QT Interval In Healthy Subjects Research Articles

Evaluation of the Potential Effect of Iptakalim Hydrochloride on the QT Interval in Single- and Multiple-Ascending-Dose Studies Using Concentration-QTc Analysis.

Cardiotoxicity has been one of the most common causes of withdrawal of drugs from the market, and prolongation of the QT interval is one of the manifestations of drug cardiotoxicity. Iptakalim hydrochloride (ITKL) is a selective ATP-sensitive potassium channel opener used to treat hypertension. It is crucial to assess the risk of cardiac repolarization of ITKL in clinical trials. This study was conducted to determine the effect of ITKL on corrected QT (QTc) interval. A randomized, double-blind, placebo-controlled single- and multidose regimen was carried out to investigate the QTc and ITKL concentration correlation. ITKL was administered at doses of 5, 10, 15, and 20 mg with single oral administration and 10 and 20 mg with multiple oral administration, along with placebo, in 83 healthy subjects. Electrocardiograms (ECGs) and blood samples were collected on a preset time schedule. A ΔΔQTcF effect above 10 milliseconds was excluded at all observed plasma levels. Among them, the highest dose was 20 mg, which is twice the therapeutic dose. We concluded that ITKL did not prolong the QT interval in healthy subjects within the therapeutic dose. Retrospectively registered: The study was registered at Chinese Clinical Trial Registry with registration number ChiCTR1800014466.

Short QT syndrome: The current evidences of diagnosis and management.

There are many cardiac arrhythmias and sudden cardiac death (SCD) related to channelopathies or ion channel disorders. Short QT syndrome (SQTS) is an inherited cardiac channelopathy principally caused by defective functioning of both potassium–calcium ion channel that lead to abnormal shortening of QT interval, and an increased risk of ventricular and atrial arrhythmias. Tall T waves in all lead electrocardiogram (ECG), peaked T waves, and narrow‐based T waves that are reminiscent of the typical “desert tent” T waves of hyperkalemia are frequently associated with SQTS. Diagnosis is based on patient's family history, evaluation of symptoms (palpitations and cardiac arrest), and 12‐lead ECG. It can be time challenging because of the wide range of QT interval in healthy subjects. Implantable cardioverter defibrillator (ICD) is the first‐line therapy in SQTS. Quinidine has the potential to be an effective pharmacological therapy for SQTS patients, especially in young children who are not feasible in ICD implantation, because of the ability to prolong QT interval.

2389. Effect of Rezafungin on QT Interval in Healthy Subjects

BackgroundRezafungin (RZF), a novel, once-weekly echinocandin for treatment and prophylaxis of invasive fungal infections, successfully met safety and efficacy endpoints in Phase 2 and is advancing to Phase 3 studies. RZF is the first echinocandin to undergo a definitive QT evaluation.MethodsThis Phase 1, single-center, randomized, double-blind, comparative study evaluated the effects of RZF on the QTcF (corrected using Fridericia’s formula) interval), heart rate, and other cardiac parameters. There were three dose groups, RZF (600 mg or 1,400 mg IV), IV placebo, and oral moxifloxacin (positive control). The 600 mg (therapeutic) and 1400 mg (supratherapeutic) doses were selected to achieve exposures approximating those after multiple doses of the highest dosage regimen assessed in the Phase 2 study (400 mg once weekly) and exposures ~2.5-fold higher, respectively. The primary endpoint was based on an analysis of change of QTcF from Baseline (ΔQTcF) as a function of RZF plasma concentration, to derive the estimated mean placebo-adjusted change of QTcF from Baseline (ΔΔQTcF) for the RZF dose groups at the geometric mean Cmax for each dose level. The outcome was defined by a comparison of the upper bounds of the 2-sided 90% CIs within 10 ms.Results60 subjects were enrolled and completed the study. Demographics included: sex (43.3% male) and age (median age 34.0 years; ranging from 20 to 51 years) approximately evenly distributed by treatment. A linear regression model best fit the data, as shown in Figure 1. From this model, the estimated mean ΔΔQTcF at the Cmax for both of the RZF doses had upper bounds <10 ms. The mean ΔΔQTcF at each time point by dose, showed all 1-sided 95% upper bounds to be <10 ms, thus supporting the conclusion of the primary analysis. Assay sensitivity was established for moxifloxacin. No clinically significant effects on any of the cardiac parameters tested (RR, QRS, HR) were observed. RZF was generally well tolerated. All adverse events (AE) were mild to moderate in severity with no discontinuations due to AEs.ConclusionRezafungin, in single IV doses up to 1,400 mg, does not prolong the QT interval. This finding supports the clinical safety and continued development of RZF. Disclosures S. Flanagan, Cidara Therapeutics: Employee and Shareholder, Salary and stock options. A. Jandourek, Cidara Therapeutics: Consultant, Consulting fee. T. Sandison, Cidara Therapeutics: Employee, Salary.

