# Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening

> **NIH NIH R01** · PURDUE UNIVERSITY · 2021 · $489,481

## Abstract

PROJECT SUMMARY/ABSTRACT
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 influence of oral progesterone on drug-induced lengthening of early and late ventricular
repolarization in postmenopausal women. Specific Aim 3: 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 4: 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&2 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 3&4 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 interv...

## Key facts

- **NIH application ID:** 10220133
- **Project number:** 5R01HL153114-02
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** James E. Tisdale
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $489,481
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220133

## Citation

> US National Institutes of Health, RePORTER application 10220133, Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening (5R01HL153114-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220133. Licensed CC0.

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