Conditions: Prolonged QT Interval in EKG and Sudden Death
Keywords: Torsades de pointes Progesterone Clinical trial Risk reduction Electrocardiography
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 19
Healthy volunteers: yes

Brief summary:
Female sex is an independent risk factor for the potentially fatal drug-induced arrhythmia (irregular heartbeat) known as torsades de pointes (TdP), which is associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram (ECG). Mechanisms for this increased risk in women are not well-understood. QTc interval duration has been shown to fluctuate throughout the phases of the menstrual cycle. Evidence indicates that the QTc interval response to drugs that may cause TdP is greater during the menses and ovulation phases of the menstrual cycle, during which serum progesterone concentrations are lowest, and lesser during the luteal phase, during which serum progesterone concentrations are highest. Additional evidence from our laboratory suggests that progesterone may be protective against TdP. Specific Aim 1: Establish the influence of oral progesterone administration as a preventive method by which to diminish the degree of drug-induced QT interval prolongation in women. Working hypothesis: Oral progesterone administration effectively attenuates enhanced drug-induced QT interval response in women. To test this hypothesis, progesterone or placebo will be administered in a crossover fashion to women during the menses phase of the menstrual cycle. QTc interval response to low-dose ibutilide, a drug known to lengthen the QT interval, will be assessed. The primary endpoint will be individually-corrected QT interval (QTcI) response to ibutilide, in the presence and absence of progesterone, which will be assessed by: 1) Effect on maximum change in QTcI, and 2) Area under the QTcI interval-time curves (AUEC). At the conclusion of this study, we will have established that oral progesterone administration is a safe and effective method of attenuating drug-induced QT interval prolongation.

Detailed description:

Arms:
arm 1: Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days arm 2: Subjects will receive oral placebo, two capsules once daily every evening for 7 days

Interventions: intervention 1: Progesterone intervention 2: Placebo intervention 3: Ibutilide
Intervention descriptions: intervention 1: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days intervention 2: Subjects will receive oral placebo two capsules once daily every evening for 7 days intervention 3: Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Protocol document: