Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

Indiana University

Status and phase: Completed; Phase 2

Conditions: Prolonged QT Interval in EKG and Sudden Death

Treatments: Drug: Placebo; Drug: Ibutilide; Drug: Progesterone

Study type: Interventional

Funder types: Other

Identifiers

NCT01929083

12GRNT12060187

Details and patient eligibility

About

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.

Enrollment: 19 patients

Sex: Female

Ages: 21 to 40 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Female
• Age 21-40 years
• Premenopausal

Exclusion criteria

Serum potassium ,< 3.6 meq/l

• Serum magnesium < 1.8 mg/dl
• Serum hemoglobin < 9.0 mg/dl
• Serum hematocrit < 26%
• Hypertension
• Coronary artery disease
• Heart failure
• Liver disease
• Kidney disease
• Serum creatinine > 1.5 mg/dl
• Taking hormone contraceptives
• Baseline Bazett's correct QTc interval > 450 ms
• Family history of long-QT syndrome, arrhythmias, sudden cardiac death
• Concomitant use of any QT prolonging drug
• Pregnancy
• weight < 45 kg
• Unwillingness to use non-hormonal forms of birth control during the study period

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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19 participants in 2 patient groups, including a placebo group

Progesterone

Experimental group

Description:

Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days

Treatment:

Drug: Progesterone

Drug: Ibutilide

Placebo

Placebo Comparator group

Description:

Subjects will receive oral placebo, two capsules once daily every evening for 7 days

Treatment:

Drug: Placebo

Drug: Ibutilide