Correction to: Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

The author would like to correct the affiliations and conflict of interest in the publication of the original article. The corrected details are given below for your reading.

Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. Part1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680mg in eight subjects. Part2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted. No clinically relevant safety observations were noted in Part1. During Part2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10ms at all timepoints and at supratherapeutic C max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful. Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438.

The impact of posture on the cardiac depolarization and repolarization phases of the QT interval in healthy subjects

BackgroundPostural changes affect both heart rate and the QT interval. ObjectiveTo investigate the effects of postural changes on the depolarization and repolarization phases of the QT interval. MethodsA three lead ECG from 12 healthy young volunteers was recorded in the standing, sitting and in the supine positions. For the purpose of this study, we defined the depolarization phase as the QRS complex plus the ST segment and the repolarization phase as the duration of the T wave. ResultsQTc did not change with changes in position. The ratio of the duration of the depolarization phase to the repolarization phase was higher in the supine position (0.98±0.13) compared to the standing position (0.83±0.17). ConclusionsThe origin of the T wave moves closer to the QRS complex during standing compared to the supine position. The observed changes are mainly due to shortening of the ST segment during standing compared to supine position.

Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects.

A randomized, partial‐blind, repeat‐dose, 3‐period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open‐label 400‐mg dose of the positive control moxifloxacin, with a 21‐day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day ‐1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3‐fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2‐sided 90% confidence intervals for ΔΔQTcF (difference in time‐matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization.

Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study.

Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects. This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supra-therapeutic dose (8-fold clinical dose in COPD patients) of 400 µg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazettcorrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability. A total of 73 healthy male (n = 35) and female (n = 38) subjects, aged between 18 and 45 years, were randomized. Glycopyrronium did not cause significant QTcF prolongation compared to placebo. The largest time-matched mean difference to placebo was 2.97 ms at 5 minutes, with the upper limit of the two-sided 90% confidence interval (CI) being 4.80 ms, excluding a relevant QT effect as defined by the ICH E14 guideline. Glycopyrronium had a slight bradycardic effect with a mean change of -2.88 (90% CI: -3.78, -1.99) beats per minutes (bpm) and a maximum of -5.87 (90% CI: -7.82, -3.92) bpm at 5 hours post-inhalation. No clinically relevant effects were seen on QTcB, other electrocardiogram (ECG) intervals, or blood pressure. Maximum plasma concentration (Cmax) of glycopyrronium was achieved shortly after inhalation (median tmax = 7 minutes). All the treatments were well tolerated with no serious adverse events. A supra-therapeutic dose of glycopyrronium had a favorable cardiovascular safety profile with no clinically relevant effect on QT interval.

Tafenoquine at therapeutic concentrations does not prolong fridericia‐corrected QT interval in healthy subjects

Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18–65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine–QTcF concentration–effect relationship demonstrated a shallow slope (0.5 ms/μg mL–1) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization.

Evaluation of the effect of ruxolitinib on cardiac repolarization: A thorough QT study.

This was a randomized, four-way crossover study that evaluated the effects of placebo, single doses of ruxolitinib 25 and 200 mg, and a single dose of moxifloxacin 400 mg on heart rate-corrected QT interval in healthy subjects. Electrocardiograms (ECGs) and pharmacokinetic samples were obtained on each dosing day; baseline ECGs were taken pre-dose. The primary endpoint was placebo-subtracted change from baseline heart rate-corrected QT (Fridericia formula [ΔΔQTcF]). The ΔΔQTcF for either dose of ruxolitinib ranged from -3.09 to 3.28 milliseconds (1-sided 95% confidence interval of 0.06-6.62 milliseconds). The ΔΔQTcF for moxifloxacin (lower confidence interval) was significantly >5 milliseconds at 1, 2, and 3 hours post-dose. Individual QTcF >450 milliseconds and QTcF from baseline >30 milliseconds following ruxolitinib were similar to placebo. Based on the International Conference on Harmonization E14 guidance, the study results were considered negative for QTc prolongation. In conclusion, ruxolitinib did not have a clinically significant effect on QT interval.

