<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/NCT03230539</url>
  </required_header>
  <id_info>
    <org_study_id>719</org_study_id>
    <nct_id>NCT03230539</nct_id>
  </id_info>
  <brief_title>A proof-of Concept, Randomized 3-month Study to Evaluate the Effects of Three Contraceptive Intrauterine Systems Delivering Copper and a Daily Dose of 5, 20 or 40 μg of Ulipristal Acetate (UPA)</brief_title>
  <official_title>A proof-of Concept, Randomized 3-month Study to Evaluate the Effects of Three Contraceptive Intrauterine Systems Delivering Copper and a Daily Dose of 5, 20 or 40 μg of Ulipristal Acetate (UPA) on Ovulation, Endometrial Changes and Bleeding Patterns in Normally Cycling Women</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Population Council</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Population Council</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The UPA doses to be tested in this new IUS, 5, 20 or 40 μg per day, are not expected to&#xD;
      suppress ovulation, however they should prevent endometrial growth resulting in endometrial&#xD;
      atrophy, minimal bleeding, or even amenorrhea. It is anticipated that with low UPA doses,&#xD;
      women will continue to ovulate and secrete progesterone (P) during the secretory phase of the&#xD;
      menstrual cycle. As a result, PRM associated endometrial changes (PAECs) that have been&#xD;
      described in previous UPA studies when ovulation was suppressed and associated with&#xD;
      amenorrhea should not occur and endometria should retain normalcy. These expectations are&#xD;
      based on our findings from a previous study in which the UPA doses tested were insufficient&#xD;
      to block ovulation and participants maintained P secretion with normal endometria (protocol&#xD;
      349). Further evidence regarding the benefit of using low doses of UPA in a copper IUS stems&#xD;
      from a small rhesus macaque proof of principle study that included an UPA-IUS delivering 40&#xD;
      or 60 μg/d of UPA, and fixed doses of E2 and cyclic P delivered via implants over 3 cycles.24&#xD;
      Indices of endometrial proliferation were significantly reduced in 3 out of 5 animals in that&#xD;
      study; the endometria were atrophied with some glandular cysts, and typical PAECs were&#xD;
      limited. Glands were generally small and tubular, however, in some animals they were large&#xD;
      and dilated; resembling cysts with minimal evidence of proliferative activity.24 No bleeding&#xD;
      was observed in the treated monkeys during progesterone withdrawal over the 3 cycles.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Intrauterine devices (IUD) such as the Copper IUD (Paragard) and the levonorgestrel (LNG) IUS&#xD;
      (Mirena®) are considered highly safe and effective long acting reversible methods of&#xD;
      contraception (LARC). Nevertheless discontinuations are high due to user complaints of heavy&#xD;
      bleeding during the first few months after insertion of IUDs or irregular bleeding in the&#xD;
      first year of use of an IUS. To prevent these bleeding problems and enhance the overall&#xD;
      safety profile, a new IUS is being developed that will deliver copper to provide its well&#xD;
      described contraceptive efficacy in combination with UPA, a progesterone receptor modulator&#xD;
      (PRM) that may decrease the amount of bleeding associated with use of a Cu IUD.&#xD;
&#xD;
      Since results of human studies delivering antiovulatory doses of UPA orally or with vaginal&#xD;
      rings have shown endometrial changes characterized as typical PAECs, the occurrence of these&#xD;
      endometrial effects with lower doses of the PRM delivered in the endometrium via this&#xD;
      investigational IUS requires evaluation with both histology assessments and measures of&#xD;
      proliferation markers. We need to determine if small doses of UPA administered locally with a&#xD;
      new Cu-IUS with UPA can result in reduced bleeding or amenorrhea, as observed in the monkey&#xD;
      study, and whether or not endometrial modifications occur.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 1, 2017</start_date>
  <completion_date type="Anticipated">May 2018</completion_date>
  <primary_completion_date type="Anticipated">January 2018</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>A proof-of concept, randomized 3-month study to evaluate the effects of three contraceptive intrauterine systems delivering Copper and a daily dose of 5, 20 or 40 μg of Ulipristal Acetate (UPA)</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The primary endpoint is the ability of the three doses of UPA as delivered by IUS to suppress bleeding.</measure>
    <time_frame>12 weeks</time_frame>
    <description>Bleeding data obtained from diaries and CRFs.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Contraception</condition>
  <arm_group>
    <arm_group_label>UPA IUS 20 μg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>UPA IUS 5 μg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>UPA IUS 40 μg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ulipristal Acetate IUS delivering Cu and 5μg</intervention_name>
    <description>This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks.</description>
    <arm_group_label>UPA IUS 5 μg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ulipristal Acetate IUS delivering Cu and 20μg</intervention_name>
    <description>This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks.</description>
