Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

Study Overview
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Brief Summary
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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.

Official Title
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Influence of Progesterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes

Conditions
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Prolonged QT Interval in EKG and Sudden Death

Intervention / Treatment
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* Drug: Progesterone
* Drug: Placebo
* Drug: Ibutilide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Progesterone<br>Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days | Drug: Progesterone<br>* Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days<br>Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval<br>|
| Placebo Comparator: Placebo<br>Subjects will receive oral placebo, two capsules once daily every evening for 7 days | Drug: Placebo<br>* Subjects will receive oral placebo two capsules once daily every evening for 7 days<br>Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline (Pre-Ibutilide) QTcI Intervals |  | After 7 days of progesterone or placebo, prior to receiving IV ibutilide | 
| Maximum Individual-corrected QT Interval (QTcI) | 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. | 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours post-ibutilide administration | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Progesterone-associated Adverse Effects Compared to Placebo |  | During 7 days of treatment with oral progesterone or placebo | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Torsades de pointes, Progesterone, Clinical trial, Risk reduction, Electrocardiography