TY - JOUR
T1 - Impact of changes of the 2020 consensus definitions of invasive aspergillosis on clinical trial design
T2 - Unintended consequences for prevention trials?
AU - Wingard, John R.
AU - Alexander, Barbara D.
AU - Baden, Lindsey R.
AU - Chen, Min
AU - Sugrue, Michele W.
AU - Leather, Helen L.
AU - Caliendo, Angela M.
AU - Clancy, Cornelius J.
AU - Denning, David W.
AU - Marty, Francisco M.
AU - Nguyen, M. Hong
AU - Wheat, L. Joseph
AU - Logan, Brent R.
AU - Horowitz, Mary M.
AU - Marr, Kieren A.
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Background: Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods: In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results: Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1-105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions: The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies.
AB - Background: Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods: In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results: Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1-105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions: The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies.
KW - Antifungal clinical trials
KW - Antifungal prophylaxis
KW - Antifungal treatment
KW - Invasive aspergillosis
KW - Invasive fungal diseases
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U2 - 10.1093/ofid/ofab441
DO - 10.1093/ofid/ofab441
M3 - Article
C2 - 34631917
AN - SCOPUS:85118939894
SN - 2328-8957
VL - 8
JO - Open Forum Infectious Diseases
JF - Open Forum Infectious Diseases
IS - 10
M1 - ofab441
ER -