坏死性软组织感染患者临床试验复合终点的验证

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

作者信息

Bulger Eileen M, May Addison, Dankner Wayne, Maislin Gregory, Robinson Bryce, Shirvan Anat

机构信息

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.

出版信息

J Trauma Acute Care Surg. 2017 Oct;83(4):622-627. doi: 10.1097/TA.0000000000001564.

DOI:10.1097/TA.0000000000001564

PMID:28538644

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.

摘要

目的

我们的目标是开发并验证一种针对坏死性软组织感染患者的综合终点指标，该指标纳入了以下内容：局部组织损伤、全身器官功能障碍和死亡率。

方法

坏死性感染临床综合终点指标（NICCE）定义如下：（i）第28天存活；（ii）第14天前清创次数为3次或更少；（iii）首次清创后无截肢；（iv）第14天改良序贯器官衰竭评估评分（mSOFA）≤1。要被视为成功，必须满足所有个体标准。使用了几个数据集来评估有效性：（i）2013年在美国12个创伤中心接受治疗的198例患者的回顾性数据集；（ii）疾病严重程度高的子集，入院时mSOFA评分为3或更高（n = 69）；（iii）来自CD28免疫调节剂（AB103）多中心2期随机试验的40例患者。评估了基于每个参数和综合评分的临床成功率。

结果

分别使用所有患者和疾病严重程度高的患者的回顾性数据集，生存率分别为92%和84%；第14天mSOFA评分为1或更低的比例分别为69%和51%；3次或更少清创的比例分别为84%和77%；且后续无截肢的比例分别为96%和94%。总体而言，满足NICCE所有成功标准的比例在所有患者中为58%，在mSOFA>3的患者中为33%。NICCE成功还与医疗资源利用减少相关，NICCE成功组与失败组相比，无重症监护病房天数的中位数（四分位间距）分别为25.3（21.9 - 28）天和19.6（4.3 - 25.1）天（单侧Wilcoxon检验p<0.001），无呼吸机天数分别为28（26 - 28）天和25（14 - 28）天（p<0.001）。使用2期数据集，治疗组（0.5mg/kg，n = 15）的NICCE成功率为73.3%，而安慰剂组（n = 10）为40%。