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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

Tracking Information
First Submitted Date  ICMJE August 22, 2013
First Posted Date  ICMJE August 27, 2013
Results First Submitted Date  ICMJE August 27, 2015
Results First Posted Date  ICMJE September 28, 2015
Last Update Posted Date October 30, 2015
Study Start Date  ICMJE April 2013
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 29, 2015)
  • Baseline (Pre-Ibutilide) QTcI Intervals [ Time Frame: After 7 days of progesterone or placebo, prior to receiving IV ibutilide ]
  • 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.
  • Maximum % Change From Baseline in QTcI Intervals Following Ibutilide Administration [ Time Frame: After 7 days of progesterone or placebo ]
  • Area Under the QTcI - Time Curve (AUEC) [ Time Frame: From beginning of 10-minute ibutilide infusion to 1 hour following ibutilide infusion ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 26, 2013)
  • Maximum Individual-corrected QT Interval (QTcI) [ Time Frame: Following 7 days of progesterone or placebo administered in randomized, crossover fashion ]
    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, 12 and 24 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.
  • Area Under the QTcI - Time Curve (AUEC) [ Time Frame: Following 7 days of progesterone or placebo ]
  • QTcI EC50 [ Time Frame: Following 7 days of progesterone or placebo ]
    Serum ibutilide concentration at 50% maximum QTcI lengthening
Change History Complete list of historical versions of study NCT01929083 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 27, 2015)
Incidence of Progesterone-associated Adverse Effects Compared to Placebo [ Time Frame: During 7 days of treatment with oral progesterone or placebo ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 26, 2013)
Incidence of progesterone-associated adverse effects [ Time Frame: During 7 days of treatment with oral progesterone ]
Current Other Pre-specified Outcome Measures
 (submitted: October 29, 2015)
  • Adverse Effects Associated With Ibutilide in the Progesterone and Placebo Phases [ Time Frame: Within 8 hours following ibutilide administration ]
  • 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.) ]
  • Serum Estradiol Concentrations During the Progesterone and Placebo Phases [ Time Frame: Following 7 days of progesterone or placebo ]
  • Serum Progesterone Concentrations During Progesterone and Placebo Phases [ Time Frame: After 7 days of progesterone or placebo ]
  • Ratio of Serum Progesterone:Estradiol Concentrations During the Progesterone and Placebo Phases [ Time Frame: After 7 days of progesterone or placebo ]
Original Other Pre-specified Outcome Measures
 (submitted: August 26, 2013)
Correlation between serum progesterone concentrations and each of the primary endpoints [ Time Frame: Following 7 days of progesterone or placebo ]
 
Descriptive Information
Brief Title  ICMJE Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening
Official Title  ICMJE Influence of Progesterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Prolonged QT Interval in EKG and Sudden Death
Intervention  ICMJE
  • Drug: Progesterone
    Subjects will receive oral progesterone 400 mg (two x 200 mg 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
Study Arms  ICMJE
  • Experimental: Progesterone
    Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days
    Interventions:
    • Drug: Progesterone
    • Drug: Ibutilide
  • Placebo Comparator: Placebo
    Subjects will receive oral placebo, two capsules once daily every evening for 7 days
    Interventions:
    • Drug: Placebo
    • Drug: Ibutilide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 12, 2015)
19
Original Estimated Enrollment  ICMJE
 (submitted: August 26, 2013)
20
Actual Study Completion Date  ICMJE June 2014
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 21 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01929083
Other Study ID Numbers  ICMJE 12GRNT12060187
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party James E. Tisdale, Purdue University
Study Sponsor  ICMJE Indiana University
Collaborators  ICMJE American Heart Association
Investigators  ICMJE
Principal Investigator: James E Tisdale, BSc, PharmD Purdue University & Indiana University
PRS Account Indiana University
Verification Date October 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP