaginal cream.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Generic Estradiol Vaginal Cream USP, 0.01%</title>
          <description>Participants were to self-administer 2 g of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
        </group>
        <group group_id="P2">
          <title>Estrace Vaginal Cream USP, 0.01%</title>
          <description>Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
        </group>
        <group group_id="P3">
          <title>Vehicle Vaginal Cream</title>
          <description>Participants were to self-administer 2 g of vehicle vaginal cream once daily at approximately the same time of the day for 7 consecutive days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="268"/>
                <participants group_id="P2" count="262"/>
                <participants group_id="P3" count="133"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Safety Population</title>
              <participants_list>
                <participants group_id="P1" count="267"/>
                <participants group_id="P2" count="262"/>
                <participants group_id="P3" count="132"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>mITT Population</title>
              <participants_list>
                <participants group_id="P1" count="267"/>
                <participants group_id="P2" count="262"/>
                <participants group_id="P3" count="132"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>PP Population</title>
              <participants_list>
                <participants group_id="P1" count="244"/>
                <participants group_id="P2" count="227"/>
                <participants group_id="P3" count="126"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="263"/>
                <participants group_id="P2" count="257"/>
                <participants group_id="P3" count="131"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Outside of Visit Window</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All participants who were randomized and administered at least 1 dose of study drug (Safety Population).</population>
      <group_list>
        <group group_id="B1">
          <title>Generic Estradiol Vaginal Cream USP, 0.01%</title>
          <description>Participants were to self-administer 2 g of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
        </group>
        <group group_id="B2">
          <title>Estrace Vaginal Cream USP, 0.01%</title>
          <description>Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
        </group>
        <group group_id="B3">
          <title>Vehicle Vaginal Cream</title>
          <description>Participants were to self-administer 2 g of vehicle vaginal cream once daily at approximately the same time of the day for 7 consecutive days.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="267"/>
            <count group_id="B2" value="262"/>
            <count group_id="B3" value="132"/>
            <count group_id="B4" value="661"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="267"/>
                    <count group_id="B2" value="262"/>
                    <count group_id="B3" value="132"/>
                    <count group_id="B4" value="661"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.5" spread="6.4"/>
                    <measurement group_id="B2" value="59.5" spread="6.5"/>
                    <measurement group_id="B3" value="60.8" spread="5.6"/>
                    <measurement group_id="B4" value="59.9" spread="6.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="267"/>
                    <count group_id="B2" value="262"/>
                    <count group_id="B3" value="132"/>
                    <count group_id="B4" value="661"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="267"/>
                    <measurement group_id="B2" value="262"/>
                    <measurement group_id="B3" value="132"/>
                    <measurement group_id="B4" value="661"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="267"/>
                    <count group_id="B2" value="262"/>
                    <count group_id="B3" value="132"/>
                    <count group_id="B4" value="661"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="79"/>
                    <measurement group_id="B2" value="88"/>
                    <measurement group_id="B3" value="42"/>
                    <measurement group_id="B4" value="209"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="188"/>
                    <measurement group_id="B2" value="174"/>
                    <measurement group_id="B3" value="90"/>
                    <measurement group_id="B4" value="452"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="267"/>
                    <count group_id="B2" value="262"/>
                    <count group_id="B3" value="132"/>
                    <count group_id="B4" value="661"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="59"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="235"/>
                    <measurement group_id="B2" value="232"/>
                    <measurement group_id="B3" value="121"/>
                    <measurement group_id="B4" value="588"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Percent of Basal/Parabasal Cells</title>
          <population>All participants who were randomized and administered at least 1 dose of study drug (Safety Population) and with evaluable basal/parabasal cells data.</population>
          <units>percent of cells</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="266"/>
                    <count group_id="B2" value="262"/>
                    <count group_id="B3" value="132"/>
                    <count group_id="B4" value="660"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="34.4" spread="35.1"/>
                    <measurement group_id="B2" value="31.5" spread="34.8"/>
                    <measurement group_id="B3" value="36.3" spread="34.3"/>
                    <measurement group_id="B4" value="34.1" spread="34.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Percent of Intermediate Cells</title>
          <population>All participants who were randomized and administered at least 1 dose of study drug (Safety Population) and with evaluable intermediate cells data.</population>
          <units>percent of cells</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="266"/>
                    <count group_id="B2" value="262"/>
                    <count group_id="B3" value="132"/>
                    <count group_id="B4" value="660"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64.7" spread="34.5"/>
                    <measurement group_id="B2" value="67.5" spread="34.3"/>
                    <measurement group_id="B3" value="62.8" spread="33.9"/>
                    <measurement group_id="B4" value="65" spread="34.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Vaginal pH</title>
