Comparing the consistency of electrocardiogram interval measurements by resting ECG versus 12-lead Holter.

In clinical trials, traditionally only a limited number of 12-lead resting electrocardiograms (ECGs) can be recorded and, thus, long intervals may elapse between assessment timepoints and valuable information may be missed during times when patients' cardiac electrical activity is not being monitored. These limitations have led to the increasing use of Holter recorders which provide continuous data registrations while reducing the burden on patients and freeing up time for clinical trial staff to perform other tasks. However, there is a shortage of data comparing the two approaches. In this study, data from a randomized, double-blind, four-period, crossover thorough QT study in 40 healthy subjects were used to compare continuous 12-lead Holter recordings to standard 12-lead resting ECGs which were recorded in parallel. Heart rate and QT interval data were estimated by averaging three consecutive heartbeats. Values exceeding the sample average by more than 5% were tagged as outliers and excluded from the analysis. Visual comparisons of the ECG waveforms of the Holter signal showed a good correlation with resting ECGs at matching timepoints. Resting ECG data revealed sex differences that Holter data did not show. Specifically, women were found to have a longer QTcF of 20 ms, while men had a lower heart rate. We found that continuous recordings provided a more accurate reflection of changes in cardiac electrical activity over 24 hr. However, manual adjudication is still required to ensure the quality and accuracy of ECG data, and that only artifacts are removed thereby avoiding loss of true signals.

Orally administered moxifloxacin prolongs QTc in healthy Chinese volunteers: a randomized, single-blind, crossover study.

AIM: To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers. METHODS: This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin. RESULTS: The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects. CONCLUSION: Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers.

Cardiac safety of rasagiline, a selective monoamine oxidase type B inhibitor for the treatment of Parkinson's disease: a thorough QT/QTc study.

AIMS: Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor, developed for the treatment of Parkinson's disease. In compliance with current regulatory requirements, rasagiline underwent a thorough QT/QTc (TQT) study to assess its potential to prolong cardiac repolarization. The primary aim of this study was to evaluate the effects of clinical (1 mg/day) and supratherapeutic (2 mg/day and 6 mg/day) multiple oral doses of rasagiline on the baseline- and placebo-adjusted QTc interval (delta delta QTc (ddQTc)). Other electrocardiogram parameters, pharmacokinetic assessments, safety and tolerability as well as vital signs were investigated. METHODS: This was a five-arm, randomized, double-blind, placebo- and active-controlled, and parallel study in healthy subjects. Moxifloxacin (400 mg) positive control was included to demonstrate assay sensitivity. RESULTS: 247 of 250 randomized subjects completed the study. Time-matched analysis of ddQTc yielded two-sided 90% confidence intervals for all rasagiline doses below the 10 ms regulatory threshold, showing no effect on cardiac repolarization. Concentration-effect analysis demonstrated no relationships between rasagiline (and its metabolite 1-aminoindan), plasma concentrations, and ddQTc. The pharmacokinetic profile of rasagiline was consistent with previous studies. Adverse events were mild to moderate in intensity and were similar across all treatment groups. There were no clinically significant changes in heart rate and systolic blood pressure. CONCLUSION: This TQT study demonstrated a favorable cardiac safety profile of rasagiline.

Assessment of drug-induced increases in blood pressure during drug development: report from the Cardiac Safety Research Consortium.

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of blood pressure (BP) responses to drugs being developed for indications not of a direct cardiovascular (CV) nature. A wide range of drugs are associated with off-target BP increases, and both scientific attention and regulatory attention to this topic are increasing. The article provides a detailed summary of scientific discussions at a Cardiac Safety Research Consortium-sponsored Think Tank held on July 18, 2012, with the intention of moving toward consensus on how to most informatively collect and analyze BP data throughout clinical drug development to prospectively identify unacceptable CV risk and evaluate the benefit-risk relationship. The overall focus in on non-CV drugs, although many of the points also pertain to CV drugs. Brief consideration of how clinical assessment can be informed by nonclinical investigation is also outlined. These discussions present current thinking and suggestions for furthering our knowledge and understanding of off-target drug-induced BP increases and do not represent regulatory guidance.

Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study.

AIMS: To assess steady-state effects of therapeutic and supra-therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control. METHODS: A double-blind, double-dummy, placebo- and active-controlled study was conducted in 120 healthy male and female volunteers (NCT00903747). Volunteers were randomized to receive prucalopride 2-10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve-lead 24 h Holter ECGs recorded at various time-points were evaluated blind and centrally. RESULTS: Estimated mean difference in study specific corrected QT interval (QT(c)SS) time-matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl -0.33, 6.38 ms]). Upper limits of the two-sided 90% CI for QT(c)SS were all <10 ms. There were no outlying QT(c)SS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT(c)SS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time-points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min(-1)), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment. CONCLUSION: Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.

Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

Ozanimod is a novel, selective, oral sphingosine-1-phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double-blind, placebo-controlled, positive-controlled, parallel-group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of moxifloxacin 400 mg or placebo was administered on days 2 and 17. The primary end point was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF). A total of 113/124 (91.1%) subjects completed the study. The upper limits of the 2-sided 90% confidence intervals for ΔΔQTcF for both ozanimod 1 and 2 mg were below the 10-millisecond regulatory threshold. No QTcF >480 milliseconds or postdose change in QTcF of >60 milliseconds was observed. There was no evidence of a positive relationship between concentrations of ozanimod and its active metabolites and ΔΔQTcF. Although ozanimod blunted the observed diurnal increase in heart rate, excursions below predose heart rates were no greater than with placebo. Results demonstrate that ozanimod does not prolong the QTc interval or cause clinically significant bradycardia, supporting ozanimod's evolving favorable cardiac safety profile.

Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies.

PURPOSE: The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed. METHODS: In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory. RESULTS: A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib Cmax, were - 0.529 ms (90% CI - 6.621, 5.562) on day 1 and - 9.202 ms (90% CI - 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI - 1.343, 2.412) and 1.16 (90% CI - 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals. CONCLUSIONS: Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters. REGISTRATION: The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.

Electrocardiographic reference ranges derived from 79,743 ambulatory subjects.

BACKGROUND: Reference ranges for electrocardiogram (ECG) intervals, heart rate, and QRS axis in general use by medical personnel and ECG readers are unrepresentative of true age- and sex-related values in large populations and are not based on modern electrocardiographic and ECG reading technology. METHODS AND RESULTS: The results of ECG interpretation by cardiologists using digital technology for viewing and interpreting ECGs were compiled from single, baseline ECGs of 79,743 individuals included in pharmaceutical company-sponsored clinical trials. Women comprised 48% of the total population. Ages ranged from 3 months to 99 years, and the bulk of the population (56%) was aged 40 to 70 years. Striking differences in numerical ECG values based on age and sex were observed. A subgroup of 46,129 individuals with a very low probability of cardiovascular disease was identified. The following were the reference ranges for this subgroup, determined using the 2nd and 98th percentiles: heart rate, 48 to 98 beats/min; PR interval, 113 to 212 milliseconds; QRS interval, 69 to 109 milliseconds; frontal plane QRS axis, -40 degrees to 91 degrees ; QT interval, 325 to 452 milliseconds; QTc-Bazett, 361 to 457 milliseconds; and QTc-Fridericia, 359 to 445 milliseconds. There were marked age- and sex-related variations in the reference ranges of this subgroup, and they differ substantially from previously reported norms. Small differences were observed in ECG values obtained using our digital methods as compared with readings done using paper tracings and values computed by 2 commercial computer algorithms. CONCLUSIONS: We observed large differences in electrocardiographic heart rate, interval, and axis reference ranges in this study compared with those reported previously and with reference ranges in general use. We also observed a large influence of age and sex upon normal values. Very large cohorts are required to fully assess age- and sex-related variation of reference ranges. Electrocardiographic reference ranges should be modernized.

Population Pharmacokinetic-Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects.

PURPOSE: The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. METHODS: This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic-pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. FINDINGS: A total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration-effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin's pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An Emax model (E[C]=[Emax⋅C]/[EC50+C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic-pharmacodynamic link model. IMPLICATIONS: The drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316.

Safety, pharmacokinetic and pharmacodynamic properties of TV-1106, a long-acting GH treatment for GH deficiency.

BACKGROUND: TV-1106 (Teva Pharmaceuticals) is a genetically fused recombinant protein of human GH (hGH) and human serum albumin, in development for treatment of GH deficiency (GHD). TV-1106 is expected to have an extended duration of action compared to daily GH treatment and may enable a reduction in the frequency of injections and improve compliance and quality of life for adults and children requiring GHD therapy. OBJECTIVE: To assess the safety, local tolerability, pharmacokinetics and pharmacodynamics of TV-1106 following single s.c. injections in healthy male volunteers. METHODS: Subjects (n=56) were assigned to one of seven ascending dose groups (3-100 mg) and received either a single dose of TV-1106 (n=6) or placebo (n=2) by s.c. injection. RESULTS: Eighteen subjects reported 43 adverse effects (AEs), which were mild to moderate; no serious AEs (SAEs) occurred. In 50, 70 and 100 mg groups there were mild to moderate increases in heart rate and systolic blood pressure that significantly correlated with higher levels of IGF1. TV-1106 showed pharmacokinetic characteristics of a long-acting hGH as demonstrated by a terminal elimination half-life of 23-35 h, delayed time of peak concentration, and systemic levels seen up to 7 days after dosing. IGF1 levels increased in a dose-dependent manner, before reaching a plateau, with levels above baseline extending beyond 7 days post dose. CONCLUSION: Single administration of TV-1106 up to 100 mg was safe in healthy volunteers. Pharmacokinetics and pharmacodynamics support once-weekly administration in patients with GHD.

