MICA: Prevention of Aortic Stenosis (PAS) Pilot Trial

我们计划进行一项随机对照双盲交叉试验，以确定sevelamer是否能降低主动脉瓣狭窄患者的血清磷酸盐。主动脉瓣狭窄是一种严重的心脏疾病，目前尚无预防措施。它是由主动脉瓣上磷酸钙晶体的逐渐沉积引起的，导致心脏血液流动受阻。在大多数情况下，除非通过手术更换瓣膜，否则会出现心功能不全的症状。在英国，大约有130万75岁以上的人患有主动脉狭窄，其中约四分之一的人受到严重影响。随着人口老龄化，这一数字预计将在未来几十年翻一番。有必要进行预防性治疗。磷酸盐结合药物sevelamer通过阻断饮食吸收来降低血液中的磷酸盐。治疗被许可用于肾衰竭患者，以降低高磷酸盐（生理水平的2-3倍），这是由于肾脏排泄失败导致的骨病。治疗减少了磷酸钙，通过减缓或阻止瓣膜钙化，提高了其在所有患者中预防主动脉狭窄的应用范围。对于磷酸盐水平在生理范围内的主动脉瓣狭窄患者，尚不清楚sevelamer是否能降低血清磷酸盐。在拟议的试点试验中，将在72例主动脉瓣狭窄患者中使用低剂量（2.4g/天）和高剂量（7.2g/天）的sevelamer与安慰剂进行比较。交叉设计（每个人都是自己的对照）提供了统计能力来评估在少数受试者中降低磷酸盐的疗效，并且两种剂量允许评估疗效和耐受性之间的权衡。这项研究将是双盲的；在研究结束之前，参与者和研究人员都不知道正在服用的是安慰剂还是西维拉默，也不知道服用的剂量是多少，从而可以对两种治疗方法进行公正的比较。除了评估疗效和可接受性外，该试点研究还将为最终试验开发招募途径，以评估sevelamer对主动脉狭窄进展的影响，以期将该药物重新用于预防人群中的主动脉狭窄。

We plan to conduct a pilot randomised placebo controlled double-blind cross-over trial to determine whether sevelamer lowers serum phosphate in patients with aortic stenosis.Aortic stenosis is a serious heart condition with no known means of prevention. It is caused by progressive deposition of calcium phosphate crystals on the aortic valve, leading to obstruction of blood flow from the heart. Death follows symptoms of cardiac insufficiency in most cases unless the valve is surgically replaced. About 1.3 million people over age 75 have aortic stenosis in the UK, about one quarter of whom are severely affected. This number is expected to double over the next few decades as the population ages. There is a need for a preventive treatment.The phosphate binding drug, sevelamer, reduces blood phosphate by blocking dietary absorption. Treatment is licensed in patients with kidney failure to lower the high phosphate (2-3 x physiological levels) which results from failed renal excretion and leads to bone disease. Treatment reduces calcium phosphate, raising the possibility of extending its use in the prevention of aortic stenosis, by slowing or arresting valve calcification, in all people with the disorder. It is not known whether sevelamer lowers serum phosphate in patients with aortic stenosis whose phosphate levels are within the physiological range.In the proposed pilot trial, sevelamer, at low dose (2.4g/day) and high dose (7.2g/day) will be compared with placebo in 72 patients with aortic stenosis. The cross-over design (each person is their own control) provides the statistical power to assess efficacy in lowering phosphate with few subjects and the 2 doses allow the trade-off between efficacy and tolerability to be assessed. The study will be double-blind; neither the participants nor the investigators will know whether the placebo or the sevelamer is being taken or at what dose, until the end of the study, allowing an unbiased comparison of the treatments. The pilot study, in addition to assessing efficacy and acceptability, will also develop the recruitment pathways for a definitive trial, to assess the effect of sevelamer on the progression of aortic stenosis, with a view to repurposing this drug for the prevention of aortic stenosis in the population.