          <units>pH</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="267"/>
                    <count group_id="B2" value="262"/>
                    <count group_id="B3" value="132"/>
                    <count group_id="B4" value="661"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6.2" spread="0.8"/>
                    <measurement group_id="B2" value="6.2" spread="0.8"/>
                    <measurement group_id="B3" value="6.1" spread="0.7"/>
                    <measurement group_id="B4" value="6.2" spread="0.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups</title>
        <description>Treatment comparison of the number of participants in the PP population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.</description>
        <time_frame>Up to Day 9</time_frame>
        <population>Participants who met I/E criteria, didn't develop a concurrent vaginal infection, completed Day 8 visit, and took 6-8 doses and didn't miss &gt;1 dose of study drug (PP Population). As pre-specified in the protocol, only the active groups (Generic Estradiol Vaginal Cream USP, 0.01% and Estrace Vaginal Cream USP, 0.01%) were included in this analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Generic Estradiol Vaginal Cream USP, 0.01%</title>
            <description>Participants were to self-administer 2 g of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
          <group group_id="O2">
            <title>Estrace Vaginal Cream USP, 0.01%</title>
            <description>Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups</title>
          <description>Treatment comparison of the number of participants in the PP population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.</description>
          <population>Participants who met I/E criteria, didn't develop a concurrent vaginal infection, completed Day 8 visit, and took 6-8 doses and didn't miss &gt;1 dose of study drug (PP Population). As pre-specified in the protocol, only the active groups (Generic Estradiol Vaginal Cream USP, 0.01% and Estrace Vaginal Cream USP, 0.01%) were included in this analysis.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="244"/>
                <count group_id="O2" value="227"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="49"/>
                    <measurement group_id="O2" value="44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Therapeutic equivalence of the generic estradiol vaginal cream group to the Estrace Vaginal Cream group based on the primary endpoint was evaluated in the PP population.</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>If the adjusted 90% confidence interval on the difference between proportions of participants considered Responders in the generic estradiol vaginal cream group and the Estrace Vaginal Cream group was contained within the equivalence range [-0.20, +0.20], then treatment with generic estradiol vaginal cream and treatment with Estrace Vaginal Cream were considered therapeutically equivalent.</non_inferiority_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.7</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-5.8</ci_lower_limit>
            <ci_upper_limit>7.2</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups</title>
        <description>Treatment comparison of the number of participants in the mITT population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5.</description>
        <time_frame>Up to Day 9</time_frame>
        <population>Participants in the PP population, administered at least 1 dose of study drug, and had a post-randomization evaluation (mITT Population). Participants who discontinued early for reasons other than efficacy were included in the mITT population using Last Observation Carried Forward (LOCF).</population>
        <group_list>
          <group group_id="O1">
            <title>Generic Estradiol Vaginal Cream USP, 0.01%</title>
            <description>Participants were to self-administer 2 g of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
          <group group_id="O2">
            <title>Estrace Vaginal Cream USP, 0.01%</title>
            <description>Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
          <group group_id="O3">
            <title>Vehicle Vaginal Cream</title>
            <description>Participants were to self-administer 2 g of vehicle vaginal cream once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups</title>
          <description>Treatment comparison of the number of participants in the mITT population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5.</description>
          <population>Participants in the PP population, administered at least 1 dose of study drug, and had a post-randomization evaluation (mITT Population). Participants who discontinued early for reasons other than efficacy were included in the mITT population using Last Observation Carried Forward (LOCF).</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="267"/>
                <count group_id="O2" value="262"/>
                <count group_id="O3" value="132"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53"/>
                    <measurement group_id="O2" value="53"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Superiority of the generic estradiol vaginal cream group and the Estrace Vaginal Cream group to the vehicle vaginal cream group based on the primary endpoint was evaluated in the mITT population.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>The proportion of participants considered as Responders in the generic estradiol vaginal cream group and the Estrace Vaginal Cream group were each compared to the proportion of Responders in the vehicle vaginal cream group. If both the generic estradiol vaginal cream group and the Estrace Vaginal Cream group demonstrated a statistically significant greater proportion of Responders than the vehicle vaginal cream group, then superiority was concluded.</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>19.9</param_value>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Superiority of the generic estradiol vaginal cream group and the Estrace Vaginal Cream group to the vehicle vaginal cream group based on the primary endpoint was evaluated in the mITT population.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>The proportion of participants considered as Responders in the generic estradiol vaginal cream group and the Estrace Vaginal Cream group were each compared to the proportion of Responders in the vehicle vaginal cream group. If both the generic estradiol vaginal cream group and the Estrace Vaginal Cream group demonstrated a statistically significant greater proportion of Responders than the vehicle vaginal cream group, then superiority was concluded.</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>20.2</param_value>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups</title>
