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Background: Thorough QT studies are typically a requirement of the clinical development program for new investigational drugs. These studies are a major cost factor in early development. The objectives of a typical thorough QT study (TQT) are to demonstrate (a) that therapeutic and supra-therapeutic doses of a new investigational drug do not prolong the ECG QT interval compared to placebo and (b) that an active control does show QT prolongation compared to placebo. In recent years, statistical research has led to substantial improvements in the design and analysis of these studies. We show one example of a recently developed, efficient study design. Methods: TQT studies conventionally follow a crossover design based on a Williams square of order four, as four treatments must be investigated. This design can be improved, since all comparisons in this design are active versus placebo. Hence it is efficient to double the number of placebo periods for each subject in order to reduce the sample size and the overall study costs. Several options for implementing this design are discussed and the preferred option is given. In addition, the corresponding changes in the analysis that are required to account for the multiple placebo periods are shown. Conclusions: Using a five period, four treatment design can lead to a reduction in the study costs of around 10%. Moreover, the number of active treatments administered is reduced which is a potential advantage for the investigation of drugs with a critical safety profile.

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. [ABSTRACT FROM AUTHOR]

Presents letters to the editor on various medical topics as of January 19, 2002. Errors which were found in an article disputing findings of a meta-analysis of antiplatelet trials which shows that low dose aspirin reduces non-fatal myocardial infarction; Ways the General Medical Council (GMC) may deal with complaints; GMC member who was forced to stand down from a disciplinary panel; Maintaining the integrity of the scientific record; Anesthetic machines and anti-hypoxia devices; Safety of acupuncture.