<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/NCT03834883</url>
  </required_header>
  <id_info>
    <org_study_id>1806935117</org_study_id>
    <nct_id>NCT03834883</nct_id>
  </id_info>
  <brief_title>Reducing the Risk of Drug-Induced QT Interval Lengthening in Women</brief_title>
  <official_title>Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening: Reducing the Risk of Drug-Induced QT Interval Lengthening in Women</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Indiana University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>American Heart Association</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Purdue University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Indiana University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research will determine if oral progesterone attenuates drug-induced QT interval&#xD;
      lengthening in a) Postmenopausal women 50 years of age or older, and b) Premenopausal women&#xD;
      studied during the ovulation phase of the menstrual cycle. This investigation will consist of&#xD;
      two concurrent prospective, randomized, double-blind, placebo-controlled crossover-design&#xD;
      studies in a) Postmenopausal women, and b) Premenopausal women. Each subject will take&#xD;
      progesterone or placebo capsules for 1 week. After a two-week &quot;washout&quot; (no progesterone or&#xD;
      placebo) each subject will then take the alternative therapy (progesterone or placebo) for 1&#xD;
      week. After 7 days of each treatment, subjects will present to the clinical research center&#xD;
      to receive a small dose of the QT interval-lengthening drug ibutilide, and the effect on the&#xD;
      QT, J-Tpeak and Tpeak-Tend intervals during the progesterone and placebo phases will be&#xD;
      compared&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Torsades de pointes (TdP) is a catastrophic arrhythmia associated with corrected QT (QTc)&#xD;
      interval prolongation, which can be induced by &gt; 150 commonly prescribed drugs. TdP risk is&#xD;
      higher in women and is modulated by the ratio of serum progesterone and estradiol; the higher&#xD;
      the serum progesterone and progesterone:estradiol ratio, the lower the risk, and vice-versa.&#xD;
      TdP risk increases with age, likely due to declining postmenopausal progesterone&#xD;
      concentrations. Methods to reduce TdP risk in postmenopausal women requiring therapy with QTc&#xD;
      interval-prolonging drugs have not been developed. In addition, the differential effects of&#xD;
      progesterone on drug-induced lengthening of early vs late ventricular repolarization in&#xD;
      humans are unknown. The investigators have previously shown that oral progesterone attenuates&#xD;
      QTc interval lengthening in young women during the menses phase when serum estradiol&#xD;
      concentrations are low. However, whether oral progesterone remains effective for attenuating&#xD;
      drug-induced QTc interval lengthening during menstrual cycle phases with higher serum&#xD;
      estradiol concentrations is unknown. The efficacy of oral progesterone for attenuating&#xD;
      drug-induced QTc interval lengthening in postmenopausal women is also unknown. Specific Aim1:&#xD;
      Determine the efficacy of oral progesterone as a preventive method to diminish drug-induced&#xD;
      QTc interval lengthening in postmenopausal women. Specific Aim 2: Determine the influence of&#xD;
      oral progesterone on drug-induced lengthening of early versus late ventricular repolarization&#xD;
      in postmenopausal women. Specific Aim 3: Determine the efficacy of oral progesterone to&#xD;
      diminish drug-induced QTc interval lengthening in premenopausal women during the ovulation&#xD;
      phase of the menstrual cycle, when serum estradiol concentrations are high. Specific Aim 4:&#xD;
      Specific Aim 4: Determine the influence of oral progesterone on drug-induced lengthening of&#xD;
      early versus late ventricular repolarization in premenopausal women during the ovulation&#xD;
      phase of the menstrual cycle, when serum estradiol concentrations are high.&#xD;
&#xD;
      Concurrent prospective, randomized, double-blind, placebo-controlled two-way crossover-design&#xD;
      studies will be conducted in a) Postmenopausal women &gt; 50 years of age (n=20) and b)&#xD;
      Premenopausal women 21-40 years of age (n=20) who will be studied during the ovulation phase&#xD;
      of the menstural cycle. QTc interval response to low-dose ibutilide will be assessed.&#xD;
      Subjects will receive, in randomized order (with a minimum two-week washout phase) oral&#xD;
      progesterone 400 mg or placebo once daily for 7 days. On the morning after the 7th dose,&#xD;
      subjects will present to the Indiana Clinical Research Center to receive one dose of the QT&#xD;
      interval-lengthening drug ibutilide 0.003 mg/kg, after which ECGs and blood for determination&#xD;
      of serum ibutilide concentrations will be obtained serially for 8 hours. Primary outcome&#xD;
      measures: 1) Baseline (pre-ibutilide) Fridericia (QTFrid) and Framingham (QTFram)-corrected&#xD;
      QT intervals, 2) Maximum QTFrid and QTFram intervals following ibutilide, 3) Maximum % change&#xD;
      in QTFrid and QTFram intervals following ibutilide, 4) Area under the QTFrid and QTFram&#xD;
      interval-time curves from 0-1 and 0-8 hours. Secondary outcome measures: 1) J-Tpeak interval,&#xD;
      2) Tpeak-Tend interval, and 5) Incidence of progesterone and ibutilide adverse effects. These&#xD;
      studies will establish oral progesterone as a safe and effective method of attenuating&#xD;
      drug-induced QTc interval lengthening in postmenopausal women.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 26, 2019</start_date>
  <completion_date type="Anticipated">January 22, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 15, 2024</primary_completion_date>
  <phase>Phase 4</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>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Baseline (pre-ibutilide) QT-F and QT-Fram intervals</measure>
    <time_frame>After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide</time_frame>
    <description>QT intervals will be corrected for heart rate using two methods: the Fridericia method and the Framingham method</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum post-ibutilide QT-F and QT-Fram intervals</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>Maximum post-ibutilide QT-F and QT-Fram intervals</description>
  </primary_outcome>
  <primary_outcome>
    <measure>% change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>% change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the QT-F and QT-Fram versus time curves during and for 1 hour following ibutilide infusion</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion</time_frame>
    <description>Area under the QT-F and QT-Fram versus time curves during and for 1 hour</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals</measure>
    <time_frame>After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide</time_frame>
    <description>Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum post-ibutilide J-Tpeakc intervals</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>Maximum post-ibutilide J-Tpeakc intervals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>% change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>% change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the J-Tpeakc versus time curve during and for 1 hour following ibutilide infusion</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion</time_frame>
    <description>Area under the J-Tpeakc versus time curve during and for 1 hour following</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the J-Tpeakc versus time curve during and for 8 hours following ibutilide infusion</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>Area under the J-Tpeakc versus time curve during and for 8 hours following</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline (pre-ibutilide) Tpeak-Tend intervals</measure>
    <time_frame>After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide</time_frame>
    <description>Baseline (pre-ibutilide) Tpeak-Tend intervals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum post-ibutilide Tpeak-Tend intervals</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>Maximum post-ibutilide Tpeak-Tend intervals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>% change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>% change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion</time_frame>
    <description>Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion</measure>
    <time_frame>Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Adverse effects</measure>
    <time_frame>During the 7 days of treatment with progesterone/placebo and at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion</time_frame>
    <description>Adverse effects fo progesterone, placebo and ibutilide will be assessed</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Long QT Syndrome</condition>
  <condition>Abnormalities, Drug-Induced</condition>
  <arm_group>
    <arm_group_label>Postmenopausal women: Progesterone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Postmenopausal women: Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will receive oral placebo, two capsules once daily every evening for 7 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Premenopausal women: Progesterone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Premenopausal women: Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will receive oral placebo, two capsules once daily every evening for 7 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Progesterone</intervention_name>
    <description>Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days</description>
    <arm_group_label>Postmenopausal women: Progesterone</arm_group_label>
    <arm_group_label>Premenopausal women: Progesterone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibutilide</intervention_name>
    <description>Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval</description>
    <arm_group_label>Postmenopausal women: Placebo</arm_group_label>
    <arm_group_label>Postmenopausal women: Progesterone</arm_group_label>
    <arm_group_label>Premenopausal women: Placebo</arm_group_label>
    <arm_group_label>Premenopausal women: Progesterone</arm_group_label>
    <other_name>Corvert</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Postmenopausal women:&#xD;
&#xD;
          -  50 years of age or older&#xD;
&#xD;
          -  No menstrual periods for 365 days or longer&#xD;
&#xD;
        Premenopausal women:&#xD;
&#xD;
        - 21-40 years of age&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of breast, uterine or ovarian cancer&#xD;
&#xD;
          -  History of hysterectomy and/or ovariectomy&#xD;
&#xD;
          -  Weight &gt; 135 kg&#xD;
&#xD;
          -  Serum K+ &lt; 3.6 mEq/L;&#xD;
&#xD;
          -  Serum Mg2+ &lt; 1.8 mg/dL;&#xD;
&#xD;
          -  Hematocrit &lt; 26%;&#xD;
&#xD;
          -  Hepatic transaminases &gt; 3x upper limit of normal;&#xD;
&#xD;
          -  Baseline Bazett's-corrected QT interval &gt; 450 ms&#xD;
&#xD;
          -  Taking hormone replacement therapy&#xD;
&#xD;
          -  Diagnosis of heart failure&#xD;
&#xD;
          -  Symptoms associated with heart failure:&#xD;
