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

NCT ID: NCT03834883

Last Updated: 2025-07-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-26
• Study Completion Date: 2024-05-23

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.

Conditions

Long QT Syndrome; Abnormalities, Drug-Induced

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Postmenopausal women: Progesterone

Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days

Group Type: EXPERIMENTAL

Progesterone

Intervention Type: DRUG

Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days

Ibutilide

Intervention Type: DRUG

Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Postmenopausal women: Placebo

Subjects will receive oral placebo, two capsules once daily every evening for 7 days

Group Type: PLACEBO_COMPARATOR

Ibutilide

Intervention Type: DRUG

Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Premenopausal women: Progesterone

Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days

Group Type: EXPERIMENTAL

Progesterone

Intervention Type: DRUG

Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days

Ibutilide

Intervention Type: DRUG

Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Premenopausal women: Placebo

Subjects will receive oral placebo, two capsules once daily every evening for 7 days

Group Type: PLACEBO_COMPARATOR

Ibutilide

Intervention Type: DRUG

Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Interventions

Progesterone

Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days

Intervention Type: DRUG

Ibutilide

Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Intervention Type: DRUG

Other Intervention Names

Corvert

Eligibility Criteria

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]

• Minimum Eligible Age: 21 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

American Heart Association

OTHER

Sponsor Role: collaborator

Purdue University

OTHER

Sponsor Role: collaborator

Indiana University

OTHER

Sponsor Role: lead

Responsible Party

James E. Tisdale

Professor, College of Pharmacy, Purdue University

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

James E Tisdale, PharmD

Role: PRINCIPAL_INVESTIGATOR

Purdue University

Locations

Indiana University

Indianapolis, Indiana, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1806935117

Identifier Type: -

Identifier Source: org_study_id