Stopping rules and study discontinuation and treatment failure
toxicity
CO-INFECTIONS
Dose limiting toxicity (DLT) in Stage-1 was defined as interruption of FCZ for 3 or more consecutive days because of toxicity and where interruption was initiated prior to day 14. The DAIDS toxicity grading system was used [Treatment failure for any participant was defined as a positive culture from a CSF sample collected at week 10 and read by week 12, or a positive last CSF culture on study if the participant died or was lost to follow up. If negative CSF culture was obtained prior to week 8, the participant entered Step-3 and received FCZ 400mg/day (or 600mg/day if receiving RIF) until week 10. Some participants in Step-1 did not enter Step-3.A core safety team consisting of chairs, co-chairs, Clinical Trials Specialist, medical officer, statisticians, and data manager was established. Additionally, A5225 was reviewed by the ACTG Co-infections Subcommitteeand and the SMC. Preplanned SMC reviews were conducted to review safety and tolerability after all participants were followed for at least 14 days for the Stage-1 1200 mg, 1600mg and 2000mg cohorts. A Stage-1 SMC review was conducted after 10 weeks of follow up on participants in the 2000 mg cohort was available to identify which Stage-1 doses would be tested in Stage-2. In Stage-2, SMC reviews were conducted approximately every six months. Additional safety reviews could be scheduled at the request of the medical officer or other team member. Data from participants in the 1600mg, 2000mg FCZ, and AMB cohorts from Stage-1 were combined with data from the Stage-2 participants in the same cohorts for the final safety, tolerability and efficacy analyses.