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Rochester, NY, United States
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Shumaker R.C.,Clinical Pharmacology and Translational Medicine | Zhou M.,iCardiac Technologies | Ren M.,Clinical Pharmacology and Translational Medicine | Fan J.,Clinical Pharmacology and Translational Medicine | And 4 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: QT assessment of oncology drugs is generally challenging because they are genotoxic and, of necessity, they require multisite evaluation in cancer patients. Lenvatinib is not genotoxic, therefore, this thorough QT (TQT) study with lenvatinib, a multityrosine kinase inhibitor, was undertaken utilizing healthy volunteers and concentration-effect modeling to project the TQT effect at high plasma levels. Methods: Fifty-two healthy subjects randomly received single doses of lenvatinib 32 mg, placebo, or moxifloxacin 400 mg in a three-way crossover study. Serial electrocardiograms were recorded, and the effect on placebo-corrected change-from-baseline QTcF (ΔΔQTcF) was evaluated. The relationship between lenvatinib plasma concentrations and QTcF was analyzed with linear mixed-effects modeling. Results: Lenvatinib mildly lowered the heart rate by 5-8 bpm during the first 12 h after dosing. ΔΔQTcF was shortened with a peak effect of -5.72 ms (90 % confidence interval (90 % CI) -7.76 to -3.69 ms) at 6 h postdosing. The upper bound of mean ΔΔQTcF did not exceed 2 ms at any time point postdosing. A concentration-dependent effect of lenvatinib on ΔΔQTcF was identified with an estimated population intercept of -2.96 ms (90 % CI -4.49 to -1.43 ms; P = 0.0016) and a negative slope of -0.0045 (90 % CI -4.49 to -1.43) ms per ng/mL, respectively. The safety profile after a single dose of lenvatinib was acceptable, with adverse events (AEs) of mild-to-moderate severity and no serious AEs. Conclusions: Lenvatinib had no clinically relevant effect on the QTc interval. Concentration-effect modeling supports the lack of QTc prolongation at high plasma concentrations. © 2014 Springer-Verlag.

Ferber G.,Statistik Georg Ferber GmbH | Zhou M.,iCardiac Technologies | Darpo B.,iCardiac Technologies | Darpo B.,Karolinska Institutet
Annals of Noninvasive Electrocardiology | Year: 2015

Background ECG assessment with exposure response analysis applied to data from First-in-Man studies has been proposed to replace the thorough QT study for the detection of small QT effects. Methods Data from five thorough QT studies, three with moxifloxacin, one study with a drug with a large QTc effect (25 ms) and one with ketoconazole with a smaller QT effect (8 ms) were used. By subsampling, studies with 6-18 subjects on drug and six on placebo were simulated 1000 times per sample size to assess whether small QTc effects using ICH E14 criteria could be excluded and the impact of sample size on the estimate and variability of the slope of the concentration/QTc relation. Results With a sample size of nine or more on drug and six on placebo, the fraction of "false negative studies" was at or below 5% with data from the studies with moxifloxacin and from the drug with a large QTc effect. With the same sample size and no underlying QTc effect (placebo), the fraction of studies in which an effect above 10 ms could be excluded was above 85%. A treatment effect in the linear concentration-effect model resulted in a lower proportion of "false negatives." Sample size had little influence on the average slope estimate of the concentration/QTc relationship. Conclusions For drugs with a QTc effect of around 12-14 ms, exposure response analysis applied to First-in-Man studies with careful ECG assessment can be used to replace the through QT study. © 2014 Wiley Periodicals, Inc.

