The alternating-sequence design (or multiple-period crossover) trial for evaluating treatment efficacy in infertility

OBJECTIVE: To determine whether a constant-sequence or an alternating-sequence design is better for the evaluation of infertility treatment efficacy when multiple cycles of treatment are undertaken. DESIGN: A simulation exercise using analytical methods. SETTING: University medical center. PATIENT(S): A hypothetical, heterogeneous population of infertile patients participating in a randomized trial comparing an experimental treatment, with effectiveness of 2.0, to no treatment. INTERVENTION(S): Comparison of a constant-sequence design in which the subject receives the same intervention or the alternating-sequence design in which experimental and control treatments are crossed over after each successive cycle. MAIN OUTCOME MEASURE(S): Relative risks of pregnancy per cycle and overall after a maximum of five cycles of treatment. RESULT(S): With both designs, the pregnancy rates in experimental and control groups showed a consistent decrease with each successive cycle. The overall effectiveness in the constant-sequence design was underestimated at 1.83, whereas in the alternating-sequence design it was overestimated at 2.06. However, by restricting the analysis in the latter design only to the odd-numbered cycles, the relative risk was precisely correct at 2.00. CONCLUSION(S): When multiple cycles of treatment are undertaken to evaluate the efficacy of infertility therapy, the alternating-sequence design with restriction of the analysis to only the odd-numbered treatment cycles provides an unbiased estimation of the treatment effect.