Validation of a clinical trial composite endpoint for patients with necrotizing soft tissue infections

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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.

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