Power-by-simulation approach
STAGGERED
Simulations were conducted to determine the appropriate sample size to achieve target level of power for the main objectives as well as to confirm that the procedures related to the interim analysis will not compromise type I error rate [Mortality among 1–11-month-(29–364 days)-old children in control group of 20 deaths/1000 PYR.Justification for the baseline mortality estimate and respective assumptions on reduction in mortality had been described in separate protocol article [Mortality in the two-dose AZI intervention group 16/1000 (20% relative reduction)Mortality in the four-dose AZI intervention group 12/1000 (40% lower than control, 25% lower than two-dose AZI)Two-year intervention with eight quarterly cycles of MDA for 50% of clusters, seven rounds for 30%, and six rounds for 20%, due to staggered entry but equal stopping calendar date.Coefficient of variation (k = sd/mean) (CV) of 0.1 in mortality among clusters.According to our estimate of 20 deaths/1000 PYR, the intra-cluster correlation (ICC) is estimated to be 0.0001 according to the findings of Gulliford et al. [Unequal number of infants per cluster: on average, 22 infants in a small village and 70 in a big village. Average for number of infants in a village being 31.Average number of infants in small and big villages (respectively) was simulated with Poisson process. Based on prior information from local census data, we inferred the mean size to be 22 for small villages and 70 for big villages.From the same data, we inferred the proportions for big and small villages to be 18% and 82%, respectively.Sample size of 1150 villagesUnequal ratio of clusters. Control vs AZI-biannual vs AZI-quarterly = 3: 4: 2One interim analysis when 60% of the planned 3-month time intervals have been completed.One-sided 2.5% type 1 error, controlling of multiple pairwise comparisons by the closed-testing procedureClosed-testing procedure will be carried out by calculating a As per the Peto’s rule, significance level is set to 0.001 at interim analysis leading to either continuing the study to second phase, dropping the control arm, or stopping the trial early.Simulations were run with 2000 iterations using aforementioned values for parameters. The simulations show that by specifying the aforementioned inputs, the study has approximately 89% power for testing the hypothesis that biannual AZI MDA will reduce mortality, > 99% power for testing the hypothesis that quarterly AZI MDA will reduce mortality, and 80% power for testing the hypothesis that quarterly AZI MDA will reduce mortality more than biannual AZI MDA. The simulations also showed that with the chosen analytical approach familywise type I error rate is controlled at the target level despite multiple pairwise comparison and interim analysis.