&#xD;
               -  Pitting edema &gt; 2+&#xD;
&#xD;
               -  Crackles or rales on lung auscultation&#xD;
&#xD;
               -  S3 or S4 heart sounds&#xD;
&#xD;
               -  Unable to climb at least 2 flights of stairs without becoming short of breath&#xD;
&#xD;
          -  Current ECG rhythm of atrial fibrillation or other tachyarrhythmia&#xD;
&#xD;
          -  Family or personal history of long-QT syndrome or sudden cardiac death not associated&#xD;
             with acute myocardial infarction&#xD;
&#xD;
          -  Concomitant use of any QTc interval-prolonging drug.&#xD;
&#xD;
          -  Permanently paced ventricular rhythm&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Using any hormonal contraceptives [oral contraceptives, hormone-secreting intrauterine&#xD;
             devices (IUDs), hormonal implants]&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Postmenopausal - 50 years of age or older and no menstrual period for 365 days or longer&#xD;
Premenopausal - 21-40 years of age</gender_description>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>James E Tisdale, PharmD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Purdue University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>James E Tisdale, PharmD</last_name>
    <phone>317-880-5418</phone>
    <email>jtisdale@purdue.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Heather Jaynes, MSN</last_name>
    <phone>317-880-5410</phone>
    <email>hwroblew@iu.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>James E Tisdale, PharmD</last_name>
      <phone>317-880-5418</phone>
      <email>jtisdale@purdue.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>February 6, 2019</study_first_submitted>
  <study_first_submitted_qc>February 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 8, 2019</study_first_posted>
  <last_update_submitted>June 30, 2023</last_update_submitted>
  <last_update_submitted_qc>June 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Indiana University</investigator_affiliation>
    <investigator_full_name>James E. Tisdale</investigator_full_name>
    <investigator_title>Professor, College of Pharmacy, Purdue University</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Long QT Syndrome</mesh_term>
    <mesh_term>Abnormalities, Drug-Induced</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ibutilide</mesh_term>
    <mesh_term>Progesterone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03834883
org study id: 1806935117
nct id: NCT03834883
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This research will determine if oral progesterone attenuates drug-induced QT interval
      lengthening in a) Postmenopausal women 50 years of age or older, and b) Premenopausal women
      studied during the ovulation phase of the menstrual cycle. This investigation will consist of
      two concurrent prospective, randomized, double-blind, placebo-controlled crossover-design
      studies in a) Postmenopausal women, and b) Premenopausal women. Each subject will take
      progesterone or placebo capsules for 1 week. After a two-week "washout" (no progesterone or
      placebo) each subject will then take the alternative therapy (progesterone or placebo) for 1
      week. After 7 days of each treatment, subjects will present to the clinical research center
      to receive a small dose of the QT interval-lengthening drug ibutilide, and the effect on the
      QT, J-Tpeak and Tpeak-Tend intervals during the progesterone and placebo phases will be
      compared
Torsades de pointes (TdP) is a catastrophic arrhythmia associated with corrected QT (QTc)
      interval prolongation, which can be induced by > 150 commonly prescribed drugs. TdP risk is
      higher in women and is modulated by the ratio of serum progesterone and estradiol; the higher
      the serum progesterone and progesterone:estradiol ratio, the lower the risk, and vice-versa.
      TdP risk increases with age, likely due to declining postmenopausal progesterone
      concentrations. Methods to reduce TdP risk in postmenopausal women requiring therapy with QTc
      interval-prolonging drugs have not been developed. In addition, the differential effects of
      progesterone on drug-induced lengthening of early vs late ventricular repolarization in
      humans are unknown. The investigators have previously shown that oral progesterone attenuates
      QTc interval lengthening in young women during the menses phase when serum estradiol
      concentrations are low. However, whether oral progesterone remains effective for attenuating
      drug-induced QTc interval lengthening during menstrual cycle phases with higher serum
      estradiol concentrations is unknown. The efficacy of oral progesterone for attenuating
      drug-induced QTc interval lengthening in postmenopausal women is also unknown. Specific Aim1:
      Determine the efficacy of oral progesterone as a preventive method to diminish drug-induced
      QTc interval lengthening in postmenopausal women. Specific Aim 2: Determine the influence of
      oral progesterone on drug-induced lengthening of early versus late ventricular repolarization
      in postmenopausal women. Specific Aim 3: Determine the efficacy of oral progesterone to
      diminish drug-induced QTc interval lengthening in premenopausal women during the ovulation
      phase of the menstrual cycle, when serum estradiol concentrations are high. Specific Aim 4:
      Specific Aim 4: Determine the influence of oral progesterone on drug-induced lengthening of
      early versus late ventricular repolarization in premenopausal women during the ovulation
      phase of the menstrual cycle, when serum estradiol concentrations are high.

