Study Design Parameters Affecting Exposure Response Analysis of QT Data: Results From Simulation Studies
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The operating characteristics of dose-escalating studies in terms of false-negative predictions of the QT effect and the power to exclude clinically relevant QT effects are not quantitatively established. One thousand single-ascending-dose (SAD) studies with 7 dose groups with 6/2 subjects on active drug/placebo were generated through simulation for each of 32 scenarios with (1) 8 different QT effects of the study drug and (2) achieved plasma concentration 2- or 4-fold above therapeutic levels. For each subject, drug-free QT data from a thorough QT study were subsampled to capture the circadian profile, on which a drug effect was added. The percentage of false-negative studies was between 4% and 9% when the drug's QT effect was set to 10 milliseconds. If a somewhat lower effect of 6.7 milliseconds was set at therapeutic concentrations, the fraction of negative studies was higher, 40% to 60% when the variability of the QT data was well controlled. When the QT effect was set to 5 milliseconds at therapeutic plasma concentrations, the power of SAD studies to exclude 10 milliseconds QT effect was generally above 70% (74% to 94%) with well-controlled QT variability, whereas the power was reduced to 36% to 69% if supratherapeutic plasma concentrations were not achieved. The rate of false-negative studies was acceptably low in placebo-controlled SAD studies. With a drug with no or a small QT effect, supratherapeutic plasma concentrations, and well-controlled variability of QT data, the power of SAD studies to exclude a relevant effect was above 70%.This study investigated the effect of eslicarbazepine acetate (ESL) on cardiac repolarization in healthy adult volunteers. A randomized, placebo/active-controlled, 4-period crossover study was conducted in 67 participants. In 3 periods, participants received once-daily doses of ESL 1200 mg, ESL 2400 mg, and placebo for 5 days; in 1 period, participants received placebo on days 1 to 4 and a 400-mg moxifloxacin single dose on day 5. In each period, 24-hour 12-lead Holter monitoring was performed on days -;1 (baseline) and 5. There was no clinically relevant effect of ESL 1200 mg and 2400 mg versus placebo on cardiac depolarization or repolarization as measured by the QRS or QTc intervals, respectively. Mean PR interval increased following ESL 1200 mg and 2400 mg, but there was no participant with a PR interval above the upper limit of the normal range (200 ms). The upper bound of the 95% confidence interval for the placebo-corrected change from baseline of the individually corrected QT interval (QTcI) following administration of ESL 1200 mg and ESL 2400 mg was <10 ms at every time point. Moxifloxacin caused an increase in QTcI above the 10-ms threshold for clinical significance at several time points, demonstrating assay sensitivity. It is concluded that administration of ESL 1200 mg and ESL 2400 mg did not induce a clinically significant prolongation of the QTcI interval.
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A randomized, double-blind study was performed to determine how morphine 0.1 mg/kg IV, or placebo administered 80 +/- 11 (means +/- SE) minutes before the end of surgery affect recovery from isoflurane/oxygen anesthesia. End-tidal isoflurane remained constant at 1.10 +/- 0.02% (means +/- SE) in both groups intraoperatively, and no other anesthetics were given after the administration of the morphine or placebo. Duration of anesthesia did not differ significantly between the morphine (172 +/- 7 minutes) and placebo (163 +/- 18 minutes) groups. Times from discontinuation of isoflurane until eye-opening in response to verbal command were similar in the morphine (19 +/- 2 minutes) and placebo (22 +/- 3 minutes) groups. At the time of eye-opening, end-tidal isoflurane concentrations did not differ between subjects receiving morphine (0.20 +/- 0.02%) and placebo (0.18 +/- 0.01%). It is concluded that the awakening concentration (MAC-awake) during recovery from isoflurane anesthesia is approximately 0.19% and is not affected by analgesic doses or morphine.
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The objective of this study was to establish effects of liraglutide on the QTc interval. In this randomized, placebo-controlled, double-blind crossover study, 51 healthy participants were administered placebo, 0.6, 1.2, and 1.8 mg liraglutide once daily for 7 days each. Electrocardiograms were recorded periodically over 24 hours at the end of placebo and highest dosing periods. Four different models for QT correction were used: QTci, as the primary endpoint, and QTciL, QTcF, and QTcB as secondary endpoints. The upper bound of the 1-sided 95% confidence interval for time-matched, baseline-corrected, placebo-subtracted QTc intervals was <10 ms for all 4 correction methods. Moxifloxacin (400 mg) increased QTc intervals by 10.6 to 12.3 ms at 2 hours. There was no concentration-exposure dependency on QTc interval changes by liraglutide and no QTc thresholds above 500 ms or QTc increases >60 ms. The authors conclude that liraglutide caused no clinically relevant increases in the QTc interval.
