Reducing the Risk of Drug-Induced QT Interval Lengthening in Women

Study Overview
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Brief Summary
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This research will determine if oral progesterone attenuates drug-induced QT interval lengthening in a) Postmenopausal women 50 years of age or older, and b) Premenopausal women studied during the ovulation phase of the menstrual cycle. This investigation will consist of two concurrent prospective, randomized, double-blind, placebo-controlled crossover-design studies in a) Postmenopausal women, and b) Premenopausal women. Each subject will take progesterone or placebo capsules for 1 week. After a two-week washout (no progesterone or placebo) each subject will then take the alternative therapy (progesterone or placebo) for 1 week. After 7 days of each treatment, subjects will present to the clinical research center to receive a small dose of the QT interval-lengthening drug ibutilide, and the effect on the QT, J-Tpeak and Tpeak-Tend intervals during the progesterone and placebo phases will be compared

Detailed Description
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Torsades de pointes (TdP) is a catastrophic arrhythmia associated with corrected QT (QTc) interval prolongation, which can be induced by > 150 commonly prescribed drugs. TdP risk is higher in women and is modulated by the ratio of serum progesterone and estradiol; the higher the serum progesterone and progesterone:estradiol ratio, the lower the risk, and vice-versa. TdP risk increases with age, likely due to declining postmenopausal progesterone concentrations. Methods to reduce TdP risk in postmenopausal women requiring therapy with QTc interval-prolonging drugs have not been developed. In addition, the differential effects of progesterone on drug-induced lengthening of early vs late ventricular repolarization in humans are unknown. The investigators have previously shown that oral progesterone attenuates QTc interval lengthening in young women during the menses phase when serum estradiol concentrations are low. However, whether oral progesterone remains effective for attenuating drug-induced QTc interval lengthening during menstrual cycle phases with higher serum estradiol concentrations is unknown. The efficacy of oral progesterone for attenuating drug-induced QTc interval lengthening in postmenopausal women is also unknown. Specific Aim1: Determine the efficacy of oral progesterone as a preventive method to diminish drug-induced QTc interval lengthening in postmenopausal women. Specific Aim 2: Determine the influence of oral progesterone on drug-induced lengthening of early versus late ventricular repolarization in postmenopausal women. Specific Aim 3: Determine the efficacy of oral progesterone to diminish drug-induced QTc interval lengthening in premenopausal women during the ovulation phase of the menstrual cycle, when serum estradiol concentrations are high. Specific Aim 4: Specific Aim 4: Determine the influence of oral progesterone on drug-induced lengthening of early versus late ventricular repolarization in premenopausal women during the ovulation phase of the menstrual cycle, when serum estradiol concentrations are high. Concurrent prospective, randomized, double-blind, placebo-controlled two-way crossover-design studies will be conducted in a) Postmenopausal women > 50 years of age (n=20) and b) Premenopausal women 21-40 years of age (n=20) who will be studied during the ovulation phase of the menstural cycle. QTc interval response to low-dose ibutilide will be assessed. Subjects will receive, in randomized order (with a minimum two-week washout phase) oral progesterone 400 mg or placebo once daily for 7 days. On the morning after the 7th dose, subjects will present to the Indiana Clinical Research Center to receive one dose of the QT interval-lengthening drug ibutilide 0.003 mg/kg, after which ECGs and blood for determination of serum ibutilide concentrations will be obtained serially for 8 hours. Primary outcome measures: 1) Baseline (pre-ibutilide) Fridericia (QTFrid) and Framingham (QTFram)-corrected QT intervals, 2) Maximum QTFrid and QTFram intervals following ibutilide, 3) Maximum % change in QTFrid and QTFram intervals following ibutilide, 4) Area under the QTFrid and QTFram interval-time curves from 0-1 and 0-8 hours. Secondary outcome measures: 1) J-Tpeak interval, 2) Tpeak-Tend interval, and 5) Incidence of progesterone and ibutilide adverse effects. These studies will establish oral progesterone as a safe and effective method of attenuating drug-induced QTc interval lengthening in postmenopausal women.

