Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

Phase 2

Completed

Conditions: Prolonged QT Interval in EKG and Sudden Death

Interventions: Drug: Progesterone
Drug: Placebo
Drug: Ibutilide

Registration Number: NCT01929083

Lead Sponsor: Indiana University

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: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 19

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Progesterone	Progesterone	Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days
Placebo	Placebo	Subjects will receive oral placebo, two capsules once daily every evening for 7 days
Placebo	Ibutilide	Subjects will receive oral placebo, two capsules once daily every evening for 7 days
Progesterone	Ibutilide	Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days

Primary Outcome Measures

Name	Time	Method
Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration	After 7 days of progesterone or placebo
Area Under the QTcI - Time Curve (AUEC)	From beginning of 10-minute ibutilide infusion to 1 hour following ibutilide infusion
Baseline (Pre-Ibutilide) QTcI Intervals	After 7 days of progesterone or placebo, prior to receiving IV ibutilide
Maximum Individual-corrected QT Interval (QTcI)	0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours post-ibutilide administration	QT intervals will be corrected as follows: Prior to randomization, subjects will come to the Indiana Clinical Research Center for a 12-hour stay, during which three ECGs, one minute apart, will be obtained at the following times: 0, 15 \& 30 minutes, and 1, 2, 4, 6, 8, and 12 hours. Subjects will be discharged, and then return then next morning for the 24 hour ECG. QT and RR intervals will be used to determine each subject's individual rate-corrected QT interval (QTcI) using the parabolic model QT = β•RRα, where RR is the interval between adjacent QRS complexes, and α and β are subject-specific correction factors.