Early repolarization and short QT interval in healthy subjects

An early repolarization (ER) pattern is common in ECGs from patients with ventricular fibrillation (VF). These patients with ER have shorter QT intervals. Morphological variants of the ER pattern also have been associated with idiopathic VF, but their prevalence in healthy subjects is unclear. The purpose of this study was to study the prevalence of ER and its morphological variants, and its association with the QTc interval in healthy subjects. Digital ECGs from 1886 healthy subjects from Phase I clinical trials were analyzed by a central ECG laboratory. ER, defined as J-point elevation ≥0.1 mV in ≥2 contiguous leads, was present in 514 subjects (27.3%), of whom 505 (98.2%) were males. The prevalence of ER declined progressively with increasing age. ER pattern was seen in lateral leads (I, aVL, V(4)-V(6)) in 26.1%, in inferior (II, III, aVF) or inferolateral leads in 8%, and was global in 1.9%. The terminal portion of the QRS complex was notched in 43.1% and slurred in 56.9%. Notching was common in inferior/lateral leads, and slurring was common in anterior leads. A non-ascending ST segment was seen in 71% of ECGs with a notched pattern but in only 12.3% of ECGs with a slurred pattern. The ER group had slower heart rates (9.3 ± 13.3 bpm [mean difference ± SD], P <.001) and shorter QTc intervals (QTcB = 20.2 ± 25.6 ms, QTcF = 11.0 ± 21.9 ms; P <.001). Four subjects in each group had a short QT interval (QTcF <350 ms). ER and all of its variants are common in healthy young males with slower heart rates and slightly shorter QTc intervals. A short QT interval (QTcF <350 ms) is rare.

Moxifloxacin versus placebo modeling of the QT interval

The objectives were to develop a population model for placebo-corrected moxifloxacin QT interval in healthy subjects using non-linear mixed effects modeling and to examine effect of covariates on the observed QT. Based on the parameters of interest, optimizations of observation times and number of subjects were proposed. A pool of four thorough QT studies was used, representing 99 subjects receiving placebo and moxifloxacin. The data was modeled using Monolix. The placebo effect on QT was satisfactorily described using a 2-oscillator model. It reflected the circadian rhythm variability which is taken into account when assessing the time-matched mean difference on QT between treatment and baseline. Based on this model, the moxifloxacin effect on QT was satisfactorily described by the same equation with the adjunct of a direct and proportional drug concentration-effect. The Emax model provided the best description of the effect. The unique covariate was gender for both baseline QTc and individual heart rate correction factor. The present design included up to 16 observations for pharmacodynamics. Using this model, 9 observation times for pharmacodynamics provided satisfactory estimates for the parameters of interest (Emax). With 15% precision limit on Emax, 60 subjects was optimal. The simultaneous placebo-moxifloxacin QT model proposed is an interesting alternative to the ICH E14 guideline in assessing QT prolongation effect. This approach provides accurate information over a range of concentrations using different relationships (slope or Emax models) to quantify the drug-response relationship versus placebo. This allowed optimizing the observation times and number of subjects.

Increased Risk of Antipsychotic-Related QT Prolongation During Nighttime

Most antipsychotic agents can cause QT prolongation, which causes torsades de pointes. The QT interval in healthy subjects is longer during nighttime than during daytime. The QT interval of patients treated with antipsychotics may be prolonged during nighttime, and the effects of antipsychotics on the QT interval may differ between antipsychotics. This study investigated the circadian dynamics of the QT interval in patients treated with antipsychotics and healthy controls, using a 24-hour Holter electrocardiogram in a clinical setting. Sixty-six patients with a diagnosis of schizophrenia that were treated with risperidone or olanzapine and 40 healthy volunteers were enrolled. The QT intervals were corrected using the Fridericia formula (QTcF = QT / RR). Mean ± SD nighttime QTcFs were 411.6 ± 29.0, 395.9 ± 21.2, and 387.8 ± 19.0 milliseconds (ms) in the risperidone, olanzapine, and control groups, respectively. The mean daytime QTcFs were 397.7 ± 23.4, 392.4 ± 18.9, and 382.6 ± 17.3 ms, respectively. The mean nighttime QTcF of the risperidone group was significantly longer than that of the olanzapine and control groups, although there was no significant difference in the mean daytime QTcF between the risperidone and olanzapine groups. The current study used 24-hour Holter electrocardiograms to reveal significantly longer QT intervals in the risperidone group especially during nighttime. In clinical practices, evaluations of the QT interval have been conducted over short periods in the daytime, but it is believed that such methods may not be able to fully elucidate the effects of antipsychotics on the QT interval.

