44
Views
6
CrossRef citations to date
0
Altmetric
Review

Design and analysis considerations for thorough QT studies employing conventional (10 s, 12-lead) ECG recordings

, &
Pages 815-839 | Published online: 10 Jan 2014

References

  • Lepeschkin E, Surawicz B. The measurement of the Q-T interval of the electrocardiogram. Circulation6, 378–388 (1952).
  • Malik M, Farbom P, Batchvarov V, Hnatkova, Camm AJ. Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval. Heart87, 220–228 (2002).
  • Malik M, Camm AJ. Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling. Drug Saf.24, 323–351 (2001).
  • Malik M, Andreas J-O, Hnatkova K et al. Thorough QT/QTc study in patients with advanced Parkinson’s disease: cardiac safety of rotigotine. Clin. Pharmacol. Ther. DOI 10.1038/clpt.2008.143 (2008) (Epub ahead of print).
  • Malik M. Problems of heart rate corrections in assessment of drug induced QT interval prolongation. J. Cardiovasc. Electrophysiol.12, 411–420 (2001).
  • Burke JH, Ehlert FA, Kruse JT, Parker MA, Goldberger JJ, Kadish AH. Gender-specific differences in the QT interval and the effect of autonomic tone and menstrual cycle in healthy adults. Am. J. Cardiol.79, 178–181 (1997).
  • Hulot J-S, Demolis J-L, Riviere R, Strabach S, Christin-Maitre S, Funck-Brentano C. Influence of endogenous oestrogens on QT interval duration. Eur. Heart J.24, 1663–1667 (2003).
  • Kadish AH, Greenland P, Limacher MC, Frishman WH, Daugherty SA, Schwartz JB. Estrogen and progestin use and the QT interval in postmenopausal women. Ann. Noninvasive Electrocardiol.9, 366–374 (2004).
  • Nakagawa M, Ooie T, Takahashi N et al. Influence of menstrual cycle on QT interval dynamics. Pacing Clin. Electrophysiol.29, 607–613 (2006).
  • Rodriguez I, Kilboron MJ, Liu X-K, Pezzullo JC, Woosley RL. Drug-induced QT prolongation in women during the menstrual cycle. JAMA285, 1322–1326 (2001).
  • Benton RE, Sale M, Flockhart DA, Woosley RL. Greater quinidine-induced QTc interval prolongation in women. Clin. Pharmacol. Ther.67, 413–418 (2000).
  • Drici M-D, Knollmann BC, Wang W-X, Woosley RL. Cardiac actions of erythromycin. JAMA280, 1774–1776 (1998).
  • Drici M-D, Clement N. Is gender a risk factor for adverse drug reactions? Drug Saf.24, 575–585 (2001).
  • Ebert SN, Liu X-K, Woosley RL. Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. J. Womens Health7, 547–557 (1998).
  • El-Eraky H, Thomas SHL. Effects of sex on the pharmacokinetic and pharmacodynamic properties of quinidine. Br. J. Clin. Pharmacol.56, 198–204 (2003).
  • Johansson M, Carlsson L. Female gender does not influence the magnitude of ibutilide-induced repolarization delay and incidence of torsades de pointes in an in vivo rabbit model of acquired long QT syndrome. J. Cardiovasc. Pharmacol. Ther.6, 247–254 (2001).
  • Lu HR, Marien R, Saels A, De Clerk F. Are there sex-specific differences in ventricular repolarization or in drug induced early afterdepolarizations in isolated rabbit purkinje fibers? J. Cardiovasc. Pharmacol.36, 132–139 (2000).
  • Lu HR, Remeysen P, Somers K, Saels A, De Clerk F. Female gender is a risk factor for drug-induced long QT and cardiac arrhythmias in an in vivo rabbit model. J. Cardiovasc. Electrophysiol.12, 538–545 (2001).
  • Shin JG, Kang WK, Shon JH et al. Possible interethnic differences in quinidine-induced QT prolongation between healthy Caucasian and Korean subjects. Br. J. Clin. Pharmacol.63(2), 206–215 (2007).
  • Williams EJ. Experimental designs balanced for the estimation of residual effects of treatments. Aust. J. Sci. Res. (A)2, 149–168 (1949).
  • Malik M, Hnatkova K, Batchvarov V, Gang Y, Smetana P, Camm J. Sample size, power calculations, and their implications for the cost of thorough studies of drug induced QT interval prolongation. Pacing Clin. Electrophysiol.27, 1659–1669 (2004).
