Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘Table 2. Examples of high-order crossover trial designs.Design type Order Treatment sequenceTwo-sequence dual design 2 × 3 ABB, BAADoubled design 2 × 4 AABB, BBAABalaam’s design 4 × 2 AA, BB, AB, BAFour-sequence design 4 × 4 AABB, BBAA, ABBA, BAABWilliams’ design with three treatments 6 × 3 ABC, ACB, BAC, BCA, CAB, CBA3 × 3 Latin square design 3 × 3 ABC, BCA, CAB4 × 4 Latin square design 4 × 4 ABDC, BCAD, CDBA, DACBAdvantages of crossover trials over parallel studiesSince each subject in a crossover trial acts as his/her own control, there is anassessment of both (all) treatments in each subject. This means that treatmentdifferences can be based on within-subject comparisons instead of between-subjectcomparisons. As there is usually less variability within a subject than betweendifferent subjects, there is an increase in the precision of observations.Therefore, fewer subjects are required to detect a treatment difference. If N parallelis the total number of subjects required for a two-way parallel trial to detecta treatment effect (δ) with 5% significance and 80% power, then the totalnumber of subjects N crossoverrequired for a 2 × 2 crossover trial to detect the sameeffect (δ) is approximately:N crossover= (1 – r) N parallel/ 2where r is a correlation coefficient among the repeated measurements of theprimary endpoint in a crossover trial. The above equation indicates that as thecorrelation increases towards 1, fewer subjects are needed for a crossover trial.Figure 2 illustrates sample sizes for a crossover trial for some selected values of rand the sample size (N parallel= 100) required by a parallel design trial for detectingthe same clinical effect. The graph shows that:• A crossover trial only needs half the sample size of that used ina parallel trial if there is no correlation among repeated measurementsof the primary endpoint.• If the correlation coefficient is 50%, a crossover trial only needsa quarter of the sample size of a parallel design.• Sample size can be drastically reduced in a crossover trial if thecorrelation increases towards 1.95