Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

14 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-05-31

Study Completion Date

2017-10-19

Brief Summary

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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.

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Detailed Description

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Conditions

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Long QT Syndrome

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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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

Group Type EXPERIMENTAL

Testosterone

Intervention Type DRUG

Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days

Progesterone

Intervention Type DRUG

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

Placebo

Intervention Type DRUG

Subjects will receive placebo transdermal gel and placebo (lactose) capsules

Ibutilide

Intervention Type DRUG

Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval

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.

Group Type EXPERIMENTAL

Testosterone

Intervention Type DRUG

Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days

Progesterone

Intervention Type DRUG

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

Placebo

Intervention Type DRUG

Subjects will receive placebo transdermal gel and placebo (lactose) capsules

Ibutilide

Intervention Type DRUG

Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval

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

Group Type EXPERIMENTAL

Testosterone

Intervention Type DRUG

Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days

Progesterone

Intervention Type DRUG

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

Placebo

Intervention Type DRUG

Subjects will receive placebo transdermal gel and placebo (lactose) capsules

Ibutilide

Intervention Type DRUG

Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval

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.

Group Type EXPERIMENTAL

Testosterone

Intervention Type DRUG

Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days

Progesterone

Intervention Type DRUG

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

Placebo

Intervention Type DRUG

Subjects will receive placebo transdermal gel and placebo (lactose) capsules

Ibutilide

Intervention Type DRUG

Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval

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.

Group Type EXPERIMENTAL

Testosterone

Intervention Type DRUG

Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days

Progesterone

Intervention Type DRUG

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

Placebo

Intervention Type DRUG

Subjects will receive placebo transdermal gel and placebo (lactose) capsules

Ibutilide

Intervention Type DRUG

Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval

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.

Group Type EXPERIMENTAL

Testosterone

Intervention Type DRUG

Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days

Progesterone

Intervention Type DRUG

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

Placebo

Intervention Type DRUG

Subjects will receive placebo transdermal gel and placebo (lactose) capsules

Ibutilide

Intervention Type DRUG

Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval

Interventions

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Testosterone

Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days

Intervention Type DRUG

Progesterone

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

Intervention Type DRUG

Placebo

Subjects will receive placebo transdermal gel and placebo (lactose) capsules

Intervention Type DRUG

Ibutilide

Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval

Intervention Type DRUG

Other Intervention Names

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Androgel Generic Lactose Corvert

Eligibility Criteria

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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.

Minimum Eligible Age

65 Years

Eligible Sex

MALE

Accepts Healthy Volunteers

Yes