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遗传代谢紊乱，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脂血症。 这些患者的治疗是具有挑战性的，因为降血糖药物无效。 低脂饮食是有帮助的，然而，尽管饮食依从性良好，但一些患者仍然患有严重的高脂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微粒形成是否会导致血清TG进一步降低，而不仅仅是限制膳食脂肪摄入量。研究者将评估肠脂肪酶抑制剂（奥利司他）和参与乳糜微粒组装和分泌的微粒体甘油三酯转运蛋白（MTP）的尿特异性抑制剂（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疗效和安全性。 本研究将在一项随机、双盲、安慰剂对照、交叉试验中入组20例I型高脂蛋白血症患者。 基线评估后，受试者将被随机分配至安慰剂/安慰剂、奥利司他/安慰剂、SLx-4090/安慰剂或奥利司他/SLx-4090，持续四周，然后是一周的洗脱期。 在每个研究阶段的最后一周，将连续三天采集空腹血样，用于血脂和生化检查。 主要终点为血清甘油三酯;次要终点变量为空腹和餐后血清乳糜微粒-TG水平、进餐耐量试验期间的餐后血清TG水平和进餐耐量试验期间的棕榈酸视黄酯水平以及急性胰腺炎发作。 重复测量方差分析将用于统计比较。

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.