Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

NCT ID: NCT01929083

Last Updated: 2015-10-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 19 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-04-30
• Study Completion Date: 2014-06-30

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.

Conditions

Prolonged QT Interval in EKG and Sudden Death

Keywords

Torsades de pointes; Progesterone; Clinical trial; Risk reduction; Electrocardiography

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Progesterone

Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days

Group Type: EXPERIMENTAL

Progesterone

Intervention Type: DRUG

Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days

Ibutilide

Intervention Type: DRUG

Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Placebo

Subjects will receive oral placebo, two capsules once daily every evening for 7 days

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Subjects will receive oral placebo two capsules once daily every evening for 7 days

Ibutilide

Intervention Type: DRUG

Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Interventions

Progesterone

Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days

Intervention Type: DRUG

Placebo

Subjects will receive oral placebo two capsules once daily every evening for 7 days

Intervention Type: DRUG

Ibutilide

Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval

Intervention Type: DRUG

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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

American Heart Association

OTHER

Sponsor Role: collaborator

Indiana University

OTHER

Sponsor Role: lead

Responsible Party

James E. Tisdale

Professor of Pharmacy Practice

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

James E Tisdale, BSc, PharmD

Role: PRINCIPAL_INVESTIGATOR

Purdue University & Indiana University

Locations

Indiana Clinical Research Center

Indianapolis, Indiana, United States

Purdue University

Indianapolis, Indiana, United States

Countries

United States

Other Identifiers

12GRNT12060187

Identifier Type: -

Identifier Source: org_study_id