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

Indiana University

Status and phase: Completed; Phase 4

Conditions: Long QT Syndrome

Treatments: Drug: Ibutilide; Drug: Progesterone; Drug: Testosterone; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02513940

1507526854

Details and patient eligibility

About

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.

Enrollment: 14 patients

Sex: Male

Ages: 65+ years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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14 participants in 6 patient groups

Testosterone - progesterone - placebo

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Testosterone

Drug: Progesterone

Drug: Ibutilide

Testosterone - placebo - progesterone

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Testosterone

Drug: Progesterone

Drug: Ibutilide

Progesterone - testosterone - placebo

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: Testosterone

Drug: Progesterone

Drug: Ibutilide

Progesterone - placebo - testosterone

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Testosterone

Drug: Progesterone

Drug: Ibutilide

Placebo - testosterone - progesterone

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Testosterone

Drug: Progesterone

Drug: Ibutilide

Placebo - progesterone - testosterone

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Testosterone

Drug: Progesterone

Drug: Ibutilide