Clinical trial NCT01929083: Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening
Official title: Influence of Progesterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prolonged QT Interval in EKG and Sudden Death
Keywords: Torsades de pointes
Progesterone
Clinical trial
Risk reduction
Electrocardiography
Lead sponsor: Indiana University
Sponsor class: OTHER
Collaborators: name: American Heart Association
First posted: 2013-08-27
Enrollment: 19
Sex: FEMALE
Minimum age (years): 21
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

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.


Eligibility criteria: 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

Primary outcomes:
measure: Baseline (Pre-Ibutilide) QTcI Intervals
timeFrame: After 7 days of progesterone or placebo, prior to receiving IV ibutilide
measure: Maximum Individual-corrected QT Interval (QTcI)
timeFrame: 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours post-ibutilide administration
measure: Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration
timeFrame: After 7 days of progesterone or placebo
measure: Area Under the QTcI - Time Curve (AUEC)
timeFrame: From beginning of 10-minute ibutilide infusion to 1 hour following ibutilide infusion
Secondary outcomes:
measure: Incidence of Progesterone-associated Adverse Effects Compared to Placebo
timeFrame: During 7 days of treatment with oral progesterone or placebo
Other outcomes:
measure: Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases
timeFrame: Within 8 hours following ibutilide administration
measure: Maximum (Peak) Serum Ibutilide Concentrations During Progesterone and Placebo Phases
timeFrame: Within 1 hour following ibutilide administration (0, 15 & 30 minutes and 1 hours.)
measure: Serum Estradiol Concentrations During the Progesterone and Placebo Phases
timeFrame: Following 7 days of progesterone or placebo
measure: Serum Progesterone Concentrations During Progesterone and Placebo Phases
timeFrame: After 7 days of progesterone or placebo
measure: Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases
timeFrame: After 7 days of progesterone or placebo
Locations:
city: Indianapolis
country: United States
facility: Indiana Clinical Research Center
state: Indiana
city: Indianapolis
country: United States
facility: Purdue University
state: Indiana
Study officials:
affiliation: Purdue University & Indiana University
name: James E Tisdale, BSc, PharmD
role: PRINCIPAL_INVESTIGATOR
References: