Use of Early Clinical Trial Data to Support Thorough QT Study Waiver for Upadacitinib and Utility of Food Effect to Demonstrate ECG Assay Sensitivity.
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ABSTRACT:
SUBMITTER: Mohamed MF
PROVIDER: S-EPMC5946993 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.
| S-EPMC8251570 | biostudies-literature
Project description:Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure-response (E-R) analysis may be more sensitive than simple changes in QT(c) interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT study from one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E-R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn.
| S-EPMC3579250 | biostudies-literature
Project description:Chemotherapy-induced nausea and vomiting is ranked among the worst side effects of chemotherapy. NEPA is an oral fixed-dose combination antiemetic under development, consisting of netupitant 300 mg, a highly selective NK1 receptor antagonist (RA), and palonosetron 0.5 mg, a pharmacologically and clinically distinct 5-HT3 RA. Although palonosetron is not associated with relevant ECG effects, this study evaluated cardiovascular safety of netupitant in combination with palonosetron, as well as its tolerability. This randomised, placebo- and positively controlled study in 197 subjects included 4 treatment groups: placebo, 200 mg netupitant + 0.5 mg palonosetron (NEPA200/0.5), 600 mg netupitant + 1.5 mg palonosetron (NEPA600/1.5, a supratherapeutic dose), and 400 mg moxifloxacin. Assessments included a 24-h baseline ECG recording, followed by a single dose of treatment and ECG measurements for 2 days. Mean placebo-corrected time-averaged changes from baseline were similar in NEPA200/0.5 and NEPA600/1.5 groups primarily for individually heart rate-corrected QT interval (QTcI: +4.7 and +3.6 ms, respectively) and for heart rate (HR: -3.3 bpm and -3.0 bpm), PR interval (-0.4 ms and 0.2 ms), and QRS interval (1 ms and 0.5 ms). The time-matched analysis showed no upper confidence interval >10 ms, with no suggestion of a QTc effect by pharmacokinetic-pharmacodynamic modeling for parent/metabolites. Moxifloxacin showed the expected placebo-corrected change from baseline (+8.4 ms time average) and the expected profile to establish assay sensitivity. No new morphologic changes of clinical relevance were observed. Treatment-related adverse events were comparable among groups. This study showed that NEPA treatments produced no significant effects on QTcI, HR, PR interval, QRS interval, and cardiac morphology relative to placebo, even at supratherapeutic doses.
| S-EPMC4124105 | biostudies-literature
Project description:Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor. To evaluate the cardiac safety of luseogliflozin, a thorough QT/QTc study was conducted in healthy Japanese subjects. The effects of moxifloxacin on QT prolongation in Japanese subjects were also evaluated. In this double-blind, placebo- and open-label positive-controlled, 4-way crossover study, 28 male and 28 female subjects received a single dose of luseogliflozin 5 mg (therapeutic dose), luseogliflozin 20 mg (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Serial triplicate digital 12-lead electrocardiograms (ECGs) were recorded before and after dosing, and results were analyzed using the Fridericia correction (QTcF) method. Serial blood sampling was performed for pharmacokinetic analyses of luseogliflozin and moxifloxacin to analyze the relationship between QTcF interval and plasma concentration. The upper limits of the two-sided 90% confidence intervals (CIs) for baseline and placebo-adjusted QTcF intervals (??QTcF) in the 5 mg and 20 mg luseogliflozin groups were less than 10 ms at all time points. No correlation between plasma luseogliflozin concentrations and ??QTcF was observed. In the moxifloxacin group, the lower limits of the two-sided 90% CIs for ??QTcF were greater than 5 ms at all time points. A positive relationship was observed between plasma moxifloxacin concentration and change in ??QTcF. Luseogliflozin was well tolerated at both dose levels. The majority of adverse events were mild in severity, and no serious or life-threatening adverse events occurred. Neither therapeutic (5 mg) nor supratherapeutic (20 mg) doses of luseogliflozin affected QT prolongation in healthy Japanese subjects.