        <description>The number of participants in the PP population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation was based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.</description>
        <time_frame>Up to Day 9</time_frame>
        <population>Participants who met I/E criteria, didn't develop a concurrent vaginal infection, completed Day 8 visit, and took 6-8 doses and didn't miss &gt;1 dose of study drug (PP Population). As pre-specified in the protocol, only the active groups (Generic Estradiol Vaginal Cream USP, 0.01% and Estrace Vaginal Cream USP, 0.01%) were included in this analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Generic Estradiol Vaginal Cream USP, 0.01%</title>
            <description>Participants were to self-administer 2 g of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
          <group group_id="O2">
            <title>Estrace Vaginal Cream USP, 0.01%</title>
            <description>Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups</title>
          <description>The number of participants in the PP population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation was based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.</description>
          <population>Participants who met I/E criteria, didn't develop a concurrent vaginal infection, completed Day 8 visit, and took 6-8 doses and didn't miss &gt;1 dose of study drug (PP Population). As pre-specified in the protocol, only the active groups (Generic Estradiol Vaginal Cream USP, 0.01% and Estrace Vaginal Cream USP, 0.01%) were included in this analysis.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="244"/>
                <count group_id="O2" value="227"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="161"/>
                    <measurement group_id="O2" value="153"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Therapeutic equivalence of the generic estradiol vaginal cream group to the Estrace Vaginal Cream group based on the secondary endpoint was evaluated in the PP population.</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>If the adjusted 90% confidence interval on the difference between proportions of participants considered Treatment Success in the generic estradiol vaginal cream group and the Estrace Vaginal Cream group was contained within the equivalence range [-0.20, +0.20], then treatment with generic estradiol vaginal cream and treatment with Estrace Vaginal Cream were considered therapeutically equivalent.</non_inferiority_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>-1.4</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-9.0</ci_lower_limit>
            <ci_upper_limit>6.2</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups</title>
        <description>The number of participants in the mITT Population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation is to be based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding.</description>
        <time_frame>Up to 9 months</time_frame>
        <population>Participants in the PP population, administered at least 1 dose of study drug, and had a post-randomization evaluation (mITT Population). Participants who discontinued early for reasons other than efficacy were included in the mITT population using LOCF.</population>
        <group_list>
          <group group_id="O1">
            <title>Generic Estradiol Vaginal Cream USP, 0.01%</title>
            <description>Participants were to self-administer 2 g of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
          <group group_id="O2">
            <title>Estrace Vaginal Cream USP, 0.01%</title>
            <description>Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
          <group group_id="O3">
            <title>Vehicle Vaginal Cream</title>
            <description>Participants were to self-administer 2 g of vehicle vaginal cream once daily at approximately the same time of the day for 7 consecutive days.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups</title>
          <description>The number of participants in the mITT Population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation is to be based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding.</description>
          <population>Participants in the PP population, administered at least 1 dose of study drug, and had a post-randomization evaluation (mITT Population). Participants who discontinued early for reasons other than efficacy were included in the mITT population using LOCF.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="267"/>
                <count group_id="O2" value="262"/>
                <count group_id="O3" value="132"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="175"/>
                    <measurement group_id="O2" value="169"/>
                    <measurement group_id="O3" value="80"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Superiority of the generic estradiol vaginal cream group and the Estrace Vaginal Cream group to the vehicle vaginal cream group based on the secondary endpoint was evaluated in the mITT population.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>The proportion of participants considered as Treatment Success in the generic estradiol vaginal cream group and the Estrace Vaginal Cream group were each compared to the proportion of Treatment Success in the vehicle vaginal cream group. If both the generic estradiol vaginal cream group and the Estrace Vaginal Cream group demonstrated a statistically significant greater proportion of Treatment Success than the vehicle vaginal cream group, then superiority was concluded.</non_inferiority_desc>
            <p_value>0.2897</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>4.9</param_value>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Superiority of the generic estradiol vaginal cream group and the Estrace Vaginal Cream group to the vehicle vaginal cream group based on the primary endpoint was evaluated in the mITT population.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>The proportion of participants considered as Treatment Success in the generic estradiol vaginal cream group and the Estrace Vaginal Cream group were each compared to the proportion of Treatment Success in the vehicle vaginal cream group. If both the generic estradiol vaginal cream group and the Estrace Vaginal Cream group demonstrated a statistically significant greater proportion of Treatment Success than the vehicle vaginal cream group, then superiority was concluded.</non_inferiority_desc>
            <p_value>0.4949</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>3.9</param_value>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Baseline up to Day 9</time_frame>
      <desc>All participants who were randomized and administered at least 1 dose of study drug (Safety Population).</desc>
