Methods
AIDS, toxicity
ADVERSE EVENTS, AIDS, CONSOLIDATION
The study was approved by the USA Food and Drug Administration. In addition, each of the multicentre sites that participated in the study received approval from their local Institutional Review Boards viz: Associacion Civil Impacta–San Miguel Jiron, Lima Peru; Research Institute for Health Sciences, Chiang Mai, Thailand; Joint Clinical Research Centre Mengo, Kampala, Uganda; Walter Reid Project Kenya Medical Research Centre, Kericho, Kenya; USC School of Medicine, Los Angeles, USA; BJ Medical College and Sassoon General Hospital Clinical Trials Unit, Pune, Maharashtra, India; MOI University Teaching Hospital, Eldoret, Rift Valley Kenya; Kilimanjaro Christian Medical Centre, Moshi, Tanzania; University of Witwatersrand CHRU, Helen Joseph Hospital, Johannesburg, South Africa; Durban International Clinical Research Site, Universtiy of KwaZulu-Natal, Durban, South Africa and AIDS Research Unit, Universtiy of Zimbabwe, Harare, Zimbabwe.The trial was registered with the United States of America National Institutes of Health Clinical Trials.gov identifier NCT00885703.All participants signed a written informed consent form. A Study Monitoring Committee (SMC) reviewed the study for safety concerns, adverse events and approved escalation to the next dose of FCZ or stopping based on protocol-defined criteria. A core safety team monitored the study safety data monthly.The study was planned in two stages (Step-2: Induction following early AMB intolerance (only for participants randomised to AMB treatment in Step-1) (FCZ at 400-800mg/day)Step-3: Consolidation treatment for AMB arm and for those whose CSF had become negative (FCZ 400mg/day) -up to week 10. Participants whose CSF did not become negative were transitioned to local standard of careStep-4: Maintenance treatment (FCZ 200mg/day) week 10–24a. Study flow for stage 1. b. Stage 2 cohorts. FCZ = fluconazole; AMB = amphotericin B; DLT = dose limiting toxicity; MTD = maximum tolerated dose; SMC = safety monitoring committee. Participants from Stage 1 for each of the 1600mg and 2000mg FCZ and AMB cohorts were combined with the participants from the Stage 2 group for the final safety and efficacy analysis.8 participants switched to standard of care AMB.Participants were followed on study for 24 weeks. The 1200mg/day FCZ arm was excluded per protocol in Stage-2 because, although safe, was associated with a higher mortality.