| S-EPMC4596473 | biostudies-literature
Project description:BackgroundDabigatran etexilate is a pro-drug of the oral reversible direct thrombin inhibitor dabigatran that interacts with the active site in the catalytic domain of the thrombin molecule.ObjectiveTo assess the electrophysiological effects of therapeutic and supratherapeutic doses of dabigatran etexilate in healthy subjects, a thorough QT study was performed.MethodsIn this single-centre, blinded, placebo- and active-controlled, four-period, crossover study, 40 healthy Caucasian subjects (20 women and 20 men) received single oral doses of dabigatran etexilate (150 mg and 600 mg), moxifloxacin 400 mg (positive control) or placebo, in a randomized order. Electrocardiogram (ECG) profiles were recorded at baseline and during the randomized study treatment in each period. The individually heart-rate-corrected QT interval (QTcI) was the primary parameter. The primary endpoint was the mean of these QTcI values obtained at 1.5, 2 and 3 h following study drug administration minus the mean of the time-matched QTcI values obtained at baseline day -1. The hypothesis tested was that the difference between each of the two doses of dabigatran etexilate (150 mg and 600 mg) and placebo, for the mean time-matched change from baseline (CfB) of QTcI between 1.5 and 3 h (the primary endpoint), was greater than or equal to 10 ms. Secondary endpoints were the time-matched CfB of QTcI between 0.5 and 24 h post-dose.ResultsAll subjects completed the study without premature discontinuation and all treatments were well tolerated. Following dabigatran etexilate administration, the mean values of the placebo-adjusted time-matched CfB of QTcI between 1.5 and 3 h post-dose were close to 0; the upper bound of the two-sided 90 % confidence interval (CI) was 1.4 ms for dabigatran etexilate 150 mg and 1.3 ms for dabigatran etexilate 600 mg. The placebo-adjusted time-matched CfB of QTcI remained close to 0 at all time points, and all 90 % CIs were between -5 ms and 5 ms, well below the pre-defined non-inferiority margin of 10 ms.ConclusionThis thorough QT study demonstrated that therapeutic and fourfold supratherapeutic doses of dabigatran etexilate do not prolong QT intervals.
| S-EPMC3634983 | biostudies-literature
Project description:BACKGROUND:Empagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment. This QT interval study assessed potential effects of empagliflozin on ventricular repolarisation and other electrocardiogram (ECG) parameters. METHODS:A randomised, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design to reduce sample size, while maintaining full statistical power. TREATMENTS:single empagliflozin doses of 25 mg (therapeutic) and 200 mg (supratherapeutic), matching placebo and open-label moxifloxacin 400 mg (positive control). Triplicate 12-lead ECGs of 10 second duration were recorded at baseline and during the first 24 hours after dosing. The primary endpoint was mean change from baseline (MCfB) in the population heart rate-corrected QT interval (QTcN) between 1-4 hours after dosing. RESULTS:Thirty volunteers (16 male, 14 female, mean [range] age: 34.5 [18-52] years) were randomised. The placebo-corrected MCfB in QTcN 1-4 hours after dosing was 0.6 (90% CI: -0.7, 1.9) ms and -0.2 (-1.4, 0.9) ms for empagliflozin 25 mg and 200 mg, respectively, below the ICH E14 defined threshold of regulatory concern 10 ms. Assay sensitivity was confirmed by a placebo-corrected MCfB in QTcN 2-4 hours post-dose of 12.4 (10.7, 14.1) ms with moxifloxacin 400 mg. Empagliflozin tolerability was good for all volunteers; 23.3% experienced adverse events (AEs) with empagliflozin and 27.6% with placebo. The most frequent AE was nasopharyngitis. CONCLUSIONS/INTERPRETATION:Single doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01195675.
| S-EPMC3648489 | biostudies-literature
Project description:INTRODUCTION:Semaglutide is a glucagon-like peptide-1 (GLP-1) analog approved for the once-weekly treatment of type 2 diabetes. The objective of this 16-week, double-blind, single-center thorough QT study was to confirm that semaglutide treatment does not prolong cardiac repolarization versus placebo. Prolongation of the QT interval is a biomarker for ventricular tachyarrhythmia. METHODS:In a parallel design, 168 healthy subjects were randomized to the treatment or placebo arms, of whom 166 were treated with subcutaneous semaglutide (N = 83; escalated to a supratherapeutic dose of 1.5 mg) or placebo (N = 83). The subjects (60% males) had a mean age of 38.2 years and body mass index of 25.1 kg/m2. To assess QT assay sensitivity, subjects in the placebo group received a single 400 mg moxifloxacin dose as positive control, and placebo in a crossover fashion. The primary endpoint was the time-matched change from baseline in QT interval corrected individually for heart rate (ΔQTcI), calculated from 11 electrocardiogram recordings from 0 to 48 h after the last 1.5 mg dose. Similar assessments were made for the therapeutic 0.5 and 1.0 mg semaglutide dose levels. RESULTS:No QTcI prolongation occurred with any semaglutide dose; the upper limits of two-sided 90% confidence intervals of the placebo-subtracted ΔQTcI were < 10 ms at all doses and time points. Exposure-response analysis showed no dependence of QTcI on semaglutide concentration. QT assay sensitivity was confirmed. The semaglutide safety profile was similar to that of other GLP-1 receptor agonists. CONCLUSION:Based on investigations of QT/QTc, no concern with regard to ventricular arrhythmias was raised as semaglutide did not prolong the cardiac repolarization duration in healthy subjects. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT 02064348. FUNDING:Novo Nordisk.