Said T.H.,Case Western Reserve University | Wilson L.D.,Case Western Reserve University | Jeyaraj D.,Case Western Reserve University | Fossa A.A.,iCardiac Technologies | Rosenbaum D.S.,Case Western Reserve University
Journal of Cardiovascular Pharmacology | Year: 2012

Torsade de Pointes (TdP) proarrhythmia is a major complication of therapeutic drugs that block the delayed rectifier current. QT interval prolongation, the principal marker used to screen drugs for proarrhythmia, is both insensitive and nonspecific. Consequently, better screening methods are needed. Drug-induced transmural dispersion of repolarization (TDR) is mechanistically linked to TdP. Therefore, we hypothesized that drug-induced enhancement of TDR is more predictive of proarrhythmia than QT interval. High-resolution transmural optical action potential mapping was performed in canine wedge preparations (n = 19) at baseline and after perfusion with 4 different QT prolonging drugs at clinically relevant concentrations. Two proarrhythmic drugs in patients (bepridil and E4031) were compared with 2 nonproarrhythmic drugs (risperidone and verapamil). Both groups prolonged the QT (all P < 0.02), least with the proarrhythmic drug bepridil, reaffirming that QT is a poor predictor of TdP. In contrast, TDR was enhanced only by proarrhythmic drugs (P < 0.03). Increased TDR was due to a preferential prolongation of midmyocardial cell, relative to epicardial cell, APD, whereas nonproarrhythmic drugs similarly prolonged both cell types. In contrast to QT prolongation, augmentation of TDR was induced by proarrhythmic but not nonproarrhythmic drugs, suggesting TDR is a superior preclinical marker of proarrhythmic risk during drug development. Copyright © 2012 by Lippincott Williams & Wilkins.

Dunne M.W.,Durata Therapeutics | Zhou M.,iCardiac Technologies | Darpo B.,iCardiac Technologies | Darpo B.,Karolinska Institutet
International Journal of Antimicrobial Agents | Year: 2015

Two hundred healthy subjects were enrolled in a randomised, partially double-blinded, single-centre, parallel design thorough QT study to demonstrate that dalbavancin had no clinical effect on the 12-lead ECG QTc. Fifty patients in each group received either dalbavancin 1000 mg intravenous (i.v.), dalbavancin 1500 mg i.v. or placebo i.v., each infused over 30 min, or 400 mg oral moxifloxacin. Ten replicate 12-lead ECGs were extracted at pre-defined time points before and up to 24 h post dosing and at corresponding time points during baseline. Dalbavancin did not have an effect on the QTcF interval, and an effect exceeding 10 ms could be excluded at all time points after a single i.v. dose of 1000 mg and 1500 mg. The largest placebo-corrected change-from-baseline QTcF (ΔΔQTcF) was 1.5 ms in the 1000 mg dalbavancin group at 6 h and 0.2 ms in the 1500 mg group at 24 h. A small concentration-dependent effect of dalbavancin on ΔΔQTcF was identified with an estimated negative population slope of -0.0051 ms per μg/mL. Assay sensitivity was demonstrated by the effect of 400 mg moxifloxacin, which peaked at 2 h at ΔΔQTcF of 12.9 ms, with the lower bound of the 90% CI of the effect exceeding 5 ms at all three pre-defined time points. Dalbavancin did not exert a relevant effect on heart rate or PR or QRS intervals. Dalbavancin in i.v. doses up to 1500 mg did not prolong the QTc interval and had no effect on heart rate or PR and QRS intervals. © 2015 The Authors. Published by Elsevier B.V. on behalf of International Society of Chemotherapy.

Darpo B.,Karolinska Institutet | Darpo B.,iCardiac Technologies
Handbook of Experimental Pharmacology | Year: 2015

With the adoption of the ICH E14 guidance, the thorough QT/QTc (TQT) study has become the focus of clinical assessment of an NCE’s effects on ECG parameters. The TQT study is used as a guide to the liability of a drug to cause proarrhythmias on the basis of delayed cardiac repolarization. Around 300 TQT studies have been performed since 2005 and through interactions between sponsors and regulators, especially FDA’s Interdisciplinary Review Team (IRT) for QT studies. These studies can today be performed more effectively and with great confidence in the generated data. This chapter will discuss technical features and the design and analysis of TQT studies, how assay sensitivity is demonstrated, and examples from recently conducted studies. ECG assessment for drugs that cannot be safely given to healthy volunteers is also addressed, and examples from studies in cancer patients and in healthy volunteers with tyrosine kinase inhibitors are discussed. The TQT study is resource intensive and designed to solely evaluate whether an NCE prolongs the QTc interval. If data with similar confidence can be generated from other studies that are routinely performed as part of the clinical development, this would represent a more optimal use of human resources. Methods and approaches to increase the confidence in ECG data derived from “early QT assessment” in single-ascending/multiple-ascending dose studies are therefore discussed, and a path toward replacing the TQT study using these approaches will be outlined. © Springer-Verlag Berlin Heidelberg 2015.

Fossa A.A.,iCardiac Technologies | Zhou M.,iCardiac Technologies | Brennan N.,Xention Ltd | Round P.,Xention Ltd | Ford J.,Xention Ltd
Annals of Noninvasive Electrocardiology | Year: 2014

Background: Standing invoked change in QT interval has been identified as a promising autonomic maneuver for the assessment of QT/QTc prolongation in patients with underlying heart abnormalities or as a positive control in healthy volunteers for drug studies. Criticism for its more widespread use is the high variability in reported results and the need for a more standardized methodology with defined normal ranges. Methods: Forty healthy male subjects underwent continuous ECG collection on the day before dosing in a double-blind, placebo-controlled, randomized, single ascending dose trial. A brisk supine to standing (3 minutes) response was conducted at three time points. Results: were grouped by treatment cohort or assessed as a pooled group at each time point. Maximum time and median change from baseline (ΔTmaxQTcF, ΔQTcF) were calculated for each individual over sequential 30-second periods staggered by 5 seconds. Results: Maximum ΔQTcF at all time points and in all groups was significant (i.e., the lower bound of 90% CI was > 5 milliseconds) which is the ICH E14 regulatory requirement for a positive control. Variability of the time to maximum response was also reduced 9-fold by the third time period. Conclusions: Standing invoked ΔQTcF can be utilized to validate the sensitivity of a study for assessment of the QT interval effect of drugs in early development. The methodology may be used to further improve its diagnostic use of long QT syndromes by reducing the variability and allowing adequate definition of normal limits. ©2013 Wiley Periodicals, Inc.

Fossa A.A.,iCardiac Technologies | Zhou M.,iCardiac Technologies | Robinson A.,Shire Pharmaceuticals | Purkayastha J.,Shire Pharmaceuticals | Martin P.,Shire Pharmaceuticals
Annals of Noninvasive Electrocardiology | Year: 2014

Background Guanfacine (Intuniv) is a centrally active alpha-2A adrenergic agonist for the new indication of attention-deficit/hyperactivity disorder. QTc (QTcF and QTcNi) was prolonged at both therapeutic (4 mg) and supratherapeutic (8 mg) doses of a thorough QT study even though guanfacine has had a safe clinical history of over 3 million prescriptions for the treatment of hypertension. In an attempt to understand this disparity, retrospective evaluation of the continuous ECG data utilized dynamic beat-to-beat and ECG restitution analyses was performed. Methods Sixty healthy subjects using 24-hour Holters were examined in a 3-arm, placebo- and positive-controlled, double-blind crossover study for effects on beat-to-beat QT, TQ, and RR intervals. Results ECG restitution analyses indicated that, at all time points, a disproportionate effect to increase the TQ interval (rest) occurred more in relationship to each QT interval lengthening resulting in a placebo-adjusted reduced QT/TQ ratio of 21% after 4 mg and 31% after 8 mg (both antiarrhythmic responses). Additionally, the percentage of time and magnitude of stress on the heart, as measured by the upper limits of the QT/TQ ratio, were reduced with guanfacine by 22% to 24%. In contrast to guanfacine, moxifloxacin did not show a significant improvement in any restitution parameters but reflected a trend toward proarrhythmia with an increase in the QT/TQ ratio of up to 11%. Conclusion These results indicate that guanfacine causes a stabilizing effect on cardiac restitution that helps reconcile the clinical evidence for a lack of arrhythmia liability despite apparent increases in typical QT/QTc prolongation measures. © 2014 Wiley Periodicals, Inc.