    <arm_group_label>UPA IUS 20 μg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ulipristal Acetate IUS delivering Cu and 40μg</intervention_name>
    <description>This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks.</description>
    <arm_group_label>UPA IUS 40 μg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy women of reproductive age (21-38 years)&#xD;
&#xD;
          -  Not at risk for pregnancy based on subject has undergone sterilization or subject is&#xD;
             monogamous and her male partner has undergone sterilization&#xD;
&#xD;
          -  Have regular menstrual cycles of 21-35 days duration&#xD;
&#xD;
          -  Have an intact uterus and both ovaries&#xD;
&#xD;
          -  Will be able to comply with the protocol&#xD;
&#xD;
          -  Capable of giving informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Women participating in another clinical trial within 30 days of initiation of this&#xD;
             clinical trial&#xD;
&#xD;
          -  Women not living in the catchment area of the clinic&#xD;
&#xD;
          -  Known hypersensitivity to progestins or antiprogestins&#xD;
&#xD;
          -  Known hypersensitivity to copper&#xD;
&#xD;
          -  Any known chronic disease including HIV/AIDS&#xD;
&#xD;
          -  All contraindications to IUD use,&#xD;
&#xD;
          -  Desire to get pregnant during the study Breastfeeding&#xD;
&#xD;
          -  Undiagnosed vaginal discharge or vaginal lesions or abnormalities&#xD;
&#xD;
          -  Women with a current abnormal Pap. In accordance with the Bethesda system of&#xD;
             classification: smear suggestive of high-grade pre-cancerous lesion(s), including&#xD;
             HGSIL, are excluded;&#xD;
&#xD;
          -  Women with LGSIL or ASCUS/high-risk HPV positive may participate if further evaluated&#xD;
             with colposcopy and biopsy and no evidence of a lesion with a severity &gt; CIN I is&#xD;
             present and/or endocervical curettage is negative.&#xD;
&#xD;
          -  Women with a biopsy finding of CIN I should have follow up for this finding per&#xD;
             standard of care; women are excluded it treatment is indicated.&#xD;
&#xD;
          -  Known benign or malignant liver tumors; known active liver disease&#xD;
&#xD;
          -  Cancer (past history of any carcinoma or sarcoma)&#xD;
&#xD;
          -  Medically diagnosed severe depression currently or in the past&#xD;
&#xD;
          -  Known or suspected alcoholism or drug abuse&#xD;
&#xD;
          -  Abnormal, clinically significant, serum fasting clinical chemistry values&#xD;
&#xD;
          -  Women with known abnormal thyroid status&#xD;
&#xD;
          -  Women with known impaired hypothalamic-pituitary-adrenal reserve&#xD;
&#xD;
          -  Average diastolic BP &gt; 85 mm or systolic BP &gt;135 mm Hg after 5-10 minutes rest&#xD;
&#xD;
          -  Body mass index (BMI) &gt; 30.0 (or ≤18) Kg/m2&#xD;
&#xD;
          -  Women with uterine anomalies&#xD;
&#xD;
          -  Use within the past 2 months of any implanted hormonal contraceptives including&#xD;
             progestin-releasing intrauterine systems (IUS) or progestin-releasing subdermal&#xD;
             implants. NOTE: Removal of implanted hormonal contraceptives must have been for&#xD;
             personal reasons unrelated to the purpose of enrollment in this study.&#xD;
&#xD;
          -  Current use of a non-hormone containing IUD. NOTE: Removal of an IUD must be for&#xD;
             personal reasons unrelated to the purpose of enrollment in this study.&#xD;
&#xD;
          -  Use of injectable contraceptives during the previous 3 months (e.g. Cyclofem) or 6&#xD;
             months (e.g. DMPA).&#xD;
&#xD;
          -  Women who do not have at least two progesterone measurements ≥10nmol/L during the&#xD;
             baseline cycle will be excluded from further participation in the study (See Section&#xD;
             13.4.1)&#xD;
&#xD;
          -  Acute pelvic inflammatory disease or a history of pelvic inflammatory disease unless&#xD;
             there has been a subsequent intrauterine pregnancy. Postpartum endometritis or&#xD;
             infected abortion in the past 3 months.&#xD;
&#xD;
          -  Genital bleeding of unknown etiology.&#xD;
&#xD;
          -  Untreated acute cervicitis or vaginitis, including bacterial vaginosis or other lower&#xD;
             genital tract infections until infection is controlled.&#xD;
&#xD;
          -  Current behavior suggesting a high risk for pelvic inflammatory disease&#xD;
&#xD;
          -  Mucopurulent cervicitis&#xD;
&#xD;
          -  Wilson's disease&#xD;
&#xD;
          -  Allergy to any component of the IUS&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>38 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ruth Merkatz, RN</last_name>
    <role>Study Director</role>
    <affiliation>Population Council</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ruth Merkatz, RN</last_name>
    <phone>212-327-8647</phone>
    <email>rmerkatz@popcouncil.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Profamilia</name>
      <address>
        <city>Santo Domingo</city>
        <country>Dominican Republic</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vivian Brache, Lic.</last_name>
      <phone>809-681-8357</phone>
      <email>biomedica@codetel.net.do</email>
    </contact>
    <investigator>
      <last_name>Vivian Brache, Lic.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Dominican Republic</country>
  </location_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>July 13, 2017</study_first_submitted>
