- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02513940
Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
August 15, 2019 updated by: James E. Tisdale, Indiana University
Torsades de pointes (TdP) is a potentially fatal ventricular arrhythmia associated with corrected QT (QTc) interval prolongation.
More than 50 commonly used drugs available on the US market may cause QTc interval prolongation and TdP.
While TdP occurs more commonly in women, 33-45% of all cases of TdP have occurred in men.
Older age is a risk factor for drug-induced TdP in men, possibly due to declining serum testosterone concentrations.
Available evidence shows an inverse relationship between QTc intervals and serum testosterone concentrations.
In addition, experimental data, including those from the investigators' laboratory, suggest that both exogenous testosterone or progesterone administration may be protective against prolongation of ventricular repolarization and TdP.
Specific Aim: Establish the influence of transdermal testosterone administration and oral progesterone administration as preventive methods by which to diminish the degree of drug-induced QT interval prolongation in men 65 years of age or older.
Hypothesis: Transdermal testosterone administration and oral progesterone administration both effectively attenuate drug-induced QT interval response in older men.
To test this hypothesis, transdermal testosterone, oral progesterone or placebo will be administered in a 3-way crossover study to men 65 years of age or older.
QTc interval response to low-dose ibutilide will be assessed.
The primary endpoints will be Fridericia-corrected QT interval (QTF) response to ibutilide, in the presence and absence of testosterone, and in the presence or absence of progesterone: 1) Effect on pre-ibutilide QTF, 2) Effect on maximum post-ibutilide QTF, 3) Effect on % change in post-ibutilide QTF, and 2) Area under the QTF interval-time curves.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
14
Phase
- 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 Locations
-
-
Indiana
-
Indianapolis, Indiana, United States, 46202
- Indiana 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
Ages Eligible for Study
63 years and older (Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
Male
Description
Inclusion Criteria:
- Men ≥ 65 years of age
Exclusion Criteria:
- Prostate cancer; history of prostate cancer;
- History of breast cancer; benign prostatic hypertrophy;
- Weight < 60 kg
- Weight > 135 kg
- Serum k+ < 3.6 mEq/L;
- Serum mg2+ < 1.8 mg/dL;
- Hemoglobin < 9.0 mg/dL;
- Hematocrit < 26%;
- Hepatic transaminases > 3x upper limit of normal;
- Baseline Bazett's-corrected QT interval > 450 ms
- Heart failure due to reduced ejection fraction (left ventricular ejection fraction < 40%)
- Family or personal history of long-QT syndrome, arrhythmias or sudden cardiac death;
- Concomitant use of any QT interval-prolonging drug.
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: Prevention
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Testosterone - progesterone - placebo
Subjects received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days.
After a washout of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days.
After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days
|
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
Experimental: Testosterone - placebo - progesterone
Subjects received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days.
After a washout of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo ( 2 capsules) once daily every morning x 7 days.
After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days.
|
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
Experimental: Progesterone - testosterone - placebo
Subjects received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days.
After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days.
After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo (2 capsules) once daily every morning x 7 days
|
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
Experimental: Progesterone - placebo - testosterone
Subjects received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days.
After a washout period of at least 13 days, they then received transdermal placebo gel once daily every morning for 7 days and oral placebo (2 capsules) once daily every morning x 7 days.
After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days.
|
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
Experimental: Placebo - testosterone - progesterone
Subjects received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days.
After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days.
After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days.
|
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
Experimental: Placebo - progesterone - testosterone
Subjects received transdermal placebo gel once daily every morning for 7 days and oral placebo once daily every morning x 7 days.
After a washout period of at least 13 days, they then received oral progesterone 400 mg (2 x 200 mg capsules) once every evening for 7 days and transdermal placebo gel once daily every morning for 7 days.
After a washout period of at least 13 days, they then received transdermal testosterone gel 1% 100 mg once daily in the morning and two (2) oral placebo capsules x 7 days.
|
Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days
Other Names:
Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days
Other Names:
Subjects will receive placebo transdermal gel and placebo (lactose) capsules
Other Names:
Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Baseline (Pre-ibutilide) Individualized Rate-corrected QT Interval (QTF)
Time Frame: Following 7 days of testosterone, progesterone or placebo
|
QT interval is an electrocardiogram (ECG) measure of ventricular repolarization.
Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death.
QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases.
QT intervals were measured using computerized high-resolution electronic calipers (EP Calipers 1.6).
QT and RR intervals at each time point were averaged over 3 consecutive complexes.
The end of the T-wave was determined via the tangent method.
Only clearly discernable QT intervals were measured.
