Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

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

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.

Study Overview

• Status: Completed
• Conditions: Prolonged QT Interval in EKG and Sudden Death
• Intervention / Treatment: Drug: Progesterone; Drug: Ibutilide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana Clinical Research Center
    • Indianapolis, Indiana, United States, 46202
      • Purdue University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 36 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Time Frame
Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases	Within 8 hours following ibutilide administration
Maximum (Peak) Serum Ibutilide Concentrations During Progesterone and Placebo Phases	Within 1 hour following ibutilide administration (0, 15 & 30 minutes and 1 hours.)
Serum Estradiol Concentrations During the Progesterone and Placebo Phases	Following 7 days of progesterone or placebo
Serum Progesterone Concentrations During Progesterone and Placebo Phases	After 7 days of progesterone or placebo
Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases	After 7 days of progesterone or placebo

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: American Heart Association
• Investigators: Principal Investigator: James E Tisdale, BSc, PharmD, Purdue University & Indiana University

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: August 22, 2013
• First Submitted That Met QC Criteria: August 26, 2013
• First Posted (Estimate): August 27, 2013

Study Record Updates

• Last Update Posted (Estimate): October 30, 2015
• Last Update Submitted That Met QC Criteria: October 29, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Clinical trial; Progesterone; Electrocardiography; Risk reduction; Torsades de pointes
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Death; Heart Defects, Congenital; Cardiovascular Abnormalities; Tachycardia, Ventricular; Tachycardia; Death, Sudden; Torsades de Pointes; Long QT Syndrome; Jervell-Lange Nielsen Syndrome; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone; Ibutilide
• Other Study ID Numbers: 12GRNT12060187