Use of continuous ECG for improvements in assessing the standing response as a positive control for QT prolongation.
BACKGROUND
Standing invoked change in QT interval has been identified as a promising autonomic maneuver for the assessment of QT/QTc prolongation in patients with underlying heart abnormalities or as a positive control in healthy volunteers for drug studies. Criticism for its more widespread use is the high variability in reported results and the need for a more standardized methodology with defined normal ranges.


METHODS
Forty healthy male subjects underwent continuous ECG collection on the day before dosing in a double-blind, placebo-controlled, randomized, single ascending dose trial. A brisk supine to standing (3 minutes) response was conducted at three time points. Results were grouped by treatment cohort or assessed as a pooled group at each time point. Maximum time and median change from baseline (ΔTmax QTcF, ΔQTcF) were calculated for each individual over sequential 30-second periods staggered by 5 seconds.


RESULTS
Maximum ΔQTcF at all time points and in all groups was significant (i.e., the lower bound of 90% CI was > 5 milliseconds) which is the ICH E14 regulatory requirement for a positive control. Variability of the time to maximum response was also reduced 9-fold by the third time period.


CONCLUSIONS
Standing invoked ΔQTcF can be utilized to validate the sensitivity of a study for assessment of the QT interval effect of drugs in early development. The methodology may be used to further improve its diagnostic use of long QT syndromes by reducing the variability and allowing adequate definition of normal limits.
iCardiac Technologies, Rochester, NY.
Anthony A
AA
Fossa
Meijian
M
Zhou
Nuala
N
Brennan
Patrick
P
Round
John
J
Ford
D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015716:Electrocardiography, Ambulatory / Q000187:drug effects* / Q000379:methods*; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011187:Posture; D016683:Supine Position; D013997:Time Factors; D055815:Young Adult
D000889:Anti-Arrhythmia Agents
QTc prolongation; autonomic; hysteresis; positive control; standing