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Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening

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ClinicalTrials.gov Identifier: NCT04675788
Recruitment Status : Recruiting
First Posted : December 19, 2020
Last Update Posted : August 5, 2022
Sponsor:
Collaborators:
Purdue University
National Heart, Lung, and Blood Institute (NHLBI)
Harvard University
Cedars-Sinai Medical Center
Information provided by (Responsible Party):
James E. Tisdale, Indiana University

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.

Condition or disease Intervention/treatment Phase
Long QT Syndrome Abnormalities, Drug-Induced Drug: Progesterone Drug: Ibutilide Drug: Testosterone Drug: Placebo Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 83 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
Actual Study Start Date : September 2, 2021
Estimated Primary Completion Date : October 31, 2024
Estimated Study Completion Date : April 30, 2025


Arm Intervention/treatment
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 Name: 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 Name: 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 Name: Corvert

Drug: Testosterone
Subjects will apply transdermal testosterone gel once daily every morning for 3 days
Other Name: 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 Name: Corvert

Drug: Placebo
Lactose capsules




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Pre-ibutilide Tpeak-Tend intervals [ Time Frame: Morning of day 8 (after 7 days of progesterone/placebo) ]
    Pre-ibutilide Tpeak-Tend intervals

  14. Pre-ibutilide Tpeak-Tend intervals [ Time Frame: Morning of day 4 (after 3 days of testosterone/placebo) ]
    Pre-ibutilide Tpeak-Tend intervals

  15. 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

  16. 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

  17. 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

  18. 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


Other Outcome Measures:
  1. 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

  2. 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

  3. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Postmenopausal Women:

  • Age 50-85 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 90 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04675788


Contacts
Layout table for location contacts
Contact: James E Tisdale, PharmD 317-880-5418 jtisdale@purdue.edu
Contact: Heather A Jaynes, MSN 317-847-2094 hwroblew@iu.edu

Locations
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United States, Indiana
Indiana Clinical Research Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Scott Denne, MD    317-274-4920    sdenne@iupui.edu   
Contact: Sharon Cromer    317-278-3446    scromer2@iupui.edu   
Principal Investigator: James E Tisdale, BSC, PharmD         
Sub-Investigator: Heather Jaynes, MSN         
Sub-Investigator: Richard J Kovacs, MD         
Sub-Investigator: Kevin M Sowinski, PharmD         
Sub-Investigator: David Flockhart, MD, PhD         
Indiana University Recruiting
Indianapolis, Indiana, United States, 46202
Contact: James E Tisdale, PharmD    317-880-5418    jtisdale@purdue.edu   
Purdue University Not yet recruiting
Indianapolis, Indiana, United States, 46202
Contact: James E Tisdale, BSc, PharmD    317-880-5418    jtisdale@purdue.edu   
Contact: Heather Jaynes, MSN    317-847-2094    hwroblew@iu.edu   
Principal Investigator: James E Tisdale, BSc, PharmD         
Sub-Investigator: Brian R Overholser, PharmD         
Sub-Investigator: Heather A Jaynes, MSN         
Sub-Investigator: Richard J Kovacs, MD         
Sub-Investigator: Kevin M Sowinski, PharmD         
Sponsors and Collaborators
Indiana University
Purdue University
National Heart, Lung, and Blood Institute (NHLBI)
Harvard University
Cedars-Sinai Medical Center
Investigators
Layout table for investigator information
Principal Investigator: James E Tisdale, PharmD Purdue University
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Responsible Party: James E. Tisdale, Professor of PharmD, Indiana University
ClinicalTrials.gov Identifier: NCT04675788    
Other Study ID Numbers: 2005890134
1R01HL153114-01 ( U.S. NIH Grant/Contract )
First Posted: December 19, 2020    Key Record Dates
Last Update Posted: August 5, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
Layout table for MeSH terms
Long QT Syndrome
Abnormalities, Drug-Induced
Congenital Abnormalities
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Cardiac Conduction System Disease
Heart Defects, Congenital
Cardiovascular Abnormalities
Pathologic Processes
Ibutilide
Testosterone
Progesterone
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Progestins
Anti-Arrhythmia Agents