84. Improving Traditional Registrational Trial Endpoints: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Acute Bacterial Skin and Skin-Structure Infections

Abstract Background The ideal primary endpoint for acute bacterial skin and skin-structure infection (ABSSSI) trials is unknown and regulatory guidance differs between U.S. and Europe. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis and interpretation of clinical trials that incorporates a benefit-risk evaluation and provides a global assessment of patient experience. Methods Drawing on prior work from the Antibacterial Resistance Leadership Group (ARLG), a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience adapted a generalized infectious diseases DOOR for ABSSSI trials (Figure 1). We then retrospectively applied this to two previously published, noninferiority, double-blind, randomized, registrational, ABSSSI trials comparing omadacycline to linezolid OASIS-1 and OASIS-2, Figure 2) to demonstrate how DOOR could be applied. We compared the DOOR distribution and probability of having a more desirable outcome between treatment groups and performed DOOR component analyses. Results For both trials, the ABSSSI DOOR demonstrated similar overall clinical outcomes between treatment groups. In OASIS-1, the probability that a participant treated with omadacycline would have a more desirable outcome than a participant treated with linezolid was 50.7% (95% confidence interval [CI], 47.7%−53.8%) (Figure 3). In OASIS-2, the probability that a participant treated with omadacycline would have a more desirable outcome than a participant treated with linezolid was 51.0% (95% CI, 48.1%–53.8%) (Figure 4). Overall, the DOOR components (clinical failure, infectious complications, serious adverse events, and death) were rare, although the DOOR component analysis provided a more in-depth understanding of the potential trade-offs between efficacy and safety when comparing omadacycline to linezolid. Conclusion DOOR can be informative in registrational ABSSSI trials. Using DOOR can provide clinicians with a better understanding of the clinical outcomes of patients with skin infections. Future trials using DOOR prospectively can continue to inform how to best use DOOR in ABSSSI trials. Disclosures Deborah Collyar, B.Sci, Apellis Pharmaceuticals, Inc.: Advisor/Consultant|Kinnate Biopharma: Advisor/Consultant Sumathi Nambiar, MD MPH, Johnson and Johnson: Stocks/Bonds (Public Company) Carol Hill, PhD, Glaxo SmithKline: Retirement Health, Cash Balance Plan|Glaxo SmithKline: Stocks/Bonds (Public Company) Thomas L. Holland, MD, Karius, Inc: Advisor/Consultant Sarah B. Doernberg, MD, MAS, Basilea Pharmaceutica: Grant/Research Support|F2G Limited: Grant/Research Support|Genentech: Advisor/Consultant|Gilead Biosciences: Grant/Research Support|Janssen/J+J: Advisor/Consultant|Pfizer, Inc: Grant/Research Support|Regeneron, Inc: Grant/Research Support|Shinogi: Grant/Research Support Henry Chambers, MD, Merck: Stocks/Bonds (Private Company)|Moderna: Stocks/Bonds (Private Company) Vance G. Fowler, MD, MHS, Affinergy: Advisor/Consultant|ArcBio: Stocks/Bonds (Private Company)|Armata: Advisor/Consultant|Astra Zeneca: Advisor/Consultant|Astra Zeneca: Grant/Research Support|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|ContraFect: Advisor/Consultant|ContraFect: Grant/Research Support|Debiopharm: Advisor/Consultant|Destiny: Advisor/Consultant|EDE: Grant/Research Support|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|GSK: Advisor/Consultant|Janssen: Advisor/Consultant|Karius: Grant/Research Support|MedImmune: Grant/Research Support|Merck: Grant/Research Support|sepsis diagnostics: Patent pending|UptoDate: Royalties|Valanbuio: Stocks/Bonds (Private Company)|Valanbuio: Stocks/Bonds (Private Company) Scott R. Evans, PhD, M.S., Abbvie: Advisor/Consultant|Advantagene: Advisor/Consultant|Akouos: Advisor/Consultant|Apellis: Advisor/Consultant|AstraZenenca: Advisor/Consultant|BARDA: Advisor/Consultant|Breast International Group: Advisor/Consultant|CDC: Grant/Research Support|Clover: Advisor/Consultant|DayOneBio: Advisor/Consultant|Degruyter: Editorial service|Duke University: Advisor/Consultant|Eli Lilly: Advisor/Consultant|FDA: Advisor/Consultant|Frontier Science Foundation: Board Member|Genentech: Advisor/Consultant|GSK: Advisor/Consultant|Henry Jackson Foundation: Grant/Research Support|International Drug Development Institute: Advisor/Consultant|Johson & Johnson: Advisor/Consultant|Medtronic: Advisor/Consultant|NIH: Grant/Research Support|Novartis: Advisor/Consultant|Pfizer: Advisor/Consultant|Rakuten: Advisor/Consultant|Roche: Advisor/Consultant|Takeda: Advisor/Consultant|Taylor & Francis: Book royalties|Teva: Advisor/Consultant|University of Penn: Advisor/Consultant|Vir: Advisor/Consultant|Wake Forest University: Advisor/Consultant|Washington University: Advisor/Consultant Helen Boucher, MD, ASM: Honoraria|Elsevier: Honoraria|Sanford Guide: Honoraria