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

Jessica Howard-Anderson, Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA.
Toshimitsu Hamasaki, Biostatistics Center and Department of Biostatics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, D.C., USA.
Weixiao Dai, Biostatistics Center and Department of Biostatics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, D.C., USA.
Deborah Collyar, Patient Advocates in Research, Danville, CA, USA.
Daniel Rubin, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Sumathi Nambiar, Johnson and Johnson, Raritan NJ, USA.
Tori Kinamon, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Heidi Leister-Tebbe, Pfizer Inc, Collegeville, PA, USA.
Carol Hill, Duke Clinical Research Institute, Durham, North Carolina, USA.
Holly Geres, Duke Clinical Research Institute, Durham, North Carolina, USA.
Thomas L. Holland, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Sarah B. Doernberg, Department of Medicine, Division of Infectious Diseases, University of California, San Francisco, USA.
Henry F. Chambers, Department of Medicine, Division of Infectious Diseases, University of California, San Francisco, USA.
Vance G. Fowler, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Scott R. Evans, Biostatistics Center and Department of Biostatics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, D.C., USA.
Helen W. Boucher, Tufts University School of Medicine and Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, USA.

Document Type

Journal Article

Publication Date

9-22-2023

Journal

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

DOI

10.1093/cid/ciad576

Keywords

and ventilator-associated bacterial pneumonia; clinical trials; desirability of outcome ranking; drug development; hospital-acquired bacterial pneumonia

Abstract

BACKGROUND: 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. METHODS: 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 two 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. RESULTS: 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. CONCLUSION: 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.

Department

Biostatistics and Bioinformatics

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