  • Zhang L, Smith B. Sex differences in QT interval variability and implication on sample size of thorough QT studies. Drug Inf. J.5, 619–628 (2007).
  • Zhang L, Dmitrienko A, Luta G. Sample size calculations in thorough QT studies. J. Biopharm. Stat.18, 468–482 (2008).
  • Extramiana F, Maison-Blanche P, Cabanis MJ, Ortemann-Renon C, Beaufils P, Leenhardt A. Clinical assessment of drug-induced QT prolongation in association with heart rate changes. Clin. Pharmacol. Ther.77, 247–258 (2005).
  • Serra DB, Affrime MB, Bedigian MP et al. QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M3 selective receptor antagonist for the treatment of overactive bladder. J. Clin. Pharmacol.45, 1038–1047 (2005).
  • Malhotra BK, Glue1 P, Sweeney K, Anziano R, Mancuso J, Wicker P. Thorough QT study with recommended and supratherapeutic doses of tolterodine. Clin. Pharmacol. Ther.81, 377–385 (2007).
  • Beasley CM, Mitchell MI, Dmitrienko AA et al. The combined use of ibutilide as an active control with intensive ECG sampling and signal averaging as a sensitive method to assess the effects of tadalafil on the human QT interval. J. Am. Coll. Cardiol.46, 678–687 (2005).
  • Zhang L, Chappell J, Gonzales C et al. QT effects of duloxetine at supratherapeutic doses: a placebo and positive controlled study. J. Cardiovasc. Pharmacol.49, 146–153 (2007).
  • Morganroth J. Design and conduct of the thorough Phase I ECG trial for new bioactive drugs. In: Cardiac Safety of Noncardiac Drugs. Morganroth J, Gussak I (Eds). Humana Press, NY, USA (2005).
  • Sarapa N, Nickens DJ, Raber SR, Reynolds RR, Amantea MA. Ritonavir 100 mg does not cause QTc prolongation in healthy subjects: a possible role as CYP3A inhibitor in thorough QTc studies. Clin. Pharmacol. Ther.83, 153–159, 2008.
  • Demolis J-L, Kubitza D, Tenneze L et al. Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects. Clin. Pharmacol. Ther.68, 658–666 (2000).
  • Nagy D, DeMeersman R, Gallagher D et al. QTc interval (cardiac repolarization): lengthening after meals. Obes. Res.5, 531–537 (1997).
  • Morganroth J, Ilson BE, Shaddinger BC et al. Evaluation of vardenafil and sidefanil on cardiac repolarization. Am. J. Cardiol.93, 1378–1383 (2004).
  • Bazett HC. An analysis of time relation of electrocardiograms. Heart20, 174–195 (1920).
  • Fridericia LS. The duration of systole in an electrocardiogram in normal humans and in patients with heart disease. Ann. Noninvasive Electrocardiol.8, 343–351 (2003)
  • Sagie A, Larson MG, Goldberg RJ, Bengtson JR, Levy D. An improved method for adjusting the QT interval for heart rate (the Framingham heart study). Am. J. Cardiol.70, 797–801 (1992).
  • Dmitrienko A, Smith B. Analysis of QT interval in clinical trials. Drug Inf. J.36, 269–279 (2002).
  • Dmitrienko A, Smith B. Repeated-measures models in the analysis of QT interval. Pharm. Stat.2, 175–190 (2003).
  • Hollister AS, Montague TH. Statistical analysis plans for ECG data: controlling the intrinsic and extrinsic variability in QT data. In: Cardiac Safety of Noncardiac Drugs. Morganroth J, Gussak I (Eds). Humana Press, NY, USA (2005).
  • Ma H, Smith B, Dmitrienko A. Statistical analysis methods for QT/QTc prolongation. J. Biopharm. Stat.18, 553–563 (2008).
  • Shah A, Hajian G. A maximum likelihood approach for estimating the QT correction factor using mixed effects model. Stat. Med.22, 1901–1909 (2003).
  • Morganroth J, Brozovich FV, McDonald JT, Jacobs RA. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am. J. Cardiol.67, 774–776 (1991).
  • Extramiana F, Maison-Blanche P, Badilini F, Pinoteau J, Deseo T, Coumel P. Circadian modulation of QT rate dependence in healthy volunteers. J. Electrocardiol.32, 33–43 (1999).
  • Patterson S, Jones B, Zariffa N. Modeling and interpreting QTc prolongation in clinical pharmacology studies. Drug Inf. J.39, 437–445 (2005).
