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).

Keywords:

• Diagnostic tests
• evaluation
• bias
• clinical trial
• Aspergillus

Acknowledgements

Principal investigators: protocol queries

M. Slavin, Peter MacCallum Cancer Centre, Melbourne (co-chair); C. O. Morrissey, Alfred Hospital, Melbourne (co-chair).

Protocol team

M. Slavin, Peter MacCallum Cancer Centre, Melbourne (co-chair); C. O. Morrissey, Alfred Hospital, Melbourne (co-chair); K. Bradstock, Westmead Hospital, Sydney; T. Sorrell, Westmead Hospital, Sydney; A. P. Schwarer, Alfred Hospital, Melbourne; J. Szer, Royal Melbourne Hospital, Melbourne; S. Chen, Westmead Hospital, Sydney; C. Halliday, Westmead Hospital, Sydney; J. McNeil, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne; R. Wolfe, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne; N. Gilroy, NSW Bone Marrow Transplant Network, Sydney.

Site investigators

Alfred Hospital: C. Chang, C. O. Morrissey, A. P. Schwarer; Peter MacCallum Cancer Centre: J. Seymour, M. Slavin; Royal Adelaide Hospital: N. Horvath; Royal Melbourne Hospital: D. Curtis, A. Grigg, A. Roberts, M. Slavin, J. Szer; St. Vincent's Hospital, Sydney: N. Gilroy, J. Harkness, D. Marriott, S. Milliken, J. Moore; Westmead Hospital: K. Bradstock, S. Chen, N. Gilroy, T. Sorrell.

Laboratory researchers

CIDMLS: C. Halliday, S. Sleiman, M. Hunyh, H. Htwe; APSMBU: G. Kularatne, A. Campbell, A.-L. Chan, S. Kidd.

Research coordinators

T. Luff, E. J. Furphy, N. Griffiths, T. Lewis, D. Barham, R. Carter, P. Plenge, C. Kesby, E. Snape, M. Kabir.

Statistical and data management center

A. Matera, J. Di Iulio, T. Morgan, J. Reynolds.

Declaration of interest

Major funding: Australian National Health and Medical Research Council (Project Grant 331305); Cancer Council New South Wales; Pfizer (Global) and Pfizer (Australia).

Minor funding: Centre for Clinical Research Excellence in Infectious Diseases, Royal Melbourne Hospital, Melbourne, VIC, Australia; Centre for Clinical Research Excellence in Infections, Bioethics and Haematological Malignancies, Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia; Merck Sharp & Dohme (Australia) and Gilead Sciences.

Industry played no role in the study design or the writing of this manuscript.

C.O.M. serves/has served on Advisory Boards for, received investigator-initiated grants from, and given lectures for Gilead Sciences, Pfizer, Merck, Schering Plough, and Orphan Australia. S.C.-A.C., T.C.S., and M.A.S. serve/have served on Advisory Boards for Pfizer, Merck, Gilead, and Schering Plough and have received investigator-initiated grants from Pfizer, Merck, and Gilead. J.S. serves/has served on Advisory Boards for and has received investigator-initiated grants from Gilead Sciences and Pfizer Australia. K.F.B. has served on Advisory Boards for Pfizer, Merck, and Schering Plough and has been a consultant for Pfizer.