Clinical antifungal efficacy trials in invasive aspergillosis: Consensus standards for trial design and room for improvement.

Despite recent improvements in outcome of invasive aspergillosis there are still high failure and fatality rates. The trial comparing voriconazole to amphotericin B deoxycholate has become a reference for clinical trials in invasive aspergillosis due to the large number of patients included, the use of definition criteria close to the international consensus criteria, the inclusion of the halo sign on chest computed tomography for the definition of probable cases, the extensive review of the data by a panel of experts including radiologists, and most important, the successful efficacy results. Similar strict methodology for eligibility and assessment of outcome has been applied in the recently completed liposomal amphotericin B trial. This study compared a standard daily dose of liposomal amphotericin B (3 mg/kg) versus a high loading dose (10 mg/kg/d). The option to include possible cases in this trial and to give the investigators a few days to upgrade the diagnosis to a probable or definite level proved to be an effective strategy, saving four months in the duration of the recruitment period. Additional progress can be expected in future trials with the use of a standardized cutoff for the galactomannan detection test and a stratification at randomization on the most critical prognostic factor such as progressive underlying malignancy or allogeneic stem cell transplantation.