Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening

NCT04675788 | Completed Phase 4 DMC FDA Drug

• 2 other identifiers: 20058901341R01HL153114-01
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 3

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.

Conditions

Long QT Syndrome; Abnormalities, Drug-Induced

Outcome Measures

Primary Outcomes (18)

• Pre-ibutilide QT-F and QT-Fram intervals

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  Pre-ibutilide Tpeak-Tend intervals

  Morning of day 8 (after 7 days of progesterone/placebo)

• Pre-ibutilide Tpeak-Tend intervals

  Pre-ibutilide Tpeak-Tend intervals

  Morning of day 4 (after 3 days of testosterone/placebo)

• Maximum post-ibutilide Tpeak-Tend intervals

  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

  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

  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

  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 Outcomes (3)

• Adverse effects of oral progesterone and 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

  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

  Adverse effects of ibutilide will be assessed during the 10-minute intravenous infusion and for 8 hours following the infusion of ibutilide

Study Arms (4)

Postmenopausal women: Progesterone

EXPERIMENTAL

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

Drug: Progesterone; Drug: Ibutilide

Postmenopausal women: Placebo

PLACEBO COMPARATOR

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

Drug: Ibutilide; Drug: Placebo

Men 65 years of age or older: Testosterone

EXPERIMENTAL

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

Drug: Ibutilide; Drug: Testosterone

Men 65 years of age or older: Placebo

PLACEBO COMPARATOR

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

Drug: Ibutilide; Drug: Placebo

Interventions

Progesterone DRUG

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

Postmenopausal women: Progesterone

Ibutilide DRUG

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

Also known as: Corvert

Men 65 years of age or older: Placebo; Men 65 years of age or older: Testosterone; Postmenopausal women: Placebo; Postmenopausal women: Progesterone

Testosterone DRUG

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

Also known as: Androgel

Men 65 years of age or older: Testosterone

Placebo DRUG

Lactose capsules

Men 65 years of age or older: Placebo; Postmenopausal women: Placebo

Eligibility Criteria

• Age: 50 Years - 99 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Indiana University: lead
• Purdue University: collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Harvard University: collaborator
• Cedars-Sinai Medical Center: collaborator

Study Sites (3)

Indiana Clinical Research Center

Indianapolis, Indiana, 46202, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Purdue University

Indianapolis, Indiana, 46202, United States

Location

MeSH Terms

Conditions

Long QT Syndrome; Abnormalities, Drug-Induced

Interventions

Progesterone; ibutilide; Testosterone

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Androstenols; Androstenes; Androstanes; Testosterone Congeners

Study Officials

• James E Tisdale, PharmD

  Purdue University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of PharmD

Study Record Dates

• First Submitted: December 4, 2020
• First Posted: December 19, 2020
• Study Start: September 2, 2021
• Primary Completion: April 16, 2025
• Study Completion: April 16, 2025
• Last Updated: March 19, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)