| S-EPMC6064589 | biostudies-literature
Project description:IntroductionAlbiglutide, a selective once-weekly glucagon-like peptide-1 receptor agonist, is being developed for the treatment of type 2 diabetes mellitus. Albiglutide's effect on cardiac repolarization (QTc interval) was assessed in a randomized, double-blind, placebo-controlled, parallel-group study in healthy subjects with a nested crossover comparison for moxifloxacin.MethodsSubjects were randomized to albiglutide (n = 85) or placebo (n = 89) and received injections of 30 mg albiglutide or placebo on Days 1 and 8 and 50 mg albiglutide or placebo on Days 15, 22, 29, and 36. In the placebo group, moxifloxacin was administered on Day -1 in half the subjects and on Day 40 in the other half. Blood samples for albiglutide plasma concentration were drawn on Days 4 and 39 and serial ECGs were extracted from continuous recordings on Days -2 (baseline), -1, 4, 39, and 40.ResultsDemographics were generally similar between albiglutide and placebo subjects: mean age was 29 years and BMI 25 kg/m(2). Mean change-from-baseline QTcI (∆QTcI, which was corrected for individual heart rate) on Day 4 after a single dose of albiglutide 30 mg and on Day 39 after repeat dosing with albiglutide 50 mg once weekly was similar to the placebo response. The placebo-corrected ΔQTcI (ΔΔQTcI) on both albiglutide doses was small with the largest ΔΔQTcI of 1.1 ms (upper bound of 90% CI 3.8 ms) on Day 4 and -0.6 ms (upper bound of CI 1.8 ms) on Day 39. Moxifloxacin caused the largest mean effect on ΔΔQTcI of 10.9 ms and the lower bound of the CI was above 5 ms at all preselected timepoints, thereby demonstrating assay sensitivity. Albiglutide was well tolerated and there were no clinically relevant differences in safety data between albiglutide and placebo.ConclusionAlbiglutide at doses up to 50 mg in healthy subjects did not prolong the QTc interval.
| S-EPMC4065291 | biostudies-literature
Project description:IntroductionDapagliflozin is a first-in-class sodium-glucose transporter 2 (SGLT2) inhibitor under investigation for the treatment of type 2 diabetes mellitus. A thorough QTc study was conducted, according to International Conference on Harmonization E14 guidelines, to characterize the effect of dapagliflozin on cardiac repolarization.MethodsThe present study was a double-blind, four-period, placebo-controlled crossover study at a single-center inpatient clinical pharmacology unit. The study enrolled 50 healthy men who were randomized to receive sequences of single doses of dapagliflozin 150 mg, dapagliflozin 20 mg, moxifloxacin 400 mg, and placebo. The sequences were randomized based on the Williams design for a cross-over study to reduce the "carryover" effects from drug-to-drug even with sufficient washout periods. Digital 12-lead electrocardiograms were recorded at nine time points over 24 hours in each period. QT intervals were corrected for heart rate using a study-specific correction factor (QTcX) and Fridericia's formula.ResultsFor dapagliflozin, the upper bound of the one-sided 95% confidence interval (CI) for time-matched, placebo-subtracted, baseline adjusted QTc intervals (ΔΔQTc) was <10 ms. ΔΔQTc was independent of dapagliflozin concentrations. No QTc thresholds >450 ms or QTc increases >30 ms were observed. Moxifloxacin increased the mean QTcX interval by 7.7 ms (lower bound 90% CI, 6.2 ms) over 1-4 hours after dosing, confirming assay sensitivity.ConclusionDapagliflozin, at supratherapeutic doses, does not have a clinically significant effect on the QT interval in healthy subjects.
| S-EPMC3173598 | biostudies-literature
Project description: Not available
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