Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening

NCT ID: NCT04675788

Last Updated: 2025-04-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 73 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-09-02
• Study Completion Date: 2025-04-16

Brief Summary

This research will determine if: 1) Oral progesterone attenuates drug-induced QT interval, J-Tpeak and Tpeak-Tend lengthening in postmenopausal women 50 years of age or older, and 2) Transdermal testosterone attenuates drug-induced QT interval, J-Tpeak and Tpeak-Tend lengthening in men 65 years of age or older. This investigation will consist of two concurrent prospective, randomized, double-blind, placebo-controlled crossover-design studies in a) Postmenopausal women, and b) Men 65 years of age or older. Study 1: Each postmenopausal woman will take progesterone or placebo capsules for 1 week. After a 14-day "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 2: Each man 65 years of age or older will apply transdermal testosterone or transdermal placebo gel for 3 days. After a 7-day "washout" (no testosterone or placebo) each subject will then apply the alternative therapy (testosterone or placebo gel) for 1 week. After 3 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 testosterone and placebo phases will be compared.

Detailed Description

Torsades de pointes (TdP) is a ventricular tachycardia associated with prolongation of the corrected QT (QTc) interval, and which may be caused by > 150 widely used drugs. TdP results in catastrophic outcomes, including sudden cardiac death. Older age is a risk factor for drug-induced TdP, possibly due to declining serum progesterone and testosterone concentrations in postmenopausal women and men, respectively. The ECG biomarkers J-Tpeak and Tpeak-Tend, represent early and late repolarization, respectively, as well as dispersion of repolarization (Tpeak-Tend). Preclinical evidence and preliminary data from our group indicate that progesterone and testosterone exert protective effects against drug-induced prolongation of ventricular repolarization. Effective means of reducing the risk of drug-induced QTc interval prolongation and TdP in high risk populations requiring therapy with QTc-prolonging drugs have not been identified, and the effects of sex hormones on early vs late ventricular repolarization and dispersion of repolarization are unknown. The objectives of this research are to evaluate novel therapeutic approaches to attenuate drug-induced QTc lengthening. Our central hypothesis is that drug-induced QTc lengthening is attenuated by administration of oral progesterone and transdermal testosterone. Specific Aim 1: Determine the efficacy of oral progesterone as a preventive method to attenuate drug-induced QTc interval lengthening in postmenopausal women. Specific Aim 2: Determine the efficacy of transdermal testosterone as a preventive method to attenuate drug-induced QTc interval lengthening in men ≥ 65 years of age. Specific Aim 3a: Determine the influence of oral progesterone on drug-induced lengthening of early and late ventricular repolarization in postmenopausal women. Specific Aim 3b: Determine the influence of transdermal testosterone on drug-induced lengthening of early and late ventricular repolarization in men ≥ 65 years of age. Specific Aims 1&3a will be achieved via a prospective, randomized, double-blind, placebo-controlled two-way crossover study in postmenopausal women age ≥ 50 years (n=48). Each subject will take oral progesterone 400 mg or matching placebo daily for 7 days (≥ 14-day washout period between phases). On day 7, each subject will receive a single dose of the QTc-lengthening drug ibutilide 0.003 mg/kg. Specific Aims 2&3b will be achieved via a prospective, randomized, double-blind, placebo-controlled two-way crossover study in men ≥ 65 years of age (n=35). Each subject will apply transdermal testosterone 1% 100 mg or transdermal placebo once daily for 3 days (≥ 7-day washout period between phases). On day 7, each subject will ibutilide 0.003 mg/kg. In both studies, post-ibutilide QT, J-Tpeak and Tpeak-Tend intervals and serum ibutilide concentrations will be determined serially. Primary outcome measures: 1) Maximum post-ibutilide QTc intervals, 2) Maximum post-ibutilide % change in QTc intervals, 3) Area under the QTc interval-time curves, and 4) J-Tpeak and Tpeak-Tend intervals. This research will identify effective approaches for reducing the risk of drug-induced QTc interval prolongation in high-risk patients.