QT intervals vary with heart rate, and therefore must be corrected for heart rate.
QT intervals were corrected using the Fridericia (QTF) method.
The baseline QTF assesses the influence of testosterone and progesterone on naturally-occurring (before ibutilide administration) QTF
|
Following 7 days of testosterone, progesterone or placebo
|
Maximum QTF Following Ibutilide 0.003 mg/kg
Time Frame: Within 8 hours following ibutilide administration
|
QT interval is an ECG measure of ventricular repolarization.
Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death.
Three 12-lead ECGs were obtained ~ 1 minute apart immediately at the end of the ibutilide infusion and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours post-infusion.
QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases.
QT intervals were measured using computerized high-resolution electronic calipers.
QT and RR intervals at each time point were averaged over 3 consecutive complexes.
The end of the T-wave was determined via the tangent method.
QT intervals vary with heart rate, and therefore must be corrected for heart rate.
QT intervals were corrected using the Fridericia (QTF) method.
Maximum QTF is the longest QTF measured following ibutilide at any time point.
|
Within 8 hours following ibutilide administration
|
Maximum Percent Change From Pretreatment Value in QTF Following Ibutilide 0.003 mg/kg
Time Frame: Within 8 hours of ibutilide administration
|
QT interval is an ECG measure of ventricular repolarization.
Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death.
Three 12-lead ECGs were obtained ~ 1 minute apart immediately at the end of the ibutilide infusion and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours post-infusion.
QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases.
QT intervals were measured using computerized high-resolution electronic calipers.
QT and RR intervals at each time point were averaged over 3 consecutive complexes.
The end of the T-wave was determined via the tangent method.
QT intervals were corrected using the Fridericia (QTF) method.
|
Within 8 hours of ibutilide administration
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Area Under the QTF Versus Time Curve for 0-1 Hour Following Ibutilide 0.003 mg/kg
Time Frame: 1 hour following ibutilide administration
|
Prolonged QT interval is a marker of increased risk of the ventricular arrhythmia known as torsades de pointes, which can cause sudden cardiac death.
Three 12-lead ECGs were obtained ~ 1 minute apart immediately at the end of the ibutilide infusion and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours post-infusion.
QT intervals were measured from ECG lead II by one investigator (E.T.M.) who was blinded to the subjects' assigned treatment phases.
QT intervals were measured using computerized high-resolution electronic calipers.
QT and RR intervals at each time point were averaged over 3 consecutive complexes.
The end of the T-wave was determined via the tangent method.
Area under the QTF curve was calculated using the trapezoidal rule and reflects overall QTF interval "exposure" over time.
|
1 hour following ibutilide administration
|
Number of Participants With Adverse Effects Associated With Testosterone, Progesterone and Placebo
Time Frame: During 7 day administration periods
|
Adverse effects were assessed by study investigators using telephone calls during the 7-day treatment period in each phase, as well as by asking participants about adverse effects on ibutilide administration days
|
During 7 day administration periods
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Muensterman Tomaselli E, Sowinski KM, Jaynes HA, Overholser BR, Kovacs RJ, Tisdale JE. Transdermal testosterone administration attenuates drug-induced QT interval lengthening in older men. Circulation 2018;138:A15197.
- Tomaselli Muensterman E, Jaynes HA, Sowinski KM, Overholser BR, Shen C, Kovacs RJ, Tisdale JE. Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men. Clin Pharmacol Ther. 2021 Jun;109(6):1499-1504. doi: 10.1002/cpt.2072. Epub 2020 Nov 15.
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)
May 1, 2016
Primary Completion (Actual)
October 19, 2017
Study Completion (Actual)
October 19, 2017
Study Registration Dates
First Submitted
July 29, 2015
First Submitted That Met QC Criteria
July 31, 2015
First Posted (Estimate)
August 3, 2015
Study Record Updates
Last Update Posted (Actual)
August 28, 2019
Last Update Submitted That Met QC Criteria
August 15, 2019
Last Verified
August 1, 2019
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Heart Diseases
- Cardiovascular Diseases
- Congenital Abnormalities
- Arrhythmias, Cardiac
- Cardiac Conduction System Disease
- Heart Defects, Congenital
- Cardiovascular Abnormalities
- Tachycardia, Ventricular
- Tachycardia
- Torsades de Pointes
- Long QT Syndrome
- Physiological Effects of Drugs
- Anti-Arrhythmia Agents
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Progestins
- Androgens
- Progesterone
- Testosterone
- Ibutilide
Other Study ID Numbers
- 1507526854
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Undecided
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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