Trial to Assess Chelation Therapy 2- TACT2 CCC

 描述（由申请人提供）：评估螯合疗法2（TACT 2）的试验的目的是在糖尿病和既往心脏病发作患者中进行TACT 1的实用和有效复制。这项试验的结果将确定乙二胺四乙酸二钠（Na 2 EDTA）螯合疗法是否获得美国食品和药物管理局（FDA）的批准，并随后被接受，以降低糖尿病患者冠状动脉疾病（CAD）的主要不良事件风险。TACT 2如果是阳性的，也将促进对益处机制的研究，并为CAD的病理生物学提供新的见解。评估螯合疗法的试验（TACT 1）是应NCCAM和国家心肺和血液研究所（NHLBI）的申请而开发的，以解决螯合使用广泛但没有安全性或有效性可靠数据的问题。令心脏病专家惊讶的是，螯合策略，与静脉和口服安慰剂相比，静脉注射EDTA二钠+口服多种维生素和多种矿物质（OMVM）多达40次输注的组合，导致50岁或以上既往心肌梗死（MI）患者首次复发心血管事件的时间显著缩短，已接受标准循证医学治疗（HR 0.74; 95%置信区间（CI）0.57- 0.95; p=0.016）。需要治疗的5年数（NNT）为12。在预先指定的糖尿病亚组（n=633）中，结果是戏剧性的：基于螯合的策略使复合主要临床终点降低了51%（HR 0.49，95%CI（0.33 0.75）; p<0.001，5年NNT 5.5），总死亡率降低了43%（p=0.011，5年NNT 12）。由于这些发现，以及心血管疾病和糖尿病对公共卫生的影响，美国国立卫生研究院（NIH）和FDA鼓励我们确认TACT 1的结果。TACT 2的三个具体目的是：1）确定糖尿病和既往MI患者中基于螯合的策略是否可改善无事件生存期; 2）确定糖尿病和既往MI患者中基于螯合的策略是否可降低死亡率; 3）对TACT 2螯合策略进行成本效益分析。TACT 2将招募1200名年龄在50岁或50岁以上的糖尿病患者，既往有MI，血清肌酐≤ 2.0 mg/dL。患者将被随机分配（1：1）接受螯合+ OMVM或双重安慰剂，并随访临床事件，直至5年试验结束。主要终点将是全因死亡率、复发性 MI、卒中、冠状动脉血运重建和因不稳定型心绞痛住院。对治疗分配设盲的临床事件委员会将裁定事件。主要次要终点将包括：（1）全因死亡率;（2）心血管死亡、复发性MI或卒中的复合终点;（3）安全性。

 DESCRIPTION (provided by applicant): The purpose of the Trial to Assess Chelation Therapy 2 (TACT2) is to perform a pragmatic and efficient replication of TACT1 in patients with diabetes and a prior heart attack. The results of this trial will determine whether disodium ethylene diamine tetraacetic acid (Na2EDTA) chelation therapy receives approval from the US Food and Drug Administration (FDA) and is subsequently accepted to reduce the risk of major adverse events from coronary artery disease (CAD) in patients with diabetes. TACT2, if positive, will also promote research into the mechanism(s) of benefits and provide novel insights into the pathobiology of CAD. The Trial to Assess Chelation Therapy (TACT1) was developed in response to a Request for Applications from NCCAM and the National Heart Lung and Blood Institute (NHLBI) to address the concern that chelation use was widespread but there were no reliable data on either safety or efficacy. Surprisingly to cardiologists, the chelation strategy, combination of up to 40 infusions with intravenous disodium EDTA plus oral multivitamins and multiminerals (OMVM) compared with intravenous and oral placebo, led to a significant reduction in the time to first recurrent cardiovascular event in patients with prior myocardial infarction (MI), age 50 or older, already treated with standard evidence based medical therapies (HR 0.74; 95% confidence intervals (CI) 0.57- 0.95; p=0.016. The 5-year number needed to treat (NNT) was 12. In the prespecified subgroup with diabetes (n=633), the results were dramatic: the chelation-based strategy reduced the composite primary clinical endpoint by 51% (HR 0.49, 95%CI (0.33 0.75); p<0.001, 5-year NNT 5.5) and reduced total mortality by 43% (p=0.011, 5-year NNT 12). As a result of these findings, and because of the public health impact of cardiovascular disease and of diabetes, we have been encouraged by the National Institutes of Health (NIH) and the FDA to confirm the results of TACT1. The three Specific Aims of TACT2 are: 1) To determine if the chelation-based strategy in patients with diabetes and prior MI improves event-free survival; 2) To determine if the chelation-based strategy in patients with diabetes and prior MI reduces mortality; 3) To perform a cost-effectiveness analysis of the TACT2 chelation strategy. TACT2 will enroll 1200 diabetic patients 50 years of age or older with a prior MI and a serum creatinine of 2.0 mg/dL or less. Patients will be randomly allocated (1:1) to receive either chelation + OMVM or double placebo and followed for clinical events until the end of the 5 year trial. The primary endpoint will be a composite of all-cause mortality, recurrent MI, stroke, coronary revascularization, and hospitalization for unstable angina. A Clinical Events Committee masked to treatment assignment will adjudicate events. Principal secondary endpoints will include: (1) all-cause mortality; (2) a composite of cardiovascular mortality, recurrent MI, or stroke; and (3) safety.