Impact of Changes of the 2020 Consensus Definitions of Invasive Aspergillosis on Clinical Trial Design: Unintended Consequences for Prevention Trials?

Abstract

Background Consensus definitions for the diagnosis of invasive fungal diseases (IFD) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cut-off 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 one probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% in hematopoietic cell transplant (HCT) patients and in no lung transplant (LT) patients. Date of diagnosis was established a median of 3 days (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.

Developments in Fungal Serology

“…Justification for this increased stringency when testing serum/plasma was based on the increased likelihood of IA associated with increased specificity (90-94%), while accepting that this could hamper enrolment into clinical trials, it was felt that this improved rigor was critical to underpinning the accuracy of clinical studies. These more stringent classifications were retrospectively applied to 226 cases of proven/probable IA and 139 cases of possible IFD in the Aspergillus Technology Consortium (AsteC) and to an antifungal prophylaxis trial [15]. From the AsTec collection, 40 cases of probable IA were reclassified as possible IFD.…”