Staessen Jan A, Kuznetsova Tatiana, Acceto Rok, Bacchieri Antonella, Brand Eva, Burnier Michel, Celis Hilde, Citterio Lorena, de Leeuw Peter W, Filipovský Jan, Fournier Albert, Kawecka-Jaszcz Kalina, Manunta Paolo, Nikitin Yuri, O'Brien Eoin T, Redón Josep, Thijs Lutgarde, Ferrari Patrizia, Valentini Giovanni, Bianchi Giuseppe
Department of Molecular and Cardiovascular Research, Hypertension and Cardiovascular Rehabilitation Unit, Study Coordinating Centre, University of Leuven, Belgium.
Pharmacogenomics. 2005 Oct;6(7):755-75. doi: 10.2217/14622416.6.7.755.
Experimental evidence and observations in humans strongly support an interactive role of mutated alpha-adducin, sodium (Na(+))/potassium (K(+))-adenosine triphosphatase (ATPase) activity and endogenous ouabain in Na(+) homeostasis and the pathogenesis of hypertension. The Ouabain and Adducin for Specific Intervention on Sodium in HyperTension (OASIS-HT) trial is an early Phase II dose-finding study, which will be conducted across 39 European centers. Following a run-in period of 4 weeks without treatment, eligible patients will be randomized to one of five oral doses of rostafuroxin consisting of 0.05, 0.15, 0.5, 1.5, or 5.0 mg/day. Each dose will be compared to a placebo in a double-blind crossover experiment with balanced randomization. Treatment will be initiated with the active drug and continued with placebo or vice versa. Each double-blind period will last 5 weeks. The primary end point is the reduction in systolic blood pressure defined as the average of three clinic readings with the patient in the sitting position. Secondary end points include the reduction in diastolic blood pressure on clinic measurement, the decrease in the 24-h blood pressure, and the incidence of end points related to safety. Secondary objectives are to investigate the dependence of the blood pressure-lowering activity on the plasma concentration of endogenous ouabain and the genetic variation of the enzymes involved in the metabolism of this hormone, and the adducin cytoskeleton proteins. Eligible patients will have Grade I or II systolic hypertension without associated conditions and no more than two additional risk factors. In conclusion, OASIS-HT is a combination of five concurrent crossover studies, one for each dose of rostafuroxin to be studied. To our knowledge, OASIS-HT is the first Phase II dose-finding study in which a genetic hypothesis is driving primary and secondary end points.
人体实验证据和观察结果有力地支持了突变的α-内收蛋白、钠（Na⁺）/钾（K⁺）-三磷酸腺苷酶（ATP酶）活性和内源性哇巴因在钠稳态及高血压发病机制中的相互作用。“高血压钠特异性干预的哇巴因与内收蛋白”（OASIS-HT）试验是一项早期II期剂量探索研究，将在39个欧洲中心开展。在为期4周的无治疗导入期后，符合条件的患者将被随机分配至五种口服剂量的罗沙呋辛之一，剂量分别为0.05、0.15、0.5、1.5或5.0毫克/天。在平衡随机化的双盲交叉实验中，每种剂量都将与安慰剂进行比较。治疗将从活性药物开始，然后持续使用安慰剂，反之亦然。每个双盲期将持续5周。主要终点是收缩压降低，定义为患者坐位时三次诊室测量值的平均值。次要终点包括诊室测量的舒张压降低、24小时血压降低以及与安全性相关的终点发生率。次要目标是研究降压活性对内源性哇巴因血浆浓度以及参与该激素代谢的酶和内收蛋白细胞骨架蛋白基因变异的依赖性。符合条件的患者将患有I级或II级收缩期高血压，无相关并发症且额外风险因素不超过两个。总之，OASIS-HT是五项同时进行的交叉研究的组合，每种待研究的罗沙呋辛剂量对应一项研究。据我们所知，OASIS-HT是首个以遗传假设驱动主要和次要终点的II期剂量探索研究。
