MICA: Prevention of Aortic Stenosis (PAS) Pilot Trial

我们计划进行一项随机安慰剂对照双盲交叉试验，以确定司维拉姆是否能降低主动脉瓣狭窄患者的血磷水平。主动脉瓣狭窄是一种严重的心脏疾病，目前尚无预防方法。它是由磷酸钙晶体在主动脉瓣上进行性沉积引起的，导致心脏血流受阻。在大多数情况下，死亡伴随着心功能不全的症状，除非手术置换瓣膜。在英国，约有130万75岁以上的人患有主动脉瓣狭窄，其中约四分之一受到严重影响。随着人口老龄化，这一数字预计在未来几十年内将翻一番。需要预防性治疗。磷酸盐结合药物司维拉姆通过阻断饮食吸收来降低血磷。治疗被许可用于肾衰竭患者，以降低高磷酸盐（2-3倍生理水平），这是由于肾排泄失败导致的，并导致骨骼疾病。治疗减少磷酸钙，提高了延长其在预防主动脉瓣狭窄中的使用的可能性，通过减缓或阻止瓣膜钙化，在所有患有这种疾病的人中。目前尚不清楚司维拉姆是否能降低磷酸盐水平在生理范围内的主动脉瓣狭窄患者的血清磷酸盐水平。在拟议的初步试验中，将在72名主动脉瓣狭窄患者中比较低剂量（2.4g/天）和高剂量（7.2g/天）的司维拉姆与安慰剂。交叉设计（每个人是他们自己的对照）提供了统计学把握度，以评估在降低磷酸盐方面的疗效，受试者较少，2种剂量允许评估疗效和耐受性之间的权衡。本研究为双盲研究;受试者和研究者均不知道是否正在服用安慰剂或司维拉姆或以何种剂量服用，直至研究结束，以便对治疗进行无偏倚比较。除了评估疗效和可接受性外，该初步研究还将为确定性试验开发招募途径，以评估司维拉姆对主动脉瓣狭窄进展的影响，以期重新利用该药物预防人群中的主动脉瓣狭窄。

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.