title: Design issues in a randomized controlled trial of a pre-emptive versus empiric antifungal strategy for invasive aspergillosis in patients with high-risk hematologic malignancies.
abstract: Invasive aspergillosis (IA) is a major cause of mortality in patients with hematological malignancies, due largely to the inability of traditional culture and biopsy methods to make an early or accurate diagnosis. Diagnostic accuracy studies suggest that Aspergillus galactomannan (GM) enzyme immunoassay (ELISA) and Aspergillus PCR-based methods may overcome these limitations, but their impact on patient outcomes should be evaluated in a diagnostic randomized controlled trial (D-RCT). This article describes the methodology of a D-RCT which compares a new pre-emptive strategy (GM-ELISA- and Aspergillus PCR-driven antifungal therapy) with the standard fever-driven empiric antifungal treatment strategy. Issues including primary end-point and patient selection, duration of screening, choice of tests for the pre-emptive strategy, antifungal prophylaxis and bias control, which were considered in the design of the trial, are discussed. We suggest that the template presented herein is considered by researchers when evaluating the utility of new diagnostic tests (ClinicalTrials.gov number, NCT00163722).
authors.affiliation: Infectious Diseases Unit, Department of Medicine, Alfred Hospital and Monash University, Melbourne, VIC, Australia. o.morrissey@alfred.org.au
authors.forename: C Orla
authors.initials: CO
authors.lastname: Morrissey
authors.forename: Sharon C-A
authors.initials: SC
authors.lastname: Chen
authors.forename: Tania C
authors.initials: TC
authors.lastname: Sorrell
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bradstock
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Szer
authors.forename: Catriona L
authors.initials: CL
authors.lastname: Halliday
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Gilroy
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Schwarer
authors.forename: Monica A
authors.initials: MA
authors.lastname: Slavin
mesh_terms: D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000175:diagnosis* / Q000188:drug therapy / Q000382:microbiology; D004797:Enzyme-Linked Immunosorbent Assay; D005690:Galactose / Q000031:analogs & derivatives; D019337:Hematologic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008351:Mannans / Q000097:blood; D016133:Polymerase Chain Reaction; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D012307:Risk Factors
chemical_list: D000935:Antifungal Agents; D008351:Mannans; C012990:galactomannan; D005690:Galactose