Influence of Progesterone Administration on Drug-Induced QT Interval Lengthening
Condition: Prolonged QT Interval in EKG and Sudden Death
MeSH terms: Torsades de Pointes; Long QT Syndrome; Jervell-Lange Nielsen Syndrome; Death, Sudden
Intervention: Progesterone; Placebo; Ibutilide
Intervention description: Subjects will receive oral progesterone 400 mg (two x 200 mg capsules) once daily every evening for 7 days; Subjects will receive oral placebo two capsules once daily every evening for 7 days; Ibutilide 0.003 mg/kg administered to all subjects to moderately lengthen the QT interval
Intervention MeSH terms: Ibutilide; Progesterone
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 19.0
Sex: Female
Minimum age: 21 Years
Maximum age: 40 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Torsades de pointes; Progesterone; Clinical trial; Risk reduction; Electrocardiography

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.
    

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