Shar Albert O, Gaudard Marie A, Heath Elisabeth I, Forastiere Arlene A, Yang Vincent W, Sontag Stephen J
The Robert Wood Johnson Foundation, Princeton, NJ 08543-2316, USA.
Contemp Clin Trials. 2009 Jan;30(1):2-7. doi: 10.1016/j.cct.2008.10.001. Epub 2008 Nov 1.
Utilizing data obtained during a multicenter investigation, this paper illustrates how the use of covariates and careful modeling techniques can be useful in assessing whether a negative outcome from a small multicenter clinical trial could be due to imbalance in baseline characteristics. The Chemoprevention for Barrett's Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett's esophagus. The primary outcomes for the original study were the proportion of biopsy samples exhibiting dysplasia in the celecoxib and placebo groups. The secondary and tertiary outcomes included histologic change and measurements of biologically relevant markers, including COX-1 and -2 mRNA, prostanoid levels, and methylation of tumor suppressor genes p16, APC, and E-cadherin. The original study reported no significant differences in primary, secondary or tertiary outcomes. In this paper, we focus on the results of one of the secondary measures, quantitative endoscopy (QE).
The study utilizes data from 56 patients in the CBET for whom baseline (BL) QE and one-year follow-up QE (F04) studies were performed. Of these, 29 were treated with celecoxib (200 mg twice daily for a minimum of 48 weeks) and 27 received the placebo. These patients are segmented as to the presence or absence of circumferential, tongues or islands of Barrett's.
The response of interest is total affected area at one year (Total F04); affected area at baseline (Total BL) is used as a covariate.
Controlling for complexity and clinic, there is a significant treatment effect. In addition, there is significant evidence that the area of Barrett's involvement decreased for patients in the treatment group.
That there was a decrease for the celecoxib over the placebo group adds to the body of evidence that relates COX-2 specific inhibitors and cancer incidence.
利用多中心调查期间获得的数据，本文阐述了协变量的使用和精细的建模技术如何有助于评估小型多中心临床试验的负面结果是否可能归因于基线特征的不平衡。巴雷特食管化学预防试验（CBET）是一项IIb期、多中心、随机、安慰剂对照试验，研究对象为巴雷特食管患者，使用塞来昔布进行治疗。原研究的主要结局是塞来昔布组和安慰剂组中显示发育异常的活检样本比例。次要和三级结局包括组织学变化以及生物学相关标志物的测量，包括COX-1和-2 mRNA、前列腺素水平以及肿瘤抑制基因p16、APC和E-钙黏蛋白的甲基化。原研究报告称，主要、次要或三级结局均无显著差异。在本文中，我们重点关注其中一项次要测量指标——定量内镜检查（QE）的结果。
该研究利用了CBET中56例患者的数据，这些患者进行了基线（BL）QE和一年随访QE（F04）研究。其中，29例接受塞来昔布治疗（每日两次，每次200 mg，至少48周），27例接受安慰剂治疗。这些患者根据是否存在巴雷特食管的环形、舌状或岛状病变进行分类。
感兴趣的反应指标是一年时的总受累面积（总F04）；基线时的受累面积（总BL）用作协变量。
在控制了复杂性和临床因素后，存在显著的治疗效果。此外，有显著证据表明治疗组患者的巴雷特食管受累面积减小。
塞来昔布组相较于安慰剂组出现了面积减小，这进一步补充了将COX-2特异性抑制剂与癌症发病率相关联的证据。
