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.