Fukimbara Satoru, Niibe Kouji, Yamamoto Michio, Yamaguchi Takuhiro
1 Data Science Development Headquarters, Ono Pharmaceutical Co Ltd, Osaka, Japan.
2 Department of Clinical Trial Data Management, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Ther Innov Regul Sci. 2017 Jan;51(1):89-99. doi: 10.1177/2168479016659103. Epub 2016 Aug 19.
To confirm the effectiveness of sivelestat, a clinical trial was conducted comparing sivelestat with conventional treatment in an open, nonrandomized, multicenter study of patients with systemic inflammatory response syndrome (SIRS)-associated acute lung injury. The primary endpoint was ventilator-free days (VFD).
This study adopted a "cluster entry" method to control for patient selection bias arising from the unblinded and nonrandomized clinical trial. Thus, all patients in the same hospital during the same entry period entered the same treatment arm, and entry periods did not overlap. In the primary analysis of VFD, adjusted mean VFD values were compared between groups using the inverse probability of treatment weighted (IPTW) method, based on propensity score, for control of confounding factors.
There were 374 patients in the sivelestat group and 168 in the conventional therapy group. The primary analysis confirmed that sivelestat was effective (between-group difference of adjusted mean was 3.5 [2-sided 95% confidence interval, 1.3-5.8]; P = .0022).
In general, a study where all patients in the same cluster enter the same treatment arm has within-cluster correlations, which need to be considered in the study analysis. However, in analysis using the IPTW method, it is usual to use a robust variance estimator, the sandwich variance estimator, which is consistent regardless of whether the specification of within-cluster correlation structure is correct. Thus, in the analysis using the IPTW method, it was found that it was not necessary to adopt any other adjustment method for within-cluster correlation.
为证实西维来司他的有效性，开展了一项临床试验，在一项针对全身炎症反应综合征（SIRS）相关急性肺损伤患者的开放性、非随机、多中心研究中，将西维来司他与传统治疗进行比较。主要终点为无呼吸机天数（VFD）。
本研究采用“整群入组”方法，以控制因非盲法和非随机临床试验产生的患者选择偏倚。因此，同一入组期间同一医院的所有患者进入同一治疗组，且入组期间不重叠。在对VFD的初步分析中，基于倾向评分，使用治疗加权逆概率（IPTW）方法比较组间调整后的平均VFD值，以控制混杂因素。
西维来司他组有374例患者，传统治疗组有168例患者。初步分析证实西维来司他有效（调整后均值的组间差异为3.5[双侧95%置信区间，1.3 - 5.8]；P = .0022）。
一般来说，同一整群中的所有患者进入同一治疗组的研究存在整群内相关性，在研究分析中需要考虑这一点。然而，在使用IPTW方法进行分析时，通常使用稳健方差估计量，即三明治方差估计量，无论整群内相关结构的设定是否正确，它都是一致的。因此，在使用IPTW方法进行分析时，发现没有必要对整群内相关性采用任何其他调整方法。
