Improving Traditional Registrational Trial End Points: Development and Application of a Desirability of Outcome Ranking End Point for Complicated Urinary Tract Infection Clinical Trials

Authors

Jessica Howard-Anderson
Toshimitsu Hamasaki
Weixiao Dai
Deborah Collyar
Daniel Rubin
Sumathi Nambiar
Tori Kinamon
Carol Hill
Steven P Gelone
David Mariano
Takamichi Baba
Thomas L Holland
Sarah B Doernberg
Henry F Chambers
Vance G Fowler
Scott R Evans
Helen W Boucher

Publication Date

2-8-2023

Journal

Clinical Infectious Diseases

Abstract

BACKGROUND: Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience.

METHODS: Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI compared cefiderocol to imipenem, and DORI-05 compared doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug.

RESULTS: In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR.

CONCLUSIONS: DOOR can effectively be used in registrational cUTI trials. The DOOR end point presented here can be adapted for other infectious disease syndromes and prospectively incorporated into future clinical trials.

Keywords

Humans, Anti-Bacterial Agents, Urinary Tract Infections, Levofloxacin, Doripenem, Imipenem

Comments

Supplementary Materials

PMID: 36031403