      <group_list>
        <group group_id="E1">
          <title>Generic Estradiol Vaginal Cream USP, 0.01%</title>
          <description>Participants were to self-administer 2 g of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
        </group>
        <group group_id="E2">
          <title>Estrace Vaginal Cream USP, 0.01%</title>
          <description>Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.</description>
        </group>
        <group group_id="E3">
          <title>Vehicle Vaginal Cream</title>
          <description>Participants were to self-administer 2 g of vehicle vaginal cream once daily at approximately the same time of the day for 7 consecutive days.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 18.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Device occlusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA 18.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="63" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="74" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="25" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Retinal tear</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal discomfort</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Abdominal pain lower</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Abdominal tenderness</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Anorectal discomfort</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cyclic vomiting syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Gastric ulcer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hiatus hernia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Mouth ulceration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Application site warmth</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Chest discomfort</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Discomfort</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Seasonal allergy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bacterial vaginosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Breast abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Gastroenteritis viral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Genital herpes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Oral herpes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Otitis media</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pyelonephritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Tooth infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Viral infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Mucosal excoriation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Fibula fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Ligament sprain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Muscle strain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Skin abrasion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Thermal burn</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Carotid bruit</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Foot deformity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Dysuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Micturition Urgency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Adnexa uteri pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Breast pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Breast tenderness</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Endometrial thickening</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Nipple pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pelvic discomfort</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Perineal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Uterine spasm</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Uterine tenderness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vaginal erosion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vaginismus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vulvovaginal burning sensation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vulvovaginal discomfort</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vulvovaginal erythema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vulvovaginal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vulvovaginal pruritus</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Vulvovaginal swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Respiratory tract congestion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Rhinitis allergic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Sinus congestion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermal cyst</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Dermatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Dermatitis allergic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Dermatitis contact</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Pruritus generalised</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Rosacea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Pterygium operation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Sinus operation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Tooth extraction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hot flush</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="132"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="267"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="262"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="132"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The results of the study may be published or presented by the Investigator(s) after the review by, and in consultation and agreement with the Sponsor, and such that confidential or proprietary information is not disclosed.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Senior Director, CE Studies</name_or_title>
      <organization>Teva Pharmaceuticals USA, Inc.</organization>
      <phone>1-888-483-8279</phone>
      <email>USMedInfo@tevapharm.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03294538
org study id: 71436001
nct id: NCT03294538
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The objectives of this study were to evaluate the therapeutic equivalence of the Test
      formulation, generic Estradiol Vaginal Cream United States Pharmacopoeia (USP), 0.01% (Teva
      Pharmaceuticals, United States of America) to the marketed product, Estrace® Cream estradiol
      vaginal cream USP, 0.01% (Warner Chilcott) in participants with atrophic vaginitis; to
      demonstrate the superiority of the Test and Reference (active) treatments over Placebo
      (vehicle) cream in participants with atrophic vaginitis; and to compare the safety of Test,
      Reference, and Placebo treatments in participants with atrophic vaginitis.
Systemic (oral or transdermal patch administration) estrogen therapies have been shown to
      effectively treat symptoms of atrophic vaginitis but bear undesirable side effects including
      increased risk of heart attacks, stroke, endometrial cancer, and breast cancer. Topical
      therapies (creams and transvaginal delivery systems) provide low doses of estrogen to the
      vaginal mucosa to provide local relief for the symptoms of atrophic vaginitis, while reducing
      the unwanted side effects associated with systemic delivery systems. Low dose, topical
      estrogen therapy is considered most appropriate and convenient for the treatment of vaginal
      symptoms associated with menopause, particularly when other symptoms including bone loss or
      vasomotor dysfunction do not need to be targeted.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups
time frame: Up to Day 9
description: Treatment comparison of the number of participants in the PP population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.
measure: Number of Participants Identified as a Responder After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups
time frame: Up to Day 9
description: Treatment comparison of the number of participants in the mITT population that were identified as responders at the end of the treatment period evaluated on Day 8 + 1 is presented. A responder was defined as a participant with at least a 25% reduction from baseline in the sum of percent basal/parabasal + percent intermediate cells on vaginal cytology and vaginal pH ≤5.0 with a change from baseline vaginal pH of at least 0.5.
measure: Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream and Estrace Vaginal Cream Groups
time frame: Up to Day 9
description: The number of participants in the PP population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation was based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding. Any participant who withdrew from the study because of lack of efficacy was included as a non-responder.
measure: Number of Participants Identified as Treatment Success After Completing Study Treatment in the Generic Estradiol Vaginal Cream, Estrace Vaginal Cream, and Vehicle Vaginal Cream Groups
time frame: Up to 9 months
description: The number of participants in the mITT Population that are identified as Treatment Success at the end of the treatment period evaluated on Day 8 ± 1 is presented. A Treatment Success is defined as a score of 0 or 1 at Day 8 ± 1 for the symptom identified at baseline as the most bothersome. This evaluation is to be based on participant self-assessed symptoms of vulvar and vaginal atrophy on a scale of 0 to 3 where 0 = none and 3 = severe. The symptoms that were evaluated were vaginal dryness, vaginal/vulvar irritation/itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding.
arm group label: Generic Estradiol Vaginal Cream USP, 0.01%
arm group type: Experimental
description: Participants were to self-administer 2 grams (g) of generic Estradiol Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.
arm group label: Estrace Vaginal Cream USP, 0.01%
arm group type: Active Comparator
description: Participants were to self-administer 2 g of Estrace Vaginal Cream USP, 0.01% once daily at approximately the same time of the day for 7 consecutive days.
arm group label: Vehicle Vaginal Cream
arm group type: Placebo Comparator
description: Participants were to self-administer 2 g of vehicle vaginal cream once daily at approximately the same time of the day for 7 consecutive days.
intervention type: Drug
intervention name: Generic Estradiol Vaginal Cream USP, 0.01%
description: Vaginal cream, generic formulation of the brand product.
arm group label: Generic Estradiol Vaginal Cream USP, 0.01%
intervention type: Drug
intervention name: Estrace® Vaginal Cream USP, 0.01%
description: Vaginal cream, brand product.
arm group label: Estrace Vaginal Cream USP, 0.01%
intervention type: Drug
intervention name: Vehicle Vaginal Cream
description: Vaginal cream, placebo. Has no active ingredient
arm group label: Vehicle Vaginal Cream
criteria: 
gender: Female
minimum age: 30 Years
maximum age: 75 Years
healthy volunteers: No
last name: Study Director
role: Study Director
affiliation: Teva Pharmaceuticals USA
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country: United States
responsible party type: Sponsor
mesh term: Vaginitis
mesh term: Atrophic Vaginitis
mesh term: Atrophy
mesh term: Estradiol 17 beta-cypionate
mesh term: Estradiol 3-benzoate
mesh term: Estradiol
mesh term: Polyestradiol phosphate
sharing ipd: No
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certain agreements: 
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