<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/NCT03798197</url>
  </required_header>
  <id_info>
    <org_study_id>MIT-Do001-C101</org_study_id>
    <secondary_id>2018-003761-34</secondary_id>
    <nct_id>NCT03798197</nct_id>
  </id_info>
  <brief_title>Effect of Food on the Bioavailability of 30 mg Estetrol (E4) Tablet in Healthy Postmenopausal Female Volunteers</brief_title>
  <official_title>An Open-label, Single-center, Randomized, Two Period, Two Sequence Crossover Study to Characterize the Effect of Food on the Bioavailability of 30 mg Estetrol (E4) Tablet in Healthy Postmenopausal Female Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Donesta Bioscience</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Donesta Bioscience</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>
      Assessment of the effect of a high fat meal on the quantity in blood of a female sex hormone&#xD;
      called estetrol (E4).&#xD;
&#xD;
      The study also aims at determining how subject tolerate the study drug and how safe it is for&#xD;
      them.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 30, 2019</start_date>
  <completion_date type="Actual">April 6, 2019</completion_date>
  <primary_completion_date type="Actual">April 6, 2019</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>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum concentration (Cmax) of Estetrol in plasma</measure>
    <time_frame>Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose</time_frame>
    <description>PK sampling</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the curve (AUC) from time zero to the last determinable concentration of Estetrol</measure>
    <time_frame>Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose</time_frame>
    <description>PK sampling</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-inf of Estetrol</measure>
    <time_frame>Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose</time_frame>
    <description>PK sampling</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time of Cmax (Tmax)</measure>
    <time_frame>Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose</time_frame>
    <description>PK sampling</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal phase rate constant (ke)</measure>
    <time_frame>Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose</time_frame>
    <description>PK sampling</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal half-life (t1/2)</measure>
    <time_frame>Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose</time_frame>
    <description>PK sampling</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with adverse events as measure of safety and tolerability</measure>
    <time_frame>From Day 28 prior screening to end of study (Day 4 of Period 2)</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>Food-effect</condition>
  <arm_group>
    <arm_group_label>30 mg estetrol (E4) without food (fasted)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Treatment A (reference): One 30 mg E4 tablet administered orally following an overnight fast of at least 10 hours.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>30 mg estetrol (E4) with food (fed)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatment B (test): One 30 mg E4 tablet administered orally 30 min after the start of an FDA prescribed high-fat breakfast preceded by at least a 10 hours overnight fast.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>30 mg estetrol (E4)</intervention_name>
    <description>All subjects received both Treatment A and Treatment B either at the first treatment period (Period 1) or at the second treatment period (Period 2). Approximately half of the subjects was randomized to receive either Treatment A followed by Treatment B (sequence AB), or Treatment B followed by Treatment A (sequence BA).</description>
    <arm_group_label>30 mg estetrol (E4) with food (fed)</arm_group_label>
    <arm_group_label>30 mg estetrol (E4) without food (fasted)</arm_group_label>
    <other_name>30 mg E4 tablet</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Overtly healthy postmenopausal females as determined by medical history, physical&#xD;
             examination including breast examination, gynecological examination, cervical smear&#xD;
             (Pap smear) if subject has cervix, vital signs, and laboratory tests performed within&#xD;
             28 days before first study drug intake.&#xD;
&#xD;
          -  Between the ages of 40 and 65 years inclusive at the time of signing the informed&#xD;
             consent (IC).&#xD;
&#xD;
          -  Between the Body Mass Index (BMI) of 18 and 30 kg/m2 inclusive and body weight ≥ 45&#xD;
             kg.&#xD;
&#xD;
          -  For non-hysterectomized women: intact uterus with bi-layer endometrial thickness ≤ 5&#xD;
             mm on transvaginal ultrasound (TVUS).&#xD;
&#xD;
          -  Non-smokers.&#xD;
&#xD;
          -  Negative test results for selected drugs of abuse and cotinine.&#xD;
&#xD;
          -  Venous access sufficient to allow blood sampling as per the protocol.&#xD;
&#xD;
          -  Subject is able to understand and comply with the protocol requirements, instructions,&#xD;
             and protocol-stated restrictions.&#xD;
&#xD;
          -  Subject has provided signed and dated written IC before participation in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  For non-hysterectomized women: uterine disease or medical condition including:&#xD;
&#xD;
               -  Bi-layer endometrial thickness &gt;5mm as determined by TVUS;&#xD;
&#xD;
               -  Presence of fibroid(s) that obscure(s) evaluation of endometrium by TVUS;&#xD;
&#xD;
               -  History or presence of uterine cancer;&#xD;
&#xD;
               -  Presence of any significant uterine, ovarian or other adnexa related abnormality&#xD;
                  as determined by TVUS;&#xD;
&#xD;
               -  Presence of an endometrial polyp.&#xD;
&#xD;
          -  Undiagnosed vaginal bleeding in the last 12 months.&#xD;
&#xD;
          -  Any history of malignancy.&#xD;
&#xD;
          -  History of venous or arterial thromboembolic disease&#xD;
&#xD;
          -  Abnormal blood pressure.&#xD;
&#xD;
          -  Use of :&#xD;
&#xD;
               -  Any prescription drugs within 28 days prior to the first study dose&#xD;
                  administration.&#xD;
&#xD;
               -  Any over-the-counter (OTC) medication or dietary supplements (vitamins included)&#xD;
                  within 14 days prior to the first study dose administration.&#xD;
&#xD;
          -  Users of progestin implants or oestrogen alone injectable drug therapy are not allowed&#xD;
