Prospective controlled study of QTc prolongation by droperidol in healthy volunteers

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Prospective controlled study of QTc prolongation
by droperidol in healthy volunteers
Anesthetic Life Support Drugs Advisory
Committee Meeting November 18, 2003 Mehul
Desai, M.D. Medical Officer Division of
Cardiovascular and Renal Drugs
Center for Drug Evaluation and Research
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Study Objective

• To determine the effect of 0.625, 2.5, 5 mg bolus
  doses of intravenous droperidol, relative to
  placebo, on the heart rate corrected QT interval
  in young, healthy volunteers.

Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Study Design

• 4 period, placebo controlled, blinded,
  randomized, crossover study of 20 healthy
  volunteers
• 0.625 mg, 2.5 mg, 5 mg, and placebo (IV bolus
  over 30 seconds)
• Healthy subjects between ages 19-40 years on no
  prescription or over the counter medications
  Normal baseline electrocardiograms.

Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Study Methods

• ECGs Baseline, 1, 2, 3, 4, 5, 8, 10, 15, 20,
  40, 60, 120, 240, 480, and 720 minutes post dose.
• Read blinded to time, treatment, and subject
  identity.
• Originally the QT and RR intervals were measured
  manually in conjunction with a digitizer board.
  Heart rate was corrected using Fridericias
  method.
• Subsequently, the ECGs were re-analyzed using
  digital technology and a subject specific heart
  rate correction. In addition, the impact of
  heart rate trending was also considered. (Dr.
  Malik)

Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Results Subject characteristics
A Asian, AA African American, C Caucasian,
F Female, M Male
Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Results(Adverse Events)

• Neuropsychiatric adverse events lead to early
  study termination
• Restlessness, anxiety, difficulty concentrating,
  claustrophobia, etc.
• One subject was unable to work the day following
  the study due to persistent symptoms

Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Results Heart rate
Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Results Individually corrected QTc
Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Results Average changes in individual QTc 10
60 minutes post dose
Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Results Maximal changes in individual QTc
Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Conclusions

• This study was underpowered secondary to early
  termination
• There is a strong suggestion that relatively low
  doses of droperidol prolong the QTc interval.

Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003
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Acknowledgements

• Indiana University
• Adegboyega A, Gorski JC, Hall SD, Hilligoss J,
  Pinto A
• FDA
• Collins JM, Jenkins JK, Honig PK, Haidar S, Huang
  SM, Hung HMJ, Kweder SL, Lee IP, Lesko LJ,
  Machado SG, Malinowski H, McCormick C, Pollock M,
  Sevka M, Temple R, Throckmorton DC
• St. Georges Hospital Medical School, London, UK
• Malik M

Anesthetics and Life Support Drugs Advisory
Committee November 18 and 19, 2003