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Reducing the Risk of Drug-Induced QT Interval Lengthening in Women

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ClinicalTrials.gov Identifier: NCT03834883
Recruitment Status : Recruiting
First Posted : February 8, 2019
Last Update Posted : May 7, 2019
Sponsor:
Collaborators:
American Heart Association
Purdue University
Information provided by (Responsible Party):
James E. Tisdale, Indiana University

Tracking Information
First Submitted Date  ICMJE February 6, 2019
First Posted Date  ICMJE February 8, 2019
Last Update Posted Date May 7, 2019
Actual Study Start Date  ICMJE March 26, 2019
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 7, 2019)
  • 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 ]
    QT intervals will be corrected for heart rate using two methods: the Fridericia method and the Framingham method
  • 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 ]
    Maximum post-ibutilide QT-F and QT-Fram intervals
  • % 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 ]
    % change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals
  • 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 ]
    Area under the QT-F and QT-Fram versus time curves during and for 1 hour
  • 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 ]
    Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion
Original Primary Outcome Measures  ICMJE
 (submitted: February 7, 2019)
  • 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 ]
    QT intervals will be corrected for heart rate using two methods: the Fridericia method and the Framingham method
  • 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 ]
  • % 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 ]
  • 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 ]
  • 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 ]
Change History Complete list of historical versions of study NCT03834883 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2019)
  • 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 ]
    Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals
  • 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 ]
    Maximum post-ibutilide J-Tpeakc intervals
  • % 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 ]
    % change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals
  • 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 ]
    Area under the J-Tpeakc versus time curve during and for 1 hour following
  • 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 ]
    Area under the J-Tpeakc versus time curve during and for 8 hours following
  • Baseline (pre-ibutilide) Tpeak-Tend intervals [ Time Frame: After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide ]
    Baseline (pre-ibutilide) Tpeak-Tend intervals
  • 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 ]
    Maximum post-ibutilide Tpeak-Tend intervals
  • % 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 ]
    % change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals
  • 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 ]
    Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion
  • 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 ]
    Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion
Original Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2019)
  • 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 ]
  • 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 ]
  • % 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 ]
  • 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 ]
  • 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 ]
  • Baseline (pre-ibutilide) Tpeak-Tend intervals [ Time Frame: After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide ]
  • 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 ]
  • % 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 ]
  • 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 ]
  • 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 ]
Current Other Pre-specified Outcome Measures
 (submitted: February 7, 2019)
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 ]
Adverse effects fo progesterone, placebo and ibutilide will be assessed
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
Official Title  ICMJE Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening: Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
Brief Summary 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
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Long QT Syndrome
  • Abnormalities, Drug-Induced
Intervention  ICMJE
  • Drug: Progesterone
    Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
  • Drug: Ibutilide
    Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval
    Other Name: Corvert
Study Arms  ICMJE
  • Experimental: Postmenopausal women: Progesterone
    Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days
    Interventions:
    • Drug: Progesterone
    • Drug: Ibutilide
  • Placebo Comparator: Postmenopausal women: Placebo
    Subjects will receive oral placebo, two capsules once daily every evening for 7 days
    Intervention: Drug: Ibutilide
  • Experimental: Premenopausal women: Progesterone
    Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days
    Interventions:
    • Drug: Progesterone
    • Drug: Ibutilide
  • Placebo Comparator: Premenopausal women: Placebo
    Subjects will receive oral placebo, two capsules once daily every evening for 7 days
    Intervention: Drug: Ibutilide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 7, 2019)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2022
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Postmenopausal women:

  • 50 years of age or older
  • No menstrual periods for 365 days or longer

Premenopausal women:

- 21-40 years of age

Exclusion Criteria:

  • History of breast, uterine or ovarian cancer
  • History of hysterectomy and/or ovariectomy
  • Weight > 135 kg
  • Serum K+ < 3.6 mEq/L;
  • Serum Mg2+ < 1.8 mg/dL;
  • Hematocrit < 26%;
  • Hepatic transaminases > 3x upper limit of normal;
  • Baseline Bazett's-corrected QT interval > 450 ms
  • Taking hormone replacement therapy
  • Diagnosis of heart failure
  • Symptoms associated with heart failure:

    • Pitting edema > 2+
    • Crackles or rales on lung auscultation
    • S3 or S4 heart sounds
    • Unable to climb at least 2 flights of stairs without becoming short of breath
  • Current ECG rhythm of atrial fibrillation or other tachyarrhythmia
  • Family or personal history of long-QT syndrome or sudden cardiac death not associated with acute myocardial infarction
  • Concomitant use of any QTc interval-prolonging drug.
  • Permanently paced ventricular rhythm
  • Pregnancy
  • Using any hormonal contraceptives [oral contraceptives, hormone-secreting intrauterine devices (IUDs), hormonal implants]
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description:

Postmenopausal - 50 years of age or older and no menstrual period for 365 days or longer

Premenopausal - 21-40 years of age

Ages  ICMJE 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: James E Tisdale, PharmD 317-880-5418 jtisdale@purdue.edu
Contact: Heather Jaynes, MSN 317-880-5410 hwroblew@iu.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03834883
Other Study ID Numbers  ICMJE 1806935117
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party James E. Tisdale, Indiana University
Study Sponsor  ICMJE Indiana University
Collaborators  ICMJE
  • American Heart Association
  • Purdue University
Investigators  ICMJE
Principal Investigator: James E Tisdale, PharmD Purdue University
PRS Account Indiana University
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP