Statistical Issues Including Design and Sample Size Calculation in Thorough QT/QTc Studies

Zhang, Joanne; Machado, Stella G.

doi:10.1080/10543400802020938

Cited by 92 publications

(87 citation statements)

References 18 publications

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“…Twenty-four-hour Holter ECGs were also obtained for baseline measurements on days -1, 36, and 72. On baseline days -1, 36, and 72, ECGs were extracted at 0.0 h (8 AM), 1,2,3,4,5,6,7,8,10,12,14, and 23 h after the 0.0-h time point. On days 9, 22, 45, 58, 81, and 94, ECGs were extracted at 0.0 h (pre-dose), 2-, 3-, 4-, 5-, 7-, 12-, and 23-h post-dose.…”

Section: Examplementioning

confidence: 99%

An efficient analysis of covariance model for crossover thorough QT studies with period‐specific pre‐dose baselines

Lu¹

2014

Pharmaceutical Statistics

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Baseline adjustment is an important consideration in thorough QT studies for non-antiarrhythmic drugs. For crossover studies with period-specific pre-dose baselines, we propose a by-time-point analysis of covariance model with change from pre-dose baseline as response, treatment as a fixed effect, pre-dose baseline for current treatment and pre-dose baseline averaged across treatments as covariates, and subject as a random effect. Additional factors such as period and sex should be included in the model as appropriate. Multiple pre-dose measurements can be averaged to obtain a pre-dose-averaged baseline and used in the model. We provide conditions under which the proposed model is more efficient than other models. We demonstrate the efficiency and robustness of the proposed model both analytically and through simulation studies. The advantage of the proposed model is also illustrated using the data from a real clinical trial.

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Section: Examplementioning

confidence: 99%

An efficient analysis of covariance model for crossover thorough QT studies with period‐specific pre‐dose baselines

Lu¹

2014

Pharmaceutical Statistics

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“…Provided serial ECG assessment and pharmacokinetic sampling are incorporated into the design, SAD and MAD studies represent an opportunity to generate ECG data with the same high quality as the TQT study [7][8][9]. Several doses of the investigational drug are typically administered to small cohorts with only six to eight subjects receiving active drug (and often only two per cohort receiving placebo), and the power to exclude small effects in a 'by timepoint' analysis for each dose group as in the TQT study is therefore unacceptably low [10]. If, on the other hand, exposure-response (ER) analysis is employed, all data across a wide range of plasma concentrations of the drug are used, and the power to detect and exclude small QT effects would be substantially improved [11].…”

Section: Introductionmentioning

confidence: 99%

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

et al. 2015

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Exposure-response (ER) analysis has evolved as an important tool to evaluate the effect of a drug on cardiac repolarization, as reflected in the QTc interval. It has been suggested that careful electrocardiogram (ECG) evaluation in 'first-in-human' studies using ER analysis could replace or serve as an alternative to the E14 'thorough QT' study. This commentary shares and discusses the results of a recently conducted study with the objective to evaluate this approach. Six drugs with a well-characterized QT effect, five of which are known QT prolongers, were evaluated in a study design similar to a conventional single-ascending-dose study. Each drug was given to nine healthy subjects (six for placebo) in two dose levels, which for the positive drugs (ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide) were chosen with the intent to cause 10-12 ms and 15-20 ms QTc prolongation. Replicate 12-lead ECGs were extracted from continuous recordings pre-dose and serially after dosing and paired with drug concentration determinations. The ER criteria for the identification of a QT effect, a statistically significant positive ER slope and an effect above 10 ms, were met with all five positive drugs, and an effect exceeding 10 ms could be excluded at the supratherapeutic dose of the negative drug, levocetirizine. The study results thereby provided evidence to support that careful QT assessment in early phase clinical studies can be used as an alternative to the thorough QT study. Clinical and regulatory implications, as well as limitations of this approach, are discussed in the commentary.

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“…The sample size of approximately 240 healthy male and female subjects was calculated by the summary means method of Zhang and Machado (18), and the study design was based on the ICH e-14 Guidance as well as direct recommendations from the FDA (3). Assuming a one-sided 0.05 significance level, an average SD of QTcF of 11 ms (observed from previous unpublished studies by the sponsor), up to 10 posttreatment assessment time points, and 3 replicate ECGs at each ECG assessment time point, a total of 60 subjects in each of the 4 treatments groups was deemed sufficient to achieve a !90% power to exclude a prolongation of !10 ms for all time-matched ddQTcF, also assuming a mean baseline-adjusted prolongation of 3 ms with placebo.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Repolarization Effects of Intravenous and Transdermal Granisetron

Mason

Selness

Moon

et al. 2012

Clinical Cancer Research

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Purpose: The need for greater clarity about the effects of 5-HT 3 receptor antagonists on cardiac repolarization is apparent in the changing product labeling across this therapeutic class. This study assessed the repolarization effects of granisetron, a 5-HT 3 receptor antagonist antiemetic, administered intravenously and by a granisetron transdermal system (GTDS).Experimental Design: In a parallel four-arm study, healthy subjects were randomized to receive intravenous granisetron, GTDS, placebo, or oral moxifloxacin (active control). The primary endpoint was difference in change from baseline in mean Fridericia-corrected QT interval (QTcF) between GTDS and placebo (ddQTcF) on days 3 and 5.Results: A total of 240 subjects were enrolled, 60 in each group. Adequate sensitivity for detection of QTc change was shown by a 5.75 ms lower bound of the 90% confidence interval (CI) for moxifloxacin versus placebo at 2 hours postdose on day 3. Day 3 ddQTcF values varied between 0.2 and 1.9 ms for GTDS (maximum upper bound of 90% CI, 6.88 ms), between À1.2 and 1.6 ms for i.v. granisetron (maximum upper bound of 90% CI, 5.86 ms), and between À3.4 and 4.7 ms for moxifloxacin (maximum upper bound of 90% CI, 13.45 ms). Day 5 findings were similar. Pharmacokinetic-ddQTcF modeling showed a minimally positive slope of 0.157 ms/(ng/mL), but a very low correlation (r ¼ 0.090).Conclusion: GTDS was not associated with statistically or clinically significant effects on QTcF or other electrocardiographic variables. This study provides useful clarification on the effect of granisetron delivered by GTDS on cardiac repolarization.

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Statistical Issues Including Design and Sample Size Calculation in Thorough QT/QTc Studies

Cited by 92 publications

References 18 publications

An efficient analysis of covariance model for crossover thorough QT studies with period‐specific pre‐dose baselines

An efficient analysis of covariance model for crossover thorough QT studies with period‐specific pre‐dose baselines

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

Pharmacokinetics and Repolarization Effects of Intravenous and Transdermal Granisetron

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