Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

NCT01929083 | Completed Phase 2 Results DMC

• 1 other identifier: 12GRNT12060187
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 2

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

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (1)

• Incidence of Progesterone-associated Adverse Effects Compared to Placebo

  During 7 days of treatment with oral progesterone or placebo

Other Outcomes (5)

• 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

Study Arms (2)

Progesterone

EXPERIMENTAL

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

Drug: Progesterone; Drug: Ibutilide

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo; Drug: Ibutilide

Interventions

Progesterone DRUG

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

Progesterone

Placebo DRUG

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

Placebo

Ibutilide DRUG

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

Placebo; Progesterone

Eligibility Criteria

• Age: 21 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Female
• Age 21-40 years
• Premenopausal

You may not qualify if:

• 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

Sponsors & Collaborators

• Indiana University: lead
• American Heart Association: collaborator

Study Sites (2)

Indiana Clinical Research Center

Indianapolis, Indiana, 46202, United States

Location

Purdue University

Indianapolis, Indiana, 46202, United States

Location

MeSH Terms

Conditions

Jervell-Lange Nielsen Syndrome; Torsades de Pointes; Risk Reduction Behavior

Interventions

Progesterone; ibutilide

Condition Hierarchy (Ancestors)

Long QT Syndrome; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Tachycardia, Ventricular; Tachycardia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones

Results Point of Contact

• Title: Dr. James E Tisdale
• Organization: Indiana University

jtisdale@purdue.edu

317-880-5418

Study Officials

• James E Tisdale, BSc, PharmD

  Purdue University & Indiana University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pharmacy Practice

Study Record Dates

• First Submitted: August 22, 2013
• First Posted: August 27, 2013
• Study Start: April 1, 2013
• Primary Completion: June 1, 2014
• Study Completion: June 1, 2014
• Last Updated: October 30, 2015
• Results First Posted: September 28, 2015

Record last verified: 2015-10

Locations

US (2)