News Article | March 6, 2014

iCardiac Technologies, Inc., a Palo Alto, CA-based global provider of cardiac safety assessment services, received an equity funding from Norwest Venture Partners. The amount of the transaction was not disclosed. In conjunction with the funding, two of NVP’s Dr. Ryan Harris and Dr. Robert Mittendorff, will join the iCardiac’s board of directors. The company will leverage the resources to pursue growth opportunities and expand its pharmaceutical and medical device clients worldwide. Led by Mikael Totterman, chief executive officer, iCardiac has developed proprietary technology that allows CROs and pharmaceutical sponsors to obtain cardiac safety assessment results with less variance of the average (according to 2013, the average cost to develop a new drug is about $1.2B and requires 10 to 15 years of development time). The platform aims to maximize precision and accuracy while decreasing the cost of cardiac safety assessments from First-in-Human studies to Phase III studies, including Thorough QT (TQT) studies. The company currently serves seven of the world’s 10 largest pharmaceutical companies, as well as numerous medium and small biotech, pharmaceutical and medical device clients.

News Article | February 22, 2017

iCardiac Technologies, Inc. announced today that it has launched QPoint, its next-generation eCOA platform, to address the growing demand for more efficient and innovative eCOA study services in drug development. In addition to a number of other benefits, QPoint delivers the shortest and most streamlined study configuration and startup in the industry. Electronic Clinical Outcome Assessment (eCOA) services support the collection of observations from patients, clinicians, or caregivers during clinical trials to help assess the impact of a new drug. iCardiac’s QPoint can measure clinical outcome assessments both directly from patients at home or during trial site visits. Capitalizing on more than a decade of experience in the eCOA space, iCardiac set out to address key industry challenges such as long study startup times. The QPoint platform is engineered for rapid configuration to clinical trial protocols, saving multiple weeks – or more – in the study startup cycle. This is accomplished by study team members being able to customize study questionnaires and how they will appear on devices in real time through RapidStart, an interactive study setup and validation portal. “Clinical trial sites and sponsors also need to have up-to-date information at their fingertips,” said Thuan Pham, Director of Software Development at iCardiac, who led the QPoint engineering team. “Our advanced reporting tool allows for timely decisions throughout the study." Other key features include a fully-integrated backend dashboard that delivers eCOA compliance data along with any corresponding respiratory and cardiac safety information. QPoint can also remotely and automatically update devices worldwide, which enables rapid, reliable deployment of all patient devices and applicable software. State-of-the-art hardware and a comprehensive pool of global network service providers ensure maximum connectivity and reliability for handheld devices. iCardiac’s global 24/7 customer support team has also been dramatically expanded to accommodate direct-to-patient troubleshooting for home-based eCOA devices. “The QPoint platform represents a major leap forward for iCardiac, our sponsors and the eCOA industry as a whole,” said Alex Zapesochny, President & CEO of iCardiac. “QPoint was built to squarely address the most pressing challenges in the use of eCOA services, and to unleash a new era of productive innovation in the industry for the benefit of drug developers and healthcare consumers.” About iCardiac Technologies: iCardiac Technologies, Inc. is an industry-leading centralized core laboratory for eCOA, respiratory and cardiac safety clinical trial services. Its largest eCOA study involved 200 sites and 1.5 million patient submissions in more than 30 countries. iCardiac serves 8 of the top 10 global pharmaceutical companies, as well as numerous small and mid-sized pharma and biotechnology firms. For more information, please visit:

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