Conditions

Long QT Syndrome; Abnormalities, Drug-Induced

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• 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 modestly 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 modestly lengthen the QT interval

Placebo

Intervention Type: DRUG

Lactose capsules

Men 65 years of age or older: Testosterone

Subjects will receive treatment with transdermal testosterone 1% (100 mg) every morning for 3 days

Group Type: EXPERIMENTAL

Ibutilide

Intervention Type: DRUG

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

Testosterone

Intervention Type: DRUG

Subjects will apply transdermal testosterone gel once daily every morning for 3 days

Men 65 years of age or older: Placebo

Subjects will receive treatment with transdermal placebo every morning for 3 days

Group Type: PLACEBO_COMPARATOR

Ibutilide

Intervention Type: DRUG

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

Placebo

Intervention Type: DRUG

Lactose capsules

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 modestly lengthen the QT interval

Intervention Type: DRUG

Testosterone

Subjects will apply transdermal testosterone gel once daily every morning for 3 days

Intervention Type: DRUG

Placebo

Lactose capsules

Intervention Type: DRUG

Other Intervention Names

Corvert; Androgel

Eligibility Criteria

Inclusion Criteria

Postmenopausal Women:

• Age 50-99 years old
• Postmenopausal (have not has a menstrual period for 12 months or longer)

Older Men:

• Age 65 years old to 99 years old

Exclusion Criteria

Postmenopausal women:

• Subject reported history of breast, uterine and ovarian cervical cancer
• Subject reported history of hysterectomy and/or ovariectomy
• Subject reported taking any hormone replacement therapy (prescription, nonprescription or herbal supplement)
• Weight < 60 kg at time of screening visit
• Weight >135 kg at time of screening visit
• Serum K+ <3.6 mEq/L at time of any ibutilide dosing visit
• Serum Mg2+ <1.8 mg/dL at time of screening visit
• Hematocrit <26%
• AST or ALT > 3x the upper limit of normal (determined by testing lab ranges) at the time of screening visit
• Baseline Bazett's-corrected QTc >450 ms (during any visit prior to ibutilide dosing)
• Baseline QRS > 120 ms (at time of baseline visit)
• Diagnosis of heart failure due to reduced or preserved ejection fraction
• Subject reported family history of long QT syndrome, TdP, or sudden cardiac death not associated with acute myocardial infarction
• Self-reported personal history of long QT syndrome, sudden cardiac death not associated with acute myocardial infarction
• Subject reported history any prolonged arrhythmia for which treatment was required
• Subject reported history of a myocardial infarction
• Subject reported history of coronary artery disease
• Sustained arrythmia found at baseline screening prior to any study visit including atrial fibrillation, atrial flutter, junctional rhythm, heart block (any)
• Permanently paced ventricular rhythm
• Current reported use of any QT prolonging medication. Investigator will check the current QT drugs list at www.crediblemeds.org during screening.
• Current reported use of any moderate or strong inhibitors of cytochrome P450 (CYP) 3A4, 3A5, or 3A7
• Current reported use of any inducers of cytochrome P-450 (CYP) 3A4, 3A5 or 3A7

• Older men:
• Subject reported diagnosis of benign prostatic hyperplasia
• Subject reported history of breast or prostate cancer
• Weight < 60 kg at time of screening visit
• Weight >135 kg at time of screening visit
• Serum K+ <3.6 mEq/L at time of any ibutilide dosing visit
• Serum Mg2+ <1.8 mg/dL at time of screening visit
• Hematocrit <26%
• AST or ALT > 3x the upper limit of normal (determined by testing lab ranges) at the time of screening visit
• Baseline Bazett's-corrected QTc >450 ms (during any visit prior to ibutilide dosing)
• Baseline QRS > 120 ms (at time of baseline visit)
• Diagnosis of heart failure due to reduced or preserved ejection fraction
• Subject reported family history of long QT syndrome, TdP, or sudden cardiac death not associated with acute myocardial infarction
• Self-reported personal history of long QT syndrome, arrhythmias (including atrial fibrillation) or sudden cardiac death not associated with acute myocardial infarction
• Sustained arrythmia found at baseline screening prior to any study visit including atrial fibrillation, atrial flutter, junctional rhythm, heart block (any)
• Permanently paced ventricular rhythm
• Current reported use of any QT prolonging medication (Investigator will check current list of QT prolonging medications listed at www.crediblemeds.org at the time of screening for the most up to date list.
• Current reported use of any moderate or strong inhibitors of cytochrome P450 (CYP) 3A
• Current reported use of any inducers of cytochrome P-450 (CYP) 3A4, 3A5 or 3A7

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Purdue University

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Harvard University

OTHER

Sponsor Role: collaborator

Cedars-Sinai Medical Center

OTHER

Sponsor Role: collaborator

Indiana University

OTHER

Sponsor Role: lead

Responsible Party

James E. Tisdale

Professor of PharmD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

James E Tisdale, PharmD

Role: PRINCIPAL_INVESTIGATOR

Purdue University

Locations

Indiana Clinical Research Center

Indianapolis, Indiana, United States

Indiana University

Indianapolis, Indiana, United States

Purdue University

Indianapolis, Indiana, United States

Countries

United States

Other Identifiers

1R01HL153114-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2005890134

Identifier Type: -

Identifier Source: org_study_id