Official Title
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Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening: Reducing the Risk of Drug-Induced QT Interval Lengthening in Women

Conditions
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Long QT Syndrome, Abnormalities, Drug-Induced

Intervention / Treatment
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* Drug: Progesterone
* Drug: Ibutilide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women: 50 years of age or older No menstrual periods for 365 days or longer Premenopausal women: - 21-40 years of age Exclusion Criteria: History of breast, uterine or ovarian cancer History of hysterectomy and/or ovariectomy Weight > 135 kg Serum K+ < 3.6 mEq/L; Serum Mg2+ < 1.8 mg/dL; Hematocrit < 26%; Hepatic transaminases > 3x upper limit of normal; Baseline Bazett's-corrected QT interval > 450 ms Taking hormone replacement therapy Diagnosis of heart failure Symptoms associated with heart failure: Pitting edema > 2+ Crackles or rales on lung auscultation S3 or S4 heart sounds Unable to climb at least 2 flights of stairs without becoming short of breath Current ECG rhythm of atrial fibrillation or other tachyarrhythmia Family or personal history of long-QT syndrome or sudden cardiac death not associated with acute myocardial infarction Concomitant use of any QTc interval-prolonging drug. Permanently paced ventricular rhythm Pregnancy Using any hormonal contraceptives [oral contraceptives, hormone-secreting intrauterine devices (IUDs), hormonal implants]

Ages Eligible for Study
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Minimum Age: 21 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: Postmenopausal women: 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>* Other names: Corvert;|
| Placebo Comparator: Postmenopausal women: Placebo<br>Subjects will receive oral placebo, two capsules once daily every evening for 7 days | Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval<br>* Other names: Corvert;|
| Experimental: Premenopausal women: 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>* Other names: Corvert;|
| Placebo Comparator: Premenopausal women: Placebo<br>Subjects will receive oral placebo, two capsules once daily every evening for 7 days | Drug: Ibutilide<br>* Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval<br>* Other names: Corvert;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline (pre-ibutilide) QT-F and QT-Fram intervals | QT intervals will be corrected for heart rate using two methods: the Fridericia method and the Framingham method | After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide | 
| Maximum post-ibutilide QT-F and QT-Fram intervals | Maximum post-ibutilide QT-F and QT-Fram intervals | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion | 
| % change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals | % change from baseline (pre-ibutilide) in maximum QT-F and QT-Fram intervals | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion | 
| Area under the QT-F and QT-Fram versus time curves during and for 1 hour following ibutilide infusion | Area under the QT-F and QT-Fram versus time curves during and for 1 hour | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion | 
| Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion | Area under the QT-F and QT-Fram versus time curves during and for 8 hours following ibutilide infusion | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals | Baseline (pre-ibutilide) heart rate-corrected J-Tpeak (J-Tpeakc) intervals | After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide | 
| Maximum post-ibutilide J-Tpeakc intervals | Maximum post-ibutilide J-Tpeakc intervals | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion | 
| % change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals | % change from baseline (pre-ibutilide) in maximum J-Tpeakc intervals | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion | 
| Area under the J-Tpeakc versus time curve during and for 1 hour following ibutilide infusion | Area under the J-Tpeakc versus time curve during and for 1 hour following | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion | 
| Area under the J-Tpeakc versus time curve during and for 8 hours following ibutilide infusion | Area under the J-Tpeakc versus time curve during and for 8 hours following | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion | 
| Baseline (pre-ibutilide) Tpeak-Tend intervals | Baseline (pre-ibutilide) Tpeak-Tend intervals | After 7 days of treatment with oral progesterone or placebo, prior to receiving ibutilide | 
| Maximum post-ibutilide Tpeak-Tend intervals | Maximum post-ibutilide Tpeak-Tend intervals | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion | 
| % change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals | % change from baseline (pre-ibutilide) maximum Tpeak-Tend intervals | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion | 
| Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion | Area under the Tpeak-Tend versus time curves during and for 1 hour following ibutilide infusion | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1 hour after the ibutilide infusion | 
| Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion | Area under the Tpeak-Tend versus time curves during and for 8 hours following ibutilide infusion | Prior to ibutilide; at 5 minutes into the 10-minute ibutilide infusion; end of infusion; and at 5, 10, 15, 20, 30, and 45 minutes and 1, 2, 4, 6, and 8 hours after the ibutilide infusion |