Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening

March 6, 2026 updated by: James E. Tisdale, Indiana University
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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
73

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.
  • Name: Heather A Jaynes, MSN
  • Phone Number: 317-847-2094
  • Email: hwroblew@iu.edu

Study Contact Backup

Study Locations

  • United States
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana University
      • Indianapolis, Indiana, United States, 46202
        • Indiana Clinical Research Center
      • Indianapolis, Indiana, United States, 46202
        • Purdue University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

50 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

Postmenopausal Women:

  • Age 50-99 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 to 99 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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 modestly 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 modestly lengthen the QT interval
Other Names:
  • Corvert
Drug: Placebo
Lactose capsules
Experimental: Men 65 years of age or older: Testosterone
Subjects will receive treatment with transdermal testosterone 1% (100 mg) every morning for 3 days
Drug: Ibutilide
Ibutilide 0.003 mg/kg administered to all subjects to modestly lengthen the QT interval
Other Names:
  • Corvert
Drug: Testosterone
Subjects will apply transdermal testosterone gel once daily every morning for 3 days
Other Names:
  • Androgel
Placebo Comparator: Men 65 years of age or older: Placebo
Subjects will receive treatment with transdermal placebo every morning for 3 days
Drug: Ibutilide
Ibutilide 0.003 mg/kg administered to all subjects to modestly lengthen the QT interval
Other Names:
  • Corvert
Drug: Placebo
Lactose capsules

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Pre-ibutilide QT-F and QT-Fram intervals
Time Frame: Morning of day 8 (after 7 days of progesterone/placebo)
QT intervals will be corrected for heart rate using two methods: the Fridericia method and the Framingham method
Morning of day 8 (after 7 days of progesterone/placebo)
Pre-ibutilide QT-F and QT-Fram intervals
Time Frame: Morning of day 4 (after 3 days of testosterone/placebo)
QT intervals will be corrected for heart rate using two methods: the Fridericia method and the Framingham method
Morning of day 4 (after 3 days of testosterone/placebo)
Maximum post-ibutilide QT-F and QT-Fram intervals
Time Frame: From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Maximum post-ibutilide QT-F and QT-Fram intervals
From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Percent change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals
Time Frame: From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Percent change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals
From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Area under the QT-F and QT-Fram versus time curves during and for 1 hour following ibutilide infusion
Time Frame: From initiation of ibutilide infusion and for 1 hour after the end of ibutilide infusion
Area under the QT-F and QT-Fram versus time curves during and for 1 hour
From initiation of ibutilide infusion and for 1 hour after the end of ibutilide infusion
Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion
Time Frame: From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion
From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Pre-ibutilide heart rate-corrected J-Tpeak (J-Tpeakc) intervals
Time Frame: Morning of day 8 (after 7 days of progesterone/placebo)
Pre-ibutilide heart rate-corrected J-Tpeak (J-Tpeakc) intervals
Morning of day 8 (after 7 days of progesterone/placebo)
Pre-ibutilide heart rate-corrected J-Tpeak (J-Tpeakc) intervals
Time Frame: Morning of day 4 (after 3 days of testosterone/placebo)
Pre-ibutilide heart rate-corrected J-Tpeak (J-Tpeakc) intervals
Morning of day 4 (after 3 days of testosterone/placebo)
Maximum post-ibutilide J-Tpeakc intervals
Time Frame: From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Maximum post-ibutilide J-Tpeakc intervals
From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Percent change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals
Time Frame: From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Percent change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals
From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Area under the J-Tpeakc versus time curve during and for 1 hour following ibutilide infusion
Time Frame: From initiation of ibutilide infusion and for 1 hour after the end of ibutilide infusion
Area under the J-Tpeakc versus time curve during and for 1 hour following ibutilide infusion
From initiation of ibutilide infusion and for 1 hour after the end of ibutilide infusion
Area under the J-Tpeakc versus time curve during and for 8 hours following ibutilide infusion
Time Frame: From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Area under the J-Tpeakc versus time curve during and for 8 hours following ibutilide infusion
From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Pre-ibutilide Tpeak-Tend intervals
Time Frame: Morning of day 8 (after 7 days of progesterone/placebo)
Pre-ibutilide Tpeak-Tend intervals
Morning of day 8 (after 7 days of progesterone/placebo)
Pre-ibutilide Tpeak-Tend intervals
Time Frame: Morning of day 4 (after 3 days of testosterone/placebo)
Pre-ibutilide Tpeak-Tend intervals
Morning of day 4 (after 3 days of testosterone/placebo)
Maximum post-ibutilide Tpeak-Tend intervals
Time Frame: From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Maximum post-ibutilide Tpeak-Tend intervals
From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Percent change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals
Time Frame: From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Percent change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals
From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion
Time Frame: From initiation of ibutilide infusion and for 1 hour after the end of ibutilide infusion
Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion
From initiation of ibutilide infusion and for 1 hour after the end of ibutilide infusion
Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion
Time Frame: From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion
Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion
From initiation of ibutilide infusion and for 8 hours after the end of ibutilide infusion

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Adverse effects of oral progesterone and placebo
Time Frame: Adverse effects will be assessed via telephone calls to subjects between days 2 and 4 and between days 5 and 7 of oral progesterone and oral placebo
Adverse effects of oral progesterone and oral placebo
Adverse effects will be assessed via telephone calls to subjects between days 2 and 4 and between days 5 and 7 of oral progesterone and oral placebo
Adverse effects of transdermal testosterone and transdermal placebo
Time Frame: Adverse effects will be assessed via telephone calls to subjects between days 1 and 3 of transdermal testosterone and transdermal placebo
Adverse effects of transdermal testosterone and transdermal placebo
Adverse effects will be assessed via telephone calls to subjects between days 1 and 3 of transdermal testosterone and transdermal placebo
Adverse effects of ibutilide
Time Frame: Adverse effects of ibutilide will be assessed during the 10-minute intravenous infusion and for 8 hours following the infusion of ibutilide
Adverse effects of ibutilide
Adverse effects of ibutilide will be assessed during the 10-minute intravenous infusion and for 8 hours following the infusion of ibutilide

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Indiana University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Heart, Lung, and Blood Institute (NHLBI)
Cedars-Sinai Medical Center
Harvard University
Purdue University

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: James E Tisdale, PharmD, Purdue University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 2, 2021

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 16, 2025

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 16, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 4, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 14, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 19, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 19, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 6, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2005890134
  • 1R01HL153114-01 (U.S. NIH Grant/Contract)

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

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