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Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening

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ClinicalTrials.gov Identifier: NCT01929083
Recruitment Status : Completed
First Posted : August 27, 2013
Results First Posted : September 28, 2015
Last Update Posted : October 30, 2015
Sponsor:
Collaborator:
American Heart Association
Information provided by (Responsible Party):
James E. Tisdale, Purdue University

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.

Condition or disease Intervention/treatment Phase
Prolonged QT Interval in EKG and Sudden Death Drug: Progesterone Drug: Placebo Drug: Ibutilide Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Influence of Progesterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
Study Start Date : April 2013
Actual Primary Completion Date : June 2014
Actual Study Completion Date : June 2014


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: 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




Primary Outcome Measures :
  1. Baseline (Pre-Ibutilide) QTcI Intervals [ Time Frame: After 7 days of progesterone or placebo, prior to receiving IV ibutilide ]
  2. Maximum Individual-corrected QT Interval (QTcI) [ Time Frame: 0, 15 & 30 minutes, and 1, 2, 4, 6, 8, and 12 hours post-ibutilide administration ]
    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.

  3. Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration [ Time Frame: After 7 days of progesterone or placebo ]
  4. Area Under the QTcI - Time Curve (AUEC) [ Time Frame: From beginning of 10-minute ibutilide infusion to 1 hour following ibutilide infusion ]

Secondary Outcome Measures :
  1. Incidence of Progesterone-associated Adverse Effects Compared to Placebo [ Time Frame: During 7 days of treatment with oral progesterone or placebo ]

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


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Ages Eligible for Study:   21 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01929083


Locations
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United States, Indiana
Indiana Clinical Research Center
Indianapolis, Indiana, United States, 46202
Purdue University
Indianapolis, Indiana, United States, 46202
Sponsors and Collaborators
Indiana University
American Heart Association
Investigators
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Principal Investigator: James E Tisdale, BSc, PharmD Purdue University & Indiana University

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Responsible Party: James E. Tisdale, Professor of Pharmacy Practice, Purdue University
ClinicalTrials.gov Identifier: NCT01929083     History of Changes
Other Study ID Numbers: 12GRNT12060187
First Posted: August 27, 2013    Key Record Dates
Results First Posted: September 28, 2015
Last Update Posted: October 30, 2015
Last Verified: October 2015
Keywords provided by James E. Tisdale, Purdue University:
Torsades de pointes
Progesterone
Clinical trial
Risk reduction
Electrocardiography
Additional relevant MeSH terms:
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Torsades de Pointes
Long QT Syndrome
Jervell-Lange Nielsen Syndrome
Death, Sudden
Death
Pathologic Processes
Tachycardia, Ventricular
Tachycardia
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Cardiac Conduction System Disease
Heart Defects, Congenital
Cardiovascular Abnormalities
Congenital Abnormalities
Ibutilide
Progesterone
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Anti-Arrhythmia Agents