Phase 2 Study of Orlistat and SLX-4090 for Type I Hyperlipoproteinemia

描述(由申请人提供)： I型高脂蛋白血症是一种罕见的常染色体隐性代谢性疾病，其特征是由于脂蛋白脂肪酶或相关蛋白缺乏而导致的极度高甘油三酯血症。这些患者的治疗是具有挑战性的，因为降低甘油三酯的药物无效。低脂肪饮食是有帮助的，然而，尽管饮食依从性良好，一些患者仍有严重的高甘油三酯血症和复发性胰腺炎，这可能危及生命。因此，本研究将探讨诱导膳食脂肪吸收不良或抑制乳糜粒形成是否会导致超出限制膳食脂肪摄入量的血清甘油三酯的进一步降低。研究人员将评估一种肠道脂肪酶抑制剂(奥利司他)和一种参与乳糜粒组装和分泌的肠道特异性微粒体甘油三酯运输蛋白(MTP)抑制剂(SLX-4090)单独和联合使用降低I型高脂蛋白血症患者血清甘油三酯水平的有效性和安全性。这项研究将招募20名I型高脂蛋白血症患者参加随机、双盲、安慰剂对照、交叉试验。在基线评估后，受试者将被随机分配到安慰剂/安慰剂、奥利司他/安慰剂、SLX-4090/安慰剂或奥利司他/SLX-4090，为期四周，然后是一周的洗脱期。在每个研究期的最后一周，将连续三天抽取空腹血样进行血脂和化学组检查。主要终点将是血清甘油三酯；次要终点变量将是空腹和餐后血清乳杆菌-甘油三酯水平、餐后耐量试验期间的餐后血清甘油三酯水平和餐耐量试验期间的视黄酸棕榈酸酯水平，以及急性胰腺炎的发作。将使用重复测量方差分析进行统计比较。

DESCRIPTION (provided by applicant): Type I hyperlipoproteinemia is a rare, autosomal recessive metabolic disorder characterized by extreme hypertriglyceridemia due to a deficiency in lipoprotein lipase or related proteins. Treatment of these patients is challenging as triglyceride-lowering medications are ineffective. A low fat diet is helpful, however, despite good dietary compliance, some patients continue to have severe hypertriglyceridemia and recurrent pancreatitis which can be life threatening. Therefore, this study will investigate whether inducing dietary fat malabsorption or inhibiting chylomicron formation will cause further lowering of serum TG beyond the effect of limiting dietary fat intake. The investigators will assess the efficacy and safety of an inhibitor of intestinal lipase (Orlistat) and an intestinal-specific inhibitor of microsomal triglyceride transport protein (MTP) involved in the assembly and secretion of chylomicrons (SLx-4090), alone and in combination, for reducing serum triglyceride levels in patients with type I hyperlipoproteinemia. This study will enroll 20 patients with type I hyperlipoproteinemia in a randomized, double-blind, placebo-controlled, cross-over trial. After a baseline evaluation, the subjects will be randomly assigned to placebo/placebo, Orlistat/placebo, SLx-4090/placebo or Orlistat/SLx-4090 for the duration of four weeks followed by a one week wash out period. During the last week of each study period, fasting blood samples will be drawn for three consecutive days for serum lipids and chemistry panel. The primary endpoint will be serum triglycerides; the secondary endpoint variables will be fasting and postprandial serum chylomicron-TG levels, postprandial serum TG levels during a meal tolerance test and retinyl palmitate levels during a meal tolerance test, and episodes of acute pancreatitis. Repeated measures analysis of variance will be used for statistical comparisons.