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

Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening: Reducing the Risk of Drug-Induced QT Interval Lengthening in Women

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

Study Overview

• Status: Completed
• Conditions: Long QT Syndrome; Abnormalities, Drug-Induced
• Intervention / Treatment: Drug: Progesterone; Drug: Ibutilide

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: Interventional
• Enrollment (Actual): 27
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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]

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	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 Names: Corvert
Placebo Comparator: Postmenopausal women: Placebo; Subjects will receive oral placebo, two 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 Names: Corvert
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	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 Names: Corvert
Placebo Comparator: Premenopausal women: Placebo; Subjects will receive oral placebo, two 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 Names: Corvert

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline (Pre-ibutilide) QT-F Intervals	QT intervals will be corrected for heart rate using the Fridericia method	After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide
Maximum Post-ibutilide QT-F Intervals	Maximum post-ibutilide QT-F intervals	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 Intervals	% change from baseline (pre-ibutilide) in maximum QT-F intervals	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 Versus Time Curves During and for 1 Hour Following Ibutilide Infusion	Area under the QT-F versus time curves during and for 1 hour	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline (Pre-ibutilide) Heart Rate-corrected J-Tpeak (J-Tpeakc) Intervals	Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals	After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide
Maximum Post-ibutilide J-Tpeakc Intervals	Maximum post-ibutilide J-Tpeakc intervals	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	% change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals	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	Area under the J-Tpeakc versus time curve during and for 1 hour following	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
Baseline (Pre-ibutilide) Tpeak-Tend Intervals	Baseline (pre-ibutilide) Tpeak-Tend intervals	After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide
Maximum Post-ibutilide Tpeak-Tend Intervals	Maximum post-ibutilide Tpeak-Tend intervals	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	% change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals	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	Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse effects	Adverse effects fo progesterone, placebo and ibutilide will be assessed	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

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: American Heart Association; Purdue University
• Investigators: Principal Investigator: James E Tisdale, PharmD, Purdue University

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2019
• Primary Completion (Actual): May 21, 2024
• Study Completion (Actual): May 23, 2024

Study Registration Dates

• First Submitted: February 6, 2019
• First Submitted That Met QC Criteria: February 7, 2019
• First Posted (Actual): February 8, 2019

Study Record Updates

• Last Update Posted (Estimated): July 1, 2025
• Last Update Submitted That Met QC Criteria: June 12, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiac Conduction System Disease; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Long QT Syndrome; Abnormalities, Drug-Induced; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Arrhythmia Agents; Progestins; Progesterone; Ibutilide
• Other Study ID Numbers: 1806935117

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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