  <study_first_submitted_qc>July 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 26, 2017</study_first_posted>
  <last_update_submitted>August 11, 2017</last_update_submitted>
  <last_update_submitted_qc>August 11, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 15, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ulipristal acetate</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03230539
org study id: 719
nct id: NCT03230539
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The UPA doses to be tested in this new IUS, 5, 20 or 40 μg per day, are not expected to
      suppress ovulation, however they should prevent endometrial growth resulting in endometrial
      atrophy, minimal bleeding, or even amenorrhea. It is anticipated that with low UPA doses,
      women will continue to ovulate and secrete progesterone (P) during the secretory phase of the
      menstrual cycle. As a result, PRM associated endometrial changes (PAECs) that have been
      described in previous UPA studies when ovulation was suppressed and associated with
      amenorrhea should not occur and endometria should retain normalcy. These expectations are
      based on our findings from a previous study in which the UPA doses tested were insufficient
      to block ovulation and participants maintained P secretion with normal endometria (protocol
      349). Further evidence regarding the benefit of using low doses of UPA in a copper IUS stems
      from a small rhesus macaque proof of principle study that included an UPA-IUS delivering 40
      or 60 μg/d of UPA, and fixed doses of E2 and cyclic P delivered via implants over 3 cycles.24
      Indices of endometrial proliferation were significantly reduced in 3 out of 5 animals in that
      study; the endometria were atrophied with some glandular cysts, and typical PAECs were
      limited. Glands were generally small and tubular, however, in some animals they were large
      and dilated; resembling cysts with minimal evidence of proliferative activity.24 No bleeding
      was observed in the treated monkeys during progesterone withdrawal over the 3 cycles.
Intrauterine devices (IUD) such as the Copper IUD (Paragard) and the levonorgestrel (LNG) IUS
      (Mirena®) are considered highly safe and effective long acting reversible methods of
      contraception (LARC). Nevertheless discontinuations are high due to user complaints of heavy
      bleeding during the first few months after insertion of IUDs or irregular bleeding in the
      first year of use of an IUS. To prevent these bleeding problems and enhance the overall
      safety profile, a new IUS is being developed that will deliver copper to provide its well
      described contraceptive efficacy in combination with UPA, a progesterone receptor modulator
      (PRM) that may decrease the amount of bleeding associated with use of a Cu IUD.

      Since results of human studies delivering antiovulatory doses of UPA orally or with vaginal
      rings have shown endometrial changes characterized as typical PAECs, the occurrence of these
      endometrial effects with lower doses of the PRM delivered in the endometrium via this
      investigational IUS requires evaluation with both histology assessments and measures of
      proliferation markers. We need to determine if small doses of UPA administered locally with a
      new Cu-IUS with UPA can result in reduced bleeding or amenorrhea, as observed in the monkey
      study, and whether or not endometrial modifications occur.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A proof-of concept, randomized 3-month study to evaluate the effects of three contraceptive intrauterine systems delivering Copper and a daily dose of 5, 20 or 40 μg of Ulipristal Acetate (UPA)
primary purpose: Supportive Care
masking: None (Open Label)
measure: The primary endpoint is the ability of the three doses of UPA as delivered by IUS to suppress bleeding.
time frame: 12 weeks
description: Bleeding data obtained from diaries and CRFs.
arm group label: UPA IUS 20 μg
arm group type: Experimental
description: This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks.
arm group label: UPA IUS 5 μg
arm group type: Experimental
description: This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks
arm group label: UPA IUS 40 μg
arm group type: Experimental
description: This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks
intervention type: Drug
intervention name: Ulipristal Acetate IUS delivering Cu and 5μg
description: This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks.
arm group label: UPA IUS 5 μg
intervention type: Drug
intervention name: Ulipristal Acetate IUS delivering Cu and 20μg
description: This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks.
arm group label: UPA IUS 20 μg
intervention type: Drug
intervention name: Ulipristal Acetate IUS delivering Cu and 40μg
description: This is a proof-of-concept study utilizing a randomized dose-finding, parallel design to assess the effects of an IUS delivering Cu and 5, 20, or 40 μg of UPA over 12 weeks.
arm group label: UPA IUS 40 μg
criteria: 
gender: Female
minimum age: 21 Years
maximum age: 38 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ruth Merkatz, RN
role: Study Director
affiliation: Population Council
last name: Ruth Merkatz, RN
phone: 212-327-8647
email: rmerkatz@popcouncil.org
facility: 
status: Recruiting
contact: 
investigator: 
country: Dominican Republic
responsible party type: Sponsor
mesh term: Ulipristal acetate