Evaluation of the effect of dapagliflozin on cardiac repolarization: a thorough QT/QTc study

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.

Cardiac safety of indacaterol in healthy subjects: a randomized, multidose, placebo- and positive-controlled, parallel-group thorough QT study

BackgroundIndacaterol is a novel once-daily ultra long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease. It is known that β2-agonists, like other adrenergic compounds, can prolong the QT-interval. This thorough QT/QTc study (as per ICH E14 guideline) evaluated the effect of indacaterol on the QT interval in healthy subjects.MethodsIn this randomized, double-blind, parallel-group, placebo- and positive-controlled (open-label moxifloxacin) study, non-smoking healthy subjects (18-55 years, body mass index: 18.5-32.0 kg/m2) were randomized (4:4:2:4:1) to 14-day treatment with once-daily indacaterol (150 μg, 300 μg, or 600 μg), placebo, or placebo/moxifloxacin (double-blind 14-day treatment with placebo and a single open-label dose of 400 mg moxifloxacin on Day 14). The primary endpoint was the change from baseline on Day 14 in QTcF (QT interval corrected for heart rate using Fridericia's formula).ResultsIn total, 404 subjects were randomized to receive indacaterol (150 [n = 108], 300 [n = 108], 600 μg [n = 54]), placebo (n = 107), or placebo/moxifloxacin (n = 27); 388 subjects completed the study. Maximal time-matched mean (90% confidence intervals) treatment differences from placebo in QTcF change from baseline on Day 14 were 2.66 (0.55, 4.77), 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) ms for indacaterol 150 μg, 300 μg and 600 μg, respectively. Study sensitivity was confirmed with moxifloxacin demonstrating a significant maximal time-matched QTcF prolongation of 13.90 (10.58, 17.22) ms compared to placebo. All indacaterol doses were well tolerated.ConclusionIndacaterol, at doses up to 600 μg once daily (2-4 times the therapeutic dose) does not have any clinically relevant effect on the QT interval.Trial RegistrationClinicalTrials.gov: NCT01263808

Acute effects of coffee on QT interval in healthy subjects

The coronary endothelial function is recognized to have an important role in the physiology of the diastolic ventricular relaxation, a phase of the heart cycle that influences the electrocardiographic QT interval. Endothelial function is investigated in vivo by flow mediated dilation (FMD) in the brachial artery and has proven to be a strong predictor of both coronary endothelial function and cardiovascular events. It has been reported that coffee acutely induces FMD changes. In particular, the brachial artery FMD seems to decrease after caffeinated coffee (CC) and to increase after decaffeinated coffee (DC) ingestion. Since the cardiovascular effects of coffee are still a debated matter, this study aimed at investigating with a randomized, double-blind crossover design, if the QT interval of adult healthy subjects (19 males and 21 females) changes in the hour following CC or DC ingestion. Both systolic and diastolic blood pressure were higher in the hour following the ingestion of CC; the heart rate significantly increased 30 minutes after CC ingestion. A significant increase of the QT duration was observed one hour after DC ingestion (398.9 ± 3.8 vs 405.3 ± 3.7 msec; P < 0.05), not after CC. The QT interval corrected for heart rate did not significantly change following CC or DC ingestion. In conclusion, despite CC and DC previously demonstrated to influence the FMD they do not seem to induce a significant unfavourable acute change of the left ventricular repolarization. Further investigations are required to elucidate the effects of coffee in subjects with cardiovascular diseases.

The Effect of L-citrulline Ingestion on ECG QT Interval and Autonomic Nervous System Activity

The purpose of this study was to investigate the effect of L-citrulline ingestion on ECG QT interval. To accomplish this purpose, nine male subjects (age: 23.4±0.5 years, weight: 57.7±5.6 kg) participated, who had no history of cardiovascular or respiratory function disorders. Each subject performed two tests (L-citrulline and placebo ingestion) on a separate day. ECG was taken before, and 60 min and 90 min after L-citrulline ingestion. The heart-rate-corrected QT interval (QTc) decreased significantly 60 min (p=0.0004) and 90 min (p=0.011) after L-citrulline ingestion. However, there were no significant changes after placebo ingestion. In addition, the interaction between L-citrulline ingestion and placebo was significant (two-way ANOVA: interaction, p=0.010). Our major finding was that L-citrulline ingestion decreases the QT interval in healthy subjects. This result suggests that transient L-citrulline ingestion may shorten the time required to complete myocardial depolarization and repolarization.