Safety, pharmacokinetics, and pharmacodynamics of TV-1380, a novel mutated butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects.

Human plasma butyrylcholinesterase (BChE) contributes to cocaine metabolism and has been considered for use in treating cocaine addiction and cocaine overdose. TV-1380 is a recombinant protein composed of the mature form of human serum albumin fused at its amino terminus to the carboxy-terminus of a truncated and mutated BChE. In preclinical studies, TV-1380 has been shown to rapidly eliminate cocaine in the plasma thus forestalling entry of cocaine into the brain and heart. Two randomized, blinded phase I studies were conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of TV-1380, following single and multiple administration in healthy subjects. TV-1380 was found to be safe and well tolerated with a long half-life (43-77 hours) and showed a dose-proportional increase in systemic exposure. Consistent with preclinical results, the ex vivo cocaine hydrolysis, TV-1380 activity clearly increased upon treatment in a dose-dependent manner. In addition, there was a direct relationship between ex vivo cocaine hydrolysis (kel ) and TV-1380 serum concentrations. There was no evidence that TV-1380 affected heart rate, the uncorrected QT interval, or the heart-rate-corrected QTcF interval. TV-1380, therefore, offers a safe once-weekly therapy to increase cocaine hydrolysis.

Clinical Development Approaches and Statistical Methodologies to Prospectively Assess the Cardiovascular Risk of New Antidiabetic Therapies for Type 2 Diabetes.

In December 2008, the US Food and Drug Administration (FDA) issued a guidance for industry requiring sponsors to demonstrate that a new antidiabetic therapy being developed to treat type 2 diabetes does not increase cardiovascular (CV) risk to an unacceptable extent. CV events reported during phase 2 and phase 3 trials should be prospectively and independently adjudicated. Before submission of a new drug application or biologics license application, sponsors should compare the incidence of major CV events occurring with the investigational agent versus the control group to show that the upper bound of the 2-sided 95% confidence interval (CI) for the estimated risk ratio is less than 1.8. If the CI includes 1.3, a postmarketing trial will be necessary to definitively show that the upper bound of the 95% CI for the estimated risk ratio is then less than 1.3. In 2012, the European Medicines Agency (EMA) issued an updated guideline on the clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus that detailed its CV safety assessment requirements. Although similar to the FDA guidance, the EMA guideline does not prospectively define any pre- or postapproval risk margins. This expert perspective, prepared by members of the Cardiac Safety Research Consortium, discusses clinical development strategies, operational issues, and statistical methodological issues to satisfy the FDA's CV safety requirements, and, where appropriate, the EMA guideline. Actual case examples, where applicable, are presented.

Cardiovascular safety and hemodynamic considerations in oncology drug development - webinar highlights October 10th 2012.

INTRODUCTION: Development of new drugs in oncology may have implications for cardiovascular risk. This report describes some aspects of our growing knowledge in the area of evaluating benefit-risk and may be of direct importance to scientists working in drug discovery and development. AREAS COVERED: This report of webinar highlights entitled "Trends in CardiOncology: the evolution of blood pressure and electrocardiogram (ECG) Markers" covers the current state of pharmacology of selected drugs which induce blood pressure elevation and best practices in employing the measurement of blood pressure elevation and cardiac safety parameters for drug development in oncology. EXPERT OPINION: Oncology drug-induced cardiotoxicity has recently been recognised as an important drug development and clinical issue. The recognition of the risks and opportunities has prompted intensive research into mechanisms of chemotherapy-induced cardiotoxicity and potential prevention strategies. Drug-induced blood pressure elevation has emerged as a key area of interest, both as a marker of efficacy of vascular targeted chemotherapies as well as a target for early intervention strategies. While further research is ongoing, current data strongly suggest that early intervention strategies may provide significant short- and long-term clinical benefits to cancer patients undergoing chemotherapy.