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

Summary

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.

Conditions

• Long QT Syndrome

Interventions

DRUG

Testosterone

Subjects will receive transdermal testosterone gel 1% 100 mg daily 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

Placebo

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

DRUG

Ibutilide

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

Sponsors & Collaborators

• American Heart Association

  collaborator OTHER

• Purdue University

  collaborator OTHER

• Indiana University

  lead OTHER

Principal Investigators

• James E Tisdale, PharmD · Purdue University

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Model

CROSSOVER

Eligibility

Min Age

65 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2016-05-31

Primary Completion

2017-10-19

Completion

2017-10-19

Countries

• United States

Study Locations