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.
Timeline
- Start
- 2013-04
- Primary completion
- 2014-06
- Completion
- 2014-06
Outcome
Met primary endpoint
registry MEAN Progesterone: 412 (Standard Deviation 15) ms MEAN Placebo: 419 (Standard Deviation 14) ms analysis (superiority or other test); Progesterone vs Placebo; p = 0.04; t-test, 2 sided NCT01929083 ↗
registry MEAN Progesterone: 443 (Standard Deviation 17) ms MEAN Placebo: 458 (Standard Deviation 19) ms analysis (superiority or other test); Progesterone vs Placebo; p = 0.003; t-test, 2 sided NCT01929083 ↗
registry MEAN Progesterone: 7.5 (Standard Deviation 2.4) percentage change from baseline value MEAN Placebo: 9.3 (Standard Deviation 3.4) percentage change from baseline value analysis (superiority or other test); Progesterone vs Placebo; p = 0.02; t-test, 2 sided NCT01929083 ↗
registry MEAN Progesterone: 497 (Standard Deviation 13) ms*hr MEAN Placebo: 510 (Standard Deviation 16) ms*hr analysis (superiority or other test); Progesterone vs Placebo; p = 0.002; t-test, 2 sided NCT01929083 ↗
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Ibutilide | Small molecule | 0.003 mg/kg | — |
| Subject | Progesterone | Other / unclassified | 400 mg | Oral |