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Which treatments for lower extremity superficial thrombophlebitis (ST) are associated with lower rates of venous thromboembolic events (VTEs) vs placebo?A dose of 2.5 mg of fondaparinux administered subcutaneously once daily for 45 days is associated with fewer cases of symptomatic VTE without an increase in major bleeding vs placebo. Low-molecular-weight heparin (LMWH) and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with lower rates of ST extension or recurrence vs placebo, but data regarding symptomatic VTE remain inconclusive. Oral rivaroxaban requires further evaluation.
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We mesured 123 patients' QTc,JTc and QT dispersion (QTd) of acute my-ocardial infarction (AMI) on first ECG with 48 hours. The results showed that QTc were greaterin patients with ventricular fibrillation (VF ,QTc mean 488. 63± 39. 36 to 405. 48±22. 31ms , P0. 01). QTc360ms and QTd60ms were significantly more in patients with VF and ventriculartachycardia (VT) during the early phase of AMI. So ,we suggeest that QTc ,JTc and/or QTd maybe significant prediction value for prognosis of AMI.
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Abstract Cenobamate is an antiseizure medication for uncontrolled focal seizures. This thorough QT study assessed the effects of therapeutic and supratherapeutic cenobamate doses (maximum recommended dose, 400 mg/day) on correct QT interval (QTc) in healthy adults (N = 108) randomly assigned to 1 of 3 treatments: (A) cenobamate (days 1‐63) up‐titrated by 50‐mg increments weekly to a 200 mg/day therapeutic dose (day 35) and then by 100 mg weekly to a 500 mg/day supratherapeutic dose (day 63), with placebo‐moxifloxacin (days −1 and 64); (B) moxifloxacin 400 mg (day −1; positive control), placebo‐cenobamate (days 1‐63), and placebo‐moxifloxacin (day 64); and (C) placebo‐moxifloxacin (day −1), placebo‐cenobamate (days 1‐64), and moxifloxacin 400 mg (day 64). The primary end point was baseline‐adjusted, placebo‐corrected QTc (ΔΔQTcF; corrected for heart rate [HR] by Fridericia's method) with cenobamate 200 and 500 mg/day. Baseline electrocardiographic parameters were balanced across groups. Mean ΔΔQTcF was negative throughout for cenobamate doses (largest: day 35, −10.8 milliseconds; day 63, −18.4 milliseconds). Based on concentration‐QTc analysis, ∆∆QTcF effect was predicted as −9.85 and −17.14 milliseconds at mean peak plasma levels of therapeutic (200 mg/day; 23.06 μg/mL) and supratherapeutic (500 mg/day; 63.96 μg/mL) doses. Cenobamate had no clinically relevant prolonging effect on electrocardiographic parameters (eg, PR, QRS); HR effects were similar to placebo. Cenobamate showed slight dose‐related shortening of QTc, but to a degree not known to be clinically relevant (no reductions ≤340 milliseconds). Cenobamate had no clinically relevant effects on HR or electrocardiographic parameters and no QTc‐prolonging effect at therapeutic/supratherapeutic doses. Cenobamate is contraindicated in patients with short‐QT syndrome and caution should be used when coadministering with drugs that shorten QT interval.
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1 Shivering is frequent during the post‐anaesthetic recovery period, and there is no clear consensus about the best strategy for its treatment. We tested the efficacy of two commonly used analgesic drugs, pethidine and metamizol. 2 A randomized, double‐blind, placebo‐controlled clinical trial was performed, including 104 adult patients who presented with post‐anaesthetic shivering during the recovery from general anaesthesia. They were randomized to receive placebo ( n =32), metamizol 25 mg kg −1 ( n =37), or pethidine 0.4 mg kg −1 ( n =35). The response to treatment was assessed 5, 15 and 45 min after drug administration, and the main outcome variable was complete suppression of shivering. 3 The efficacy at 5, 15 and 45 min was as follows: placebo 6%, 16% and 37%; metamizol 13.5%, 32% and 76%, and pethidine 89%, 91% and 89%. With both active drugs the efficacy at all three time intervals was significantly higher than that with placebo ( P <0.05). The differences (at 5 and 15, but not at 45 min) between pethidine and metamizol were statistically significant ( P <0.05). Both drugs were well tolerated. 4 The persistence of shivering at 45 min in two thirds of placebo‐treated patients indicates that drug treatment is worthwhile; metamizol produces a better post‐anaesthetic shivering response than placebo, especially 15 and 45 min after drug administration; the efficacy of pethidine was the highest and the response to it appeared more quickly; however, at 45 min it was similar to that observed with metamizol. 5 Both metamizol and pethidine suppress postanaesthetic shivering, but the latter induces a quicker and more reliable response.