  • Berger RL. Multiparameter hypothesis testing and acceptance sampling. Technometrics.24, 295–300 (1982).
  • Offen W, Chuang-Stein C, Dmitrienko A et al. Multiple co-primary endpoints: Medical and statistical solutions. A report from the Multiple Endpoints Expert Team of the Pharmaceutical Research and Manufacturers of America. Drug Inf. J.41, 31–46 (2007).
  • Patterson S, Agin M, Anziano R et al. Investigating drug-induced QT and QTc prolongation in the clinic: a review of statistical design and analysis considerations. Report from the Pharmaceutical Research and Manufacturers of America QT Statistics Expert Team. Drug Inf. J.39, 243–266 (2005).
  • Hutmacher MM, Chapel S, Agin M, Fleishaker JC, Lalonde RL. Performance characteristics for some typical QT study designs under the ICH E-14 guidance. J. Clin. Pharmacol.48, 215–224 (2008).
  • Eaton ML, Muirhead RJ, Mancuso JY, Lolluri S. A CI for the maximal mean QT interval change due drug effect. Drug Inf. J.40, 267–271 (2006).
  • Boos D, Hoffman D, Kringle R, Zhang J. New confidence bounds for QT studies. Stat. Med.26, 3801–3817 (2007).
  • Westfall PH, Young SS. Resampling-based Multiple Testing: Examples and Methods for P-value Adjustment. Wiley, NY, USA (1993).
  • Sethuraman V, Sun Q. Impact of baseline ECG collection on the planning, analysis and interpretation of ‘thorough’ QT trials. Pharm. Stat. DOI 10.1002/pst.338 (2008) (Epub ahead of print).
  • Burnham KP, Anderson DR. Model Selection and Multimodel Inference: A Practical Information-Theoretic Approach (2nd Edition). Springer, NY, USA (2002).
  • Garnett CE, Beasley N, Bhattaram VA et al. Concentration-QT relationships play a key role in evaluation of proarrhythmic risk during regulatory review. J. Clin. Pharmacol.48, 13–18 (2008).
  • Tsong Y, Shen M, Zhong J, Zhang J. Statistical issues of QT prolongation assessment based on linear concentration modeling. J. Biopharm. Stat.18, 564–584 (2008).
  • Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin. Pharmacol. Ther.73, 292–303 (2003).
  • Noel GJ, Goodman DB, Chien S, Solanki B, Padmanabhan M, Natarajan J. Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings. J. Clin. Pharmacol.44, 464–473 (2004).
  • Extramiana F, Maison-Blanche P, Cabanis M-J, Ortemann-Renon C, Beaufils P, Leenhardt A. Clinical assessment of drug-induced QT prolongation in association with heart rate changes. Clin. Pharmacol. Ther.77, 247–258 (2005).
  • Hulhoven R, Rosillon D. Levoceririzine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study. Eur. J. Clin. Pharmacol.63, 1011–1017 (2007).
  • Kubitza D, Mueck W, Becka M. Randomized, double-blind, crossover study to investigate the effect of rivarobaxan on QT-interval prolongation. Drug Saf.31, 67–77 (2008).
  • Davis JD, Hackman F, Layton G, Higgins T, Sudworth D, Weissgerber G. Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects. Br. J. Clin. Pharmacol.65(Suppl. 1), 68–75 (2008).
  • Iwamoto M, Kost JT, Mistry GC et al. Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. J. Clin. Pharmacol.48, 726–733 (2008).
  • Hulhoven R, Rosillon D, Bridson WE, Meeus M-A, Salas E, Stockis A. Effect of levetiracetam on cardiac repolarization in healthy subjects: a single-dose, randomized, placebo- and active-controlled, four-way crossover study. Clin. Ther.30, 260–270 (2008).
  • Peeters M, Janssen K, Kakuda TN et al. Etravirine has no effect on QT and corrected QT interval in HIV-negative volunteers. Ann. Pharmacother.42, 757–765 (2008).
  • Dixon R, Job S, Oliver R et al.Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects. Br. J. Clin. Pharmacol.66, 396–404 (2008).
  • Rosillon D, Astruc B, Hulhoven R et al. Effect of brivaracetam on cardiac repolarization. Curr. Med. Res. Opin.24, 2327–2337 (2008).

Websites

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.