Fig 1.
Illustration of the design and analysis of a crossover trial.
Carryover effect: If A is an active intervention and B is a placebo, then the BA sequence is unlikely to be affected by a carryover effect, but the AB sequence is potentially susceptible. In the AB sequence, when some effect of the active intervention A is carried over to the second period, placebo could demonstrate artificial “effectiveness”. Under this scenario, the treatment effect of A compared to B would be under-estimated for the AB sequence, and so for both sequences combined [7]. Thus, if there are differential carryover effects in the two treatment sequences, the design can yield biased estimates of the treatment effect [1–4]. Washout period: To minimize a possible carryover effect between periods in a crossover trial, investigators use a “washout” phase that is sufficiently long to eliminate the first intervention’s effects [1, 2]. Although some researchers have recommended estimating and testing for the carryover effect, and when the effect is present, analyzing data collected from the first period only, this method has been shown to lead to biased estimates of effect [9]. Senn and others have taken the position that the crossover design should be used only when the assumption that there is a minimal carryover effect is likely to hold [1]. In such cases, instead of testing for carryover effect, one proceeds as if there were none. There also is the ethical consideration with using a washout period in participants with a chronic condition; in such cases, giving no treatment may not be in a participant’s best interests.
Table 1.
Analysis of a crossover trial–an illustrative example.
Table 2.
Results of the illustrative crossover trial presented in Table 1.
Table 3.
Reported design characteristics of included crossover trials (n = 83).
Table 4.
Reported analysis characteristics of included crossover trials (n = 83).
Table 5.
Reporting of results of included crossover trials (n = 83).
Table 6.
Number of crossover trials that would be included in a meta-analysis, assuming inclusion based on different design and analysis characteristics (n = 83).
Table 7.
Reporting of continuous outcomes from a two-treatment, two-period crossover trial.