Control of type 1 error in a hybrid complete two‐period vaccine efficacy trial

A complete two-period experimental design has been defined as one in which subjects are randomized to treatment, observed for the occurrence of an event of interest, re-randomized, and observed again for the event in a second period. A 4-year vaccine efficacy trial was planned to compare a high-dose vaccine with a standard dose vaccine. Subjects would be randomized each year, and subjects who had participated in a previous year would be allowed to re-enroll in a subsequent year and would be re-randomized. A question of interest is whether positive correlation between observations on subjects who re-enrolled would inflate the variance of test statistics. The effect of re-enrollment and correlation on type 1 error in a 4-year trial is investigated by simulation. As conducted, the trial met its power requirements after two years. Subjects therefore included some who participated for a single year and others who participated in both years. Those who participated in both years constituted a complete two-period design. An algebraic expression for the variance of the treatment difference in a complete two-period design is derived. It is shown that under a 'no difference' null, correlation does not result in variance inflation in this design. When there is a treatment difference, there is variance inflation but it is small. In the vaccine efficacy trial, the effect of correlation on the statistical inference was negligible.