Sample size
toxicity, CM
EVENTS, EVENT
The sample size was designed to have a 90% power and a one-sided 0.10 alpha test to detect a change in log10 CFU//ml CSF of about 80% of the standard deviation of the values in Stage 1. Based on this a sample size of 24 was determined and would also permit a dose limiting toxicity rate of >25%. This permitted the identification of the maximum tolerated dose (MTD). The same rationale was used to determine the sample size in Stage 2 once the MTD was identified. In the conduct of Stage 1, the 1200mg FCZ dose was associated with a high mortality and excluded from Stage 2. Up to the maximum dose of 2000mg FCZ there was no MTD, hence the 1600mg and 2000mg FCZ doses were tested in Stage 2.In Stage-1, substitution was permitted for participants who were HIV negative, CM negative with confirmatory tests in a DAIDS approved laboratory, or who withdrew consent.The combined Stage-1 and Stage-2 sample size of 48 participants per dose ensured that the width of a 90% CI for proportion culture negative within a treatment cohort was no more than 25%. It also allowed for the detection of a 25% difference in efficacy between 2 doses with 90% power and a one sided 0.10 test. Additionally, with >40 evaluable participants per dose, there is an 87% chance of seeing one or more rare events if the rare or unexpected toxicity event occurs at a rate of 5% or higher.