Eileen M Bulger1, Addison May, Wayne Dankner, Gregory Maislin, Bryce Robinson, Anat Shirvan. 1. From the Department of Surgery (E.M.B., B.R.), University of Washington, Seattle, Washington; Department of Surgery (A.M.), Vanderbilt Medical Center, Nashville, Tennessee; Atox Bio Ltd (W.D., A.S.), Ness-Ziona, Israel; Biostatistician, Biomedical Statistical Consulting (G.M.), Philadelphia, Pennsylvania.
Abstract
OBJECTIVE: Our objective was to develop and validate a composite endpoint for patients with necrotizing soft tissue infections that incorporates: local tissue injury, systemic organ dysfunction, and mortality. METHODS: The Necrotizing Infection Clinical Composite Endpoint (NICCE) was defined as follows:(i) alive at day 28, (ii) three or less debridements before day 14, (iii) no amputation beyond first debridement, (iv) modified sequential organ failure assessment score score (mSOFA) at day 14 ≤ 1. To be considered a success, all individual criteria must be met. Several data sets were used to assess validity: (i) a retrospective data set of 198 patients treated during 2013 at 12 US trauma centers; (ii) a subset with high disease acuity, admission mSOFA score of 3 or higher (n = 69); and (iii) 40 patients from a multicenter, phase 2 randomized trial of a CD28 immunomodulator (AB103). Clinical success based on each parameter and the composite score was assessed. RESULTS: Using the retrospective data set for all patients and those with high disease severity (respectively), survival rates were 92% and 84%; day 14 mSOFA 1 or lower score was 69% and 51%; three or less debridements was 84% and 77%; and no subsequent amputations were 96% and 94%. Overall, the percent meeting all success criteria for NICCE was 58% (all patients) and 33% (mSOFA > 3). NICCE success was also associated with reduced utilization of health care resources, intensive care unit-free days were median (interquartile range) of 25.3 (21.9-28) and 19.6 (4.3-25.1) days (one-sided Wilcoxon p < 0.001) and ventilator-free days were 28 (26-28) versus 25 (14-28) (p < 0.001) for NICCE success versus failure, respectively. Using the phase 2 data set, the treated group (0.5 mg/kg, n = 15) demonstrated a NICCE success rate of 73.3% versus 40% for placebo (n = 10). CONCLUSION: These data demonstrate internal consistency of the components and face and criterion validity of the NICCE endpoint. NICCE offers an opportunity to demonstrate a clinically relevant treatment effect for patients enrolled in clinical trials for necrotizing soft tissue infection. LEVEL OF EVIDENCE: Prognostic/Epidemiological, level III; Therapeutic, level IV.
RCT Entities:
OBJECTIVE: Our objective was to develop and validate a composite endpoint for patients with necrotizing soft tissue infections that incorporates: local tissue injury, systemic organ dysfunction, and mortality. METHODS: The Necrotizing Infection Clinical Composite Endpoint (NICCE) was defined as follows:(i) alive at day 28, (ii) three or less debridements before day 14, (iii) no amputation beyond first debridement, (iv) modified sequential organ failure assessment score score (mSOFA) at day 14 ≤ 1. To be considered a success, all individual criteria must be met. Several data sets were used to assess validity: (i) a retrospective data set of 198 patients treated during 2013 at 12 US trauma centers; (ii) a subset with high disease acuity, admission mSOFA score of 3 or higher (n = 69); and (iii) 40 patients from a multicenter, phase 2 randomized trial of a CD28 immunomodulator (AB103). Clinical success based on each parameter and the composite score was assessed. RESULTS: Using the retrospective data set for all patients and those with high disease severity (respectively), survival rates were 92% and 84%; day 14 mSOFA 1 or lower score was 69% and 51%; three or less debridements was 84% and 77%; and no subsequent amputations were 96% and 94%. Overall, the percent meeting all success criteria for NICCE was 58% (all patients) and 33% (mSOFA > 3). NICCE success was also associated with reduced utilization of health care resources, intensive care unit-free days were median (interquartile range) of 25.3 (21.9-28) and 19.6 (4.3-25.1) days (one-sided Wilcoxon p < 0.001) and ventilator-free days were 28 (26-28) versus 25 (14-28) (p < 0.001) for NICCE success versus failure, respectively. Using the phase 2 data set, the treated group (0.5 mg/kg, n = 15) demonstrated a NICCE success rate of 73.3% versus 40% for placebo (n = 10). CONCLUSION: These data demonstrate internal consistency of the components and face and criterion validity of the NICCE endpoint. NICCE offers an opportunity to demonstrate a clinically relevant treatment effect for patients enrolled in clinical trials for necrotizing soft tissue infection. LEVEL OF EVIDENCE: Prognostic/Epidemiological, level III; Therapeutic, level IV.
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