             to participate unless treatment was stopped more than 3 months prior to screening.&#xD;
&#xD;
          -  Users of oestrogen pellet or progestin injectable drug therapy are not allowed to&#xD;
             participate unless treatment was stopped more than 6 months prior to screening.&#xD;
&#xD;
          -  Subjects who are not in euthyroid condition.&#xD;
&#xD;
          -  History of hypersensitivity or existing contraindication to E4 or intolerance to any&#xD;
             component of the formulations or test meal.&#xD;
&#xD;
          -  Presence or history of gallbladder disease, unless cholecystectomy has been performed.&#xD;
&#xD;
          -  Any surgical or medical condition which might significantly alter the absorption,&#xD;
             distribution, metabolism, or excretion of drugs, or which may jeopardize the subject&#xD;
             in case of participation in the study.&#xD;
&#xD;
          -  History or presence of immunodeficiency diseases including a positive human&#xD;
             immunodeficiency virus (HIV) test result, positive hepatitis B surface antigen (HBsAg)&#xD;
             or hepatitis C test result.&#xD;
&#xD;
          -  History of illicit drug or alcohol abuse within 12 months prior to first study dose or&#xD;
             evidence of such abuse as indicated by laboratory values within 28 days prior to first&#xD;
             study dose.&#xD;
&#xD;
          -  Consumption of foods or beverages containing the following products during the&#xD;
             specified timeframes prior to study drug administration in Period 1: caffeine or&#xD;
             xanthine - 48 hours; alcohol - 48 hours; grapefruit/seville orange/citrus fruit and/or&#xD;
             star fruit - 7 days. Others Fruit juices: 72 hours prior to study drug administration.&#xD;
&#xD;
          -  Donation or loss of&#xD;
&#xD;
               -  ≥ 450 mL blood within 1 month prior to initial study drug administration.&#xD;
&#xD;
               -  ≥ 250 mL blood within 2 weeks prior to initial study drug administration.&#xD;
&#xD;
          -  Sponsor, Contract Research Organization (CRO) or Investigator's site personnel or&#xD;
             their relatives directly affiliated with this study.&#xD;
&#xD;
          -  History or presence of clinically relevant disease of any major system organ class&#xD;
             (SOC) (e.g. cardiovascular, pulmonary, renal, hepatic, gastrointestinal, reproductive,&#xD;
             endocrinological, neurological, psychiatric or orthopedic disease) as judged by the&#xD;
             Investigator.&#xD;
&#xD;
          -  Previous completion or withdrawal from this study.&#xD;
&#xD;
          -  Participation in another investigational drug clinical study within 1 month (30 days)&#xD;
             or have received an investigational drug within the last 3 months (90 days) prior to&#xD;
             study entry.&#xD;
&#xD;
          -  Is judged by the Investigator to be unsuitable for any reason.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dobrin Svinarov, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>MC Comac Medical Ltd.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>MC Comac Medical Ltd.</name>
      <address>
        <city>Sofia</city>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Bulgaria</country>
  </location_countries>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>January 7, 2019</study_first_submitted>
  <study_first_submitted_qc>January 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 9, 2019</study_first_posted>
  <last_update_submitted>May 3, 2019</last_update_submitted>
  <last_update_submitted_qc>May 3, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 7, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Estetrol</keyword>
  <keyword>Menopausal hormone therapy</keyword>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03798197
org study id: MIT-Do001-C101
secondary id: 2018-003761-34
nct id: NCT03798197
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Assessment of the effect of a high fat meal on the quantity in blood of a female sex hormone
      called estetrol (E4).

      The study also aims at determining how subject tolerate the study drug and how safe it is for
      them.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Maximum concentration (Cmax) of Estetrol in plasma
time frame: Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
description: PK sampling
measure: Area under the curve (AUC) from time zero to the last determinable concentration of Estetrol
time frame: Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
description: PK sampling
measure: AUC0-inf of Estetrol
time frame: Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
description: PK sampling
measure: Time of Cmax (Tmax)
time frame: Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
description: PK sampling
measure: Terminal phase rate constant (ke)
time frame: Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
description: PK sampling
measure: Terminal half-life (t1/2)
time frame: Predose, 10, 20, 30, 45 min, 1, 1.25, 1.5, 1.75, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours post-dose
description: PK sampling
measure: Number of subjects with adverse events as measure of safety and tolerability
time frame: From Day 28 prior screening to end of study (Day 4 of Period 2)
arm group label: 30 mg estetrol (E4) without food (fasted)
arm group type: Active Comparator
description: Treatment A (reference): One 30 mg E4 tablet administered orally following an overnight fast of at least 10 hours.
arm group label: 30 mg estetrol (E4) with food (fed)
arm group type: Experimental
description: Treatment B (test): One 30 mg E4 tablet administered orally 30 min after the start of an FDA prescribed high-fat breakfast preceded by at least a 10 hours overnight fast.
intervention type: Drug
intervention name: 30 mg estetrol (E4)
description: All subjects received both Treatment A and Treatment B either at the first treatment period (Period 1) or at the second treatment period (Period 2). Approximately half of the subjects was randomized to receive either Treatment A followed by Treatment B (sequence AB), or Treatment B followed by Treatment A (sequence BA).
arm group label: 30 mg estetrol (E4) with food (fed)
arm group label: 30 mg estetrol (E4) without food (fasted)
other name: 30 mg E4 tablet
criteria: 
gender: Female
minimum age: 40 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Dobrin Svinarov, MD
role: Principal Investigator
affiliation: MC Comac Medical Ltd.
facility: 
country: Bulgaria
responsible party type: Sponsor
sharing ipd: No