Dataset Information

A Randomized, Single-Blind, Placebo-Controlled, 3-Way Crossover Study to Evaluate the Effect of Therapeutic and Supratherapeutic Doses of Edaravone on QT/QTc Interval in Healthy Subjects.

ABSTRACT: This randomized, single-blind, 3-way crossover study assessed the effect of edaravone on QT interval, including an exposure-response analysis. Twenty-seven healthy Japanese male volunteers, aged 20 to 49 years, were randomly assigned to receive a single intravenous dose of each treatment in 1 of 3 sequences (n = 9 each): ACB, BAC, and CBA, where A was edaravone 60 mg (therapeutic dose), B was edaravone 300 mg (supratherapeutic dose), and C was normal saline (placebo). Electrocardiographs were collected to assess treatment effects. In an exposure-response analysis, a linear model was determined to be valid and indicated no statistically significant positive slope for the relationship between change from baseline in QTcF (?QTcF) and edaravone concentration (0.000155 ms/(ng/mL); P = .1478); upper bounds of 2-sided 90% confidence intervals after placebo adjustment (??QTcF) were <10 milliseconds at the geometric mean maximum concentration for each edaravone dose. Overall estimated values by time point of ??QTcF ?0.9 milliseconds, no outlier values, and no morphologic changes suggestive of repolarization abnormalities were observed. Analysis of heart rate, PR interval, and QRS duration also revealed no adverse findings. These data indicate that edaravone, even at supratherapeutic doses, does not produce clinically meaningful QT prolongation and has no clinically relevant cardiac effects.

SUBMITTER: Shimizu H

PROVIDER: S-EPMC7818234 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A Randomized, Single-Blind, Placebo-Controlled, 3-Way Crossover Study to Evaluate the Effect of Therapeutic and Supratherapeutic Doses of Edaravone on QT/QTc Interval in Healthy Subjects.

Shimizu Hidetoshi H Inoue Shinsuke S Endo Mai M Nakamaru Yoshinobu Y Yoshida Kaori K Natori Tomoko T Kakubari Masae M Akimoto Makoto M Kondo Kazuoki K

Clinical pharmacology in drug development 20200615 1

This randomized, single-blind, 3-way crossover study assessed the effect of edaravone on QT interval, including an exposure-response analysis. Twenty-seven healthy Japanese male volunteers, aged 20 to 49 years, were randomly assigned to receive a single intravenous dose of each treatment in 1 of 3 sequences (n = 9 each): ACB, BAC, and CBA, where A was edaravone 60 mg (therapeutic dose), B was edaravone 300 mg (supratherapeutic dose), and C was normal saline (placebo). Electrocardiographs were co ...[more]

PMID: 32543120

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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.

Project description:BackgroundNumerous antineoplastic drugs such as chemotherapeutics have cardiotoxic side effects and can lead to long QT syndrome (LQTS). When diagnosed and treated in time, the potentially fatal outcomes of LQTS can be prevented. Therefore, regular electrocardiogram (ECG) assessments are critical to ensure patient safety. However, these assessments are associated with patient discomfort and require timely support of the attending oncologist by a cardiologist.ObjectiveThis study aimed to examine whether this approach can be made more efficient and comfortable by a smartphone app (QTc Tracker), supporting single-lead ECG records on site and transferring to a tele-cardiologist for an immediate diagnosis.MethodsTo evaluate the QTc Tracker, it was implemented in 54 cancer centers in Germany. In total, 266 corrected QT interval (QTc) diagnoses of 122 patients were recorded. Moreover, a questionnaire on routine ECG workflow, turnaround time, and satisfaction (1=best, 6=worst) was answered by the centers before and after the implementation of the QTc Tracker.ResultsCompared to the routine ECG workflow, the QTc Tracker enabled a substantial turnaround time reduction of 98% (mean 2.67, 95% CI 1.72-2.67 h) and even further time efficiency in combination with a cardiologic on-call service (mean 12.10, 95% CI 5.67-18.67 min). Additionally, nurses and patients reported higher satisfaction when using the QTc Tracker. In particular, patients' satisfaction sharply improved from 2.59 (95% CI 2.41-2.88) for the routine ECG workflow to 1.25 (95% CI 0.99-1.51) for the QTc Tracker workflow.ConclusionsThese results reveal a significant improvement regarding reduced turnaround time and increased user satisfaction. Best patient care might be guaranteed as the exposure of patients with an uncontrolled risk of QTc prolongations can be avoided by using the fast and easy QTc Tracker. In particular, as regular side-effect monitoring, the QTc Tracker app promises more convenience for patients and their physicians. Finally, future studies are needed to empirically test the usability and validity of such mobile ECG assessment methods.Trial registrationClinicalTrials.gov NCT04055493; https://classic.clinicaltrials.gov/ct2/show/NCT04055493.

Dataset Information

A Randomized, Single-Blind, Placebo-Controlled, 3-Way Crossover Study to Evaluate the Effect of Therapeutic and Supratherapeutic Doses of Edaravone on QT/QTc Interval in Healthy Subjects.

Publications

A Randomized, Single-Blind, Placebo-Controlled, 3-Way Crossover Study to Evaluate the Effect of Therapeutic and Supratherapeutic Doses of Edaravone on QT/QTc Interval in Healthy Subjects.

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