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

• Status: Completed
• Trial end date: 2017-10-19
• Target enrollment: 0
• Participant gender: Male

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Indiana University
• Collaborators: American Heart Association; Purdue University
• Treatments: Ibutilide; Methyltestosterone; Progesterone; Testosterone; Testosterone 17 beta-cypionate; Testosterone enanthate; Testosterone undecanoate

Criteria

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.