University of Connecticut School of Medicine, Farmington, 06030-3940, USA.
Am Heart J. 2011 Oct;162(4):620-626.e1. doi: 10.1016/j.ahj.2011.08.004. Epub 2011 Sep 14.
Comprehensive safety evaluation of new drugs for diabetes mellitus is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk. Alogliptin, a dipeptidyl peptidase 4 inhibitor, is under development for the treatment of type 2 diabetes mellitus alone or in combination with other antidiabetic therapies. Long-term CV safety of alogliptin is being established in a randomized, placebo-controlled clinical study in patients with acute coronary syndrome (ACS) using an analytical approach that has both an interim and final assessment. The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. Approximately 5,400 men and women with type 2 diabetes and ACS (acute myocardial infarction or unstable angina) are being recruited and will be followed up for up to 4.5 years postrandomization. The statistical plan for the trial uses a design that evaluates the hazard ratio (HR) of alogliptin to placebo first based on the primary CV composite end point after accrual of 80 to 150 primary CV events and again when there are 550 to 650 primary CV events. In the first series of analyses, the upper bound of a group-sequential 1-sided repeated CI for the HR must be ≤1.8 for registration in the United States. At end of study, the upper bound of a subsequent group-sequential 1-sided repeated CI for the HR must be ≤1.3. For both group sequential analyses, the repeated CIs are calculated to insure simultaneous coverage probabilities of 97.5% for the true HR. Study progress: More than 2,000 ACS patients were randomized as of June 2011. EXAMINE will define the CV safety profile of this dipeptidyl peptidase 4 inhibitor in patients at high risk for CV events.
需要对糖尿病治疗药物的心血管结局进行全面的安全性评估，尤其是在心血管风险较高的人群中。阿格列汀是一种二肽基肽酶 4 抑制剂，目前正处于开发阶段，可用于治疗 2 型糖尿病，也可与其他抗糖尿病药物联合应用。阿格列汀的长期心血管安全性正在一项针对急性冠脉综合征（ACS）患者的随机、安慰剂对照临床试验中建立，该试验采用了一种分析方法，该方法具有中期和最终评估。这项试验的主要心血管终点是心血管死亡、非致死性心肌梗死和非致死性卒中等复合终点。约 5400 名患有 2 型糖尿病和 ACS（急性心肌梗死或不稳定型心绞痛）的男性和女性正在入组，他们将在随机分组后随访 4.5 年。该试验的统计计划采用了一种设计，首先根据 80 至 150 例主要心血管复合终点事件累积后，以及当主要心血管事件达到 550 至 650 例时，根据主要心血管复合终点评估阿格列汀与安慰剂的风险比（HR）。在第一系列分析中，对于在美国注册，群体序贯单侧重复置信区间的上限必须≤1.8。在研究结束时，随后的群体序贯单侧重复置信区间上限必须≤1.3。对于这两种群体序贯分析，重复置信区间的计算可以确保真实 HR 的同时覆盖率概率为 97.5%。研究进展：截至 2011 年 6 月，已有超过 2000 名 ACS 患者被随机分组。EXAMINE 将确定这种二肽基肽酶 4 抑制剂在心血管事件高危患者中的心血管安全性特征。