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This thorough QT/ QT interval corrected for heart rate (QTc) study was designed to assess the potential of semagacestat, a functional gamma-secretase inhibitor, to delay cardiac repolarization.In this Phase I, single-dose, randomized, 4-period crossover study, semagacestat was compared with placebo in 54 healthy male and female subjects between the ages of 19 and 63 years, inclusive. Each study period included single oral-dose administrations of semagacestat 140 mg, semagacestat 280 mg, moxifloxacin 400 mg, or placebo. Study subjects and the investigator were blinded to the identity of semagacestat and placebo; however, moxifloxacin was administered as open-label. Moxifloxacin was compared with placebo for assay sensitivity analysis. Pharmacokinetic parameters were also assessed.For each QTc, the upper bound of the 2-sided 90% confidence interval (CI) for the least squares mean difference between semagacestat (at both the 140- and 280-mg dose levels) and placebo was < 10 msec at all time points, and thus, within the limits set for clinical relevance in regulatory guidelines.The results of this study indicate that single doses of 140 and 280 mg semagacestat did not prolong QTc to a clinically significant degree.
Crossover study
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Laryngoscopic intubation and supraglottic airway device insertion can prolong the corrected QT (QTc) interval during anaesthetic induction even in healthy patients. No prior study has compared the effect of laryngoscopic intubation and supraglottic airway device, i-gel, insertion on the QTc interval change.Patients were randomised to either the intubation group (N.=25) or the i-gel group (N.=25) before induction. The QT interval was sequentially measured in lead II following a standard anaesthetic technique for induction using propofol and sevoflurane. Four sequential QT values were applied to the Bazett's formula to correct for the effect of heart rate on the QT interval, and then averaged. The peak QTc interval, the duration of QTc prolongation >20 ms compared to the QTc value immediately before intubation or i-gel insertion and the incidence of the QTc intervals >500 ms were measured.The peak QTc interval was lower in i-gel group (458.4±24.3 ms) than in intubation group (488.6±32.6 ms) (P=0.001). The duration of QTc prolongation >20 ms compared to the QTc values at immediately before intubation or i-gel insertion was significantly longer in the intubation group (136.5±104.5 s) than that of the i-gel group (56.9±56.5 s) (P=0.031). The number of patients with QTc interval >500 ms was significantly lower in the i-gel group (4%) than in the intubation group (48%).The insertion of the i-gel produces less QTc interval change than laryngoscopic intubation. The i-gel may be advantageous to patients who are at risk of QTc prolongation, high blood pressure and tachycardia.
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This double-blind, randomized, placebo- and active-controlled, parallel group trial evaluated the potential for multiple-dose fasiglifam to prolong the QT/QTc interval in healthy adults. A total of 280 men and women aged 18-50 years were randomized to receive 14 days of fasiglifam 50 mg (n = 69), fasiglifam 400 mg (n = 70), or placebo (n = 70), or 13 days of placebo followed by single-dose moxifloxacin 400 mg (positive control; n = 71). The primary endpoint was the least square mean difference between fasiglifam and placebo in time-matched change from baseline to last dosing day in QT interval corrected using the Fridericia method (QTcF, calculated as QT/RR(0) (.333) ). For both fasiglifam doses, differences from placebo in QTcF were between -4.9 and 3.0 milliseconds at all postdose time points; maximum upper bounds of the one-sided 95% confidence interval for the difference were 5.7 milliseconds for fasiglifam 50 mg and 2.3 milliseconds for fasiglifam 400 mg, meeting predefined criteria for absence of prolongation. Alternate correction methods (Bazett and Individual) showed similar results. Fasiglifam was well tolerated; no subject withdrew due to an adverse event after receiving fasiglifam. In summary, multiple-dose fasiglifam did not affect cardiac repolarization at therapeutic and supratherapeutic doses and was well tolerated in healthy subjects.
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