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Moving Beyond Mortality: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

Authors
  • Howard-Anderson, Jessica1
  • Hamasaki, Toshimitsu2
  • Dai, Weixiao2
  • Collyar, Deborah3
  • Rubin, Daniel4
  • Nambiar, Sumathi5
  • Kinamon, Tori6
  • Leister-Tebbe, Heidi7
  • Hill, Carol8
  • Geres, Holly8
  • Holland, Thomas L6, 8
  • Doernberg, Sarah B9
  • Chambers, Henry F9
  • Fowler, Vance G Jr6, 8
  • Evans, Scott R2
  • Boucher, Helen W10, 11
  • 1 Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. , (Georgia)
  • 2 Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, District of Columbia, USA.
  • 3 Patient Advocates in Research, Danville, California, USA.
  • 4 Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
  • 5 Johnson and Johnson, Raritan, New Jersey, USA. , (Jersey)
  • 6 Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
  • 7 Pfizer Inc, Collegeville, Pennsylvania, USA.
  • 8 Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.
  • 9 Division of Infectious Diseases, Department of Medicine, University of California, SanFrancisco, USA.
  • 10 Division of Geographic Medicine and Infectious Diseases, Department of Medicine, Tufts University School of Medicine.
  • 11 Tufts Medicine, Boston, Massachusetts, USA.
Type
Published Article
Journal
Clinical Infectious Diseases
Publisher
Oxford University Press
Publication Date
Feb 17, 2024
Volume
78
Issue
2
Pages
259–268
Identifiers
DOI: 10.1093/cid/ciad576
PMID: 37740559
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation. A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses. In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%--55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%-52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid. The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR. © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: [email protected].

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