With Hedgehog Pathway the protocol. One subject was withdrawn for AEs. Two subjects were withdrawn at the request of the investigator, one for pruritus and urticaria, and the other because he developed a resting heart rate 50 beats/min before dosing in one period. The final subject withdrawn from the study developed hypertension, he later admitted to stopping hypertension medications before randomization, and thus was ineligible for inclusion in the study. QTc Interval The value of the study specific correction factor for QTcX was 0.209. The placebo subtracted, baseline adjusted mean QTcX for dapagliflozin was 5 ms at each time point, and all upper bounds of the two sided 90% CI for the contrasts were 10 ms. The maximum placebo subtracted, baseline adjusted mean effect of dapagliflozin 150 mg for QTcX was 1.
2 ms at 3 hours after dosing, and the upper bound of the CI was 3.4 ms. For dapagliflozin Lopinavir 20 mg, the maximum placebo corrected, baseline adjusted mean effect for QTcX was 2.3 ms at 8 hours after dosing . Similar findings were observed using QTcF. The maximum placebo subtracted, baseline adjusted mean effect for QTcF was 2.8 ms and 1.6 ms for the 20 mg and 150 mg dapagliflozin doses, respectively. The findings for QTcB were consistent with those for QTcF. For moxifloxacin, with the exception of the contrast at 0.5 and 12 hours after dosing, all point estimates for the contrasts between moxifloxacin 400 mg and placebo for QTcX were 5 ms, and the lower bounds of the 90% CI were 5 ms at 3 and 4 hours. The maximum placebo corrected, baseline adjusted mean effect of moxifloxacin 400 mg for QTcX was 9.
7 ms at 4 hours after dosing, and the lower bound of the two sided 90% CI was 7.5 ms. Assay sensitivity was demonstrated by comparing the moxifloxacin and placebo treatments using the primary analysis model for QTcX averaged over the 1, 2, 3, and 4 hour postdose time points. The average 1 4 hour effect of moxifloxacin on the placebo corrected, baseline adjusted QTcX was 7.7 ms, with a lower bound of the 90% CI of 6.2 ms. QTc Interval Increase From Baseline and Absolute QTc Interval Prolongation Figure 2 presents a plot of the shift from baseline to the maximum observed QTcX interval by treatment.There was no increase from baseline 30 ms for QTcX over the 24 hour period following dapagliflozin or placebo administration.
Only one subject had an increase from baseline 30 ms for QTcX after administration of moxifloxacin 400 mg. Two subjects had an increase from baseline of 30 ms for QTcF over the 24 hours of treatment with moxifloxacin. These values, 30.2 and 31.1 ms, occurred at 4 and 3 hours after dosing, respectively. No subject had an increase from baseline for QTcF 30 ms for any dose of dapagliflozin. No subjects had a QTcX or QTcF value 450 ms during the study. Concentration QT Relationship Mean individual QTcX intervals versus dapagliflozin plasma concentration are presented in Figure 3. There was no apparent concentration dependent effect of dapagliflozin on QTcX. The estimated slope was 0.29 ms/g per mL, and the test of the null hypothesis of zero slopes was not statistically significant. Effect on RR, QRS, and PR Intervals There was little effect of dapagliflozin on heart rate. The mean change from baseline in the RR interval at each time point ranged.