Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening

• Status: Recruiting
• Trial end date: 2025-08-31
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Indiana University
• Collaborators: Cedars-Sinai Medical Center; Harvard University; National Heart, Lung, and Blood Institute (NHLBI); Purdue University
• Treatments: Ibutilide; Progesterone; Testosterone

Criteria

Inclusion Criteria:

Postmenopausal Women:

• Age ≥ 50 years old

• Postmenopausal (have not has a menstrual period for 12 months or longer)

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

Inclusion Criteria:

Older Men:

• Age ≥ 65 years old

Exclusion Criteria:

• 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