Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

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.

Conditions

• Prolonged QT Interval in EKG and Sudden Death

Interventions

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 oral placebo two capsules once daily every evening for 7 days

DRUG

Ibutilide

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

Sponsors & Collaborators

• American Heart Association

  collaborator OTHER

• Indiana University

  lead OTHER

Principal Investigators

• James E Tisdale, BSc, PharmD · Purdue University & Indiana University

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Model

CROSSOVER

Eligibility

Min Age

21 Years

Max Age

40 Years

Sex

FEMALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2013-04-30

Primary Completion

2014-06-30

Completion

2014-06-30

Countries

• United States

Study Locations