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

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作   者：

Jessica,Howard-Anderson;  Toshimitsu,Hamasaki;  Weixiao,Dai;  Deborah,Collyar;  Daniel,Rubin;  Sumathi,Nambiar;  Tori,Kinamon;  Heidi,Leister-Tebbe;  Carol,Hill;  Holly,Geres;  Thomas L,Holland;  Sarah B,Doernberg;  Henry F,Chambers;  Vance G,Fowler;  Scott R,Evans;  Helen W,Boucher; 

作者机构：

Biostatistics Center and Department of Biostatistics and Bioinformatics;  Department of Medicine;  Johnson and Johnson;  Center for Drug Evaluation and Research;  Duke University School of Medicine;  Tufts University;  Patient Advocates in Research;  Duke University Medical Center;  University of California;  US Food and Drug Administration;  Pfizer Inc;  Duke Clinical Research Institute;  Division of Infectious Diseases;  Division of Geographic Medicine and Infectious Diseases;  Department of Medicine;  Milken Institute School of;  Emory University School of Medicine; 

关键词：

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

期刊名称：

Clinical infectious diseases

i s s n：

1058-4838

年卷期：

2024 年 78 卷 2 期

页   码：

259-268

页   码：

摘   要：

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 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.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.Conclusions 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.