      Concurrent prospective, randomized, double-blind, placebo-controlled two-way crossover-design
      studies will be conducted in a) Postmenopausal women > 50 years of age (n=20) and b)
      Premenopausal women 21-40 years of age (n=20) who will be studied during the ovulation phase
      of the menstural cycle. QTc interval response to low-dose ibutilide will be assessed.
      Subjects will receive, in randomized order (with a minimum two-week washout phase) oral
      progesterone 400 mg or placebo once daily for 7 days. On the morning after the 7th dose,
      subjects will present to the Indiana Clinical Research Center to receive one dose of the QT
      interval-lengthening drug ibutilide 0.003 mg/kg, after which ECGs and blood for determination
      of serum ibutilide concentrations will be obtained serially for 8 hours. Primary outcome
      measures: 1) Baseline (pre-ibutilide) Fridericia (QTFrid) and Framingham (QTFram)-corrected
      QT intervals, 2) Maximum QTFrid and QTFram intervals following ibutilide, 3) Maximum % change
      in QTFrid and QTFram intervals following ibutilide, 4) Area under the QTFrid and QTFram
      interval-time curves from 0-1 and 0-8 hours. Secondary outcome measures: 1) J-Tpeak interval,
      2) Tpeak-Tend interval, and 5) Incidence of progesterone and ibutilide adverse effects. These
      studies will establish oral progesterone as a safe and effective method of attenuating
      drug-induced QTc interval lengthening in postmenopausal women.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Baseline (pre-ibutilide) QT-F and QT-Fram intervals
time frame: After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide
description: QT intervals will be corrected for heart rate using two methods: the Fridericia method and the Framingham method
measure: Maximum post-ibutilide QT-F and QT-Fram intervals
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: Maximum post-ibutilide QT-F and QT-Fram intervals
measure: % change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: % change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals
measure: Area under the QT-F and QT-Fram versus time curves during and for 1 hour following ibutilide infusion
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion
description: Area under the QT-F and QT-Fram versus time curves during and for 1 hour
measure: Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion
measure: Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals
time frame: After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide
description: Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals
measure: Maximum post-ibutilide J-Tpeakc intervals
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: Maximum post-ibutilide J-Tpeakc intervals
measure: % change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: % change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals
measure: Area under the J-Tpeakc versus time curve during and for 1 hour following ibutilide infusion
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion
description: Area under the J-Tpeakc versus time curve during and for 1 hour following
measure: Area under the J-Tpeakc versus time curve during and for 8 hours following ibutilide infusion
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: Area under the J-Tpeakc versus time curve during and for 8 hours following
measure: Baseline (pre-ibutilide) Tpeak-Tend intervals
time frame: After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide
description: Baseline (pre-ibutilide) Tpeak-Tend intervals
measure: Maximum post-ibutilide Tpeak-Tend intervals
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: Maximum post-ibutilide Tpeak-Tend intervals
measure: % change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: % change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals
measure: Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion
description: Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion
measure: Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion
time frame: Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion
measure: Adverse effects
time frame: During the 7 days of treatment with progesterone/placebo and at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion
description: Adverse effects fo progesterone, placebo and ibutilide will be assessed
arm group label: Postmenopausal women: Progesterone
arm group type: Experimental
description: Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days
arm group label: Postmenopausal women: Placebo
arm group type: Placebo Comparator
description: Subjects will receive oral placebo, two capsules once daily every evening for 7 days
arm group label: Premenopausal women: Progesterone
arm group type: Experimental
description: Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days
arm group label: Premenopausal women: Placebo
arm group type: Placebo Comparator
description: Subjects will receive oral placebo, two capsules once daily every evening for 7 days
intervention type: Drug
intervention name: Progesterone
description: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
arm group label: Postmenopausal women: Progesterone
arm group label: Premenopausal women: Progesterone
intervention type: Drug
intervention name: Ibutilide
description: Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval
arm group label: Postmenopausal women: Placebo
arm group label: Postmenopausal women: Progesterone
arm group label: Premenopausal women: Placebo
arm group label: Premenopausal women: Progesterone
other name: Corvert
criteria: 
gender: Female
gender based: Yes
gender description: Postmenopausal - 50 years of age or older and no menstrual period for 365 days or longer
Premenopausal - 21-40 years of age
minimum age: 21 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: James E Tisdale, PharmD
role: Principal Investigator
affiliation: Purdue University
last name: James E Tisdale, PharmD
phone: 317-880-5418
email: jtisdale@purdue.edu
last name: Heather Jaynes, MSN
phone: 317-880-5410
email: hwroblew@iu.edu
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Indiana University
investigator full name: James E. Tisdale
investigator title: Professor, College of Pharmacy, Purdue University
mesh term: Long QT Syndrome
mesh term: Abnormalities, Drug-Induced
mesh term: Ibutilide
mesh term: Progesterone
sharing ipd: No