Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
Condition: Long QT Syndrome
MeSH terms: Long QT Syndrome; Torsades de Pointes
Intervention: Testosterone; Progesterone; Placebo; Ibutilide
Intervention description: Subjects will receive transdermal testosterone gel 1% 100 mg daily for 7 days; Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days; Subjects will receive placebo transdermal gel and placebo (lactose) capsules; Ibutilide 0.003 mg/kg administered to all subjects in all phases to moderately lengthen the QT interval
Intervention MeSH terms: Ibutilide; Testosterone; Progesterone
Phase: Phase 4
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 14.0
Sex: Male
Minimum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Torsades de pointes; Testosterone; Progesterone; Clinical trial; Risk reduction; Electrocardiography

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.
    

Eligibility 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.