Single-dose ticagrelor does not prolong the QT interval in healthy subjects

Ticagrelor (AZD6140), the first reversibly binding oral platelet P2Y12 receptor inhibitor, is currently under development for reduction of thrombotic events in patients with acute coronary syndrome (ACS). This study was designed to assess the potential effects of a single oral dose of ticagrelor on QT interval. In this randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study, 36 healthy males received single doses of ticagrelor 900 mg, moxifloxacin (positive control) 400 mg, or placebo in three treatment periods. This ticagrelor dose is substantially higher than the proposed therapeutic dose (90 mg twice daily after a 180 mg loading dose). QT intervals were assessed from 12-lead digital electrocardiogram (ECG) recordings over 24 h. Plasma levels of ticagrelor and its major metabolite AR-C124910XX were measured. Exploratory analyses of exposure-QTc interval relationships were conducted. Safety assessments were made throughout the study. Mean QTcX, QTcF, and QTcB intervals were similar between ticagrelor and placebo. All point estimates for comparisons between ticagrelor and placebo in QTcX over 24 h post dosing were < 5 milliseconds and all upper confidence limits (UCL) from two-sided 95% confidence intervals were < 10 milliseconds (maximum time-matched mean effect 2.27 milliseconds with UCL 6.05 milliseconds at 12 h). With moxifloxacin, all point estimates and UCLs (except at 24 h post dose) were > 5 milliseconds and > 10 milliseconds, respectively, versus placebo; indicating the study had sufficient sensitivity to detect clinically meaningful changes in QT interval. There was no apparent relationship between ticagrelor or AR-C124910XX levels and QT intervals. Ticagrelor was well tolerated at the tested dose. A single oral dose of 900 mg ticagrelor did not prolong the QT interval in healthy volunteers compared with placebo. Thus, it is expected that ticagrelor will not affect cardiac repolarization in ACS patients.

Lack of effect of dalcetrapib on QT interval in healthy subjects following multiple dosing

Evaluate dalcetrapib's potential to prolong QT intervals in healthy subjects. This was a single-center, randomized, active and placebo-controlled, six-sequence, three-period cross-over study. Participants [18-65 years; body mass index (BMI) 18-30 kg/m(2)] were randomized to daily doses of dalcetrapib 600 mg (therapeutic) or 3,900 mg (supratherapeutic) or to dalcetrapib-matched placebo for 7 days. On Day 8, subjects received single-dose moxifloxacin 400 mg (active control) or placebo, following the placebo or dalcetrapib, respectively. Electrocardiographic parameters were recorded on Days -1, 1, 7, and 8. The primary endpoint was the difference to placebo of time-matched change from baseline in the study-specific corrected QT interval (QTcS) at seven time-points within 24 h after dalcetrapib 3,900 mg on Day 7. An upper 95% confidence interval (CI) <10 ms confirmed the absence of a significant effect. Pharmacokinetic and lipid-related parameters were measured. Subjects (n = 49) were predominantly male (71%), and all were white, with a mean age of 45 years and mean BMI of 25 kg/m(2). For the primary analysis, the upper 95% CI for dalcetrapib 3,900 mg was <10 ms at all time-points. Similar findings were obtained for dalcetrapib 600 mg. Following the administration of moxifloxacin, the QTcS increased by >5 ms. At Day 7, exposure for dalcetrapib 3,900 mg was approximately eightfold higher than that for dalcetrapib 600 mg [mean area under the plasma concentration-time curve between time 0 and 24 h 68,500 vs. 8,280 ng*h/mL; mean peak concentration 6,810 vs. 861 ng/mL]. Cholesteryl ester transfer protein activity was inhibited by 30%, and high-density lipoprotein cholesterol increased by 26% for dalcetrapib 600 mg. Dalcetrapib was well tolerated. Dalcetrapib is not associated with QT interval prolongation, even at doses markedly greater than intended therapeutically.

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations. Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin. Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms.