Long term efficacy and safety of orlistat for type 1 hyperlipoproteinemia: a randomized, double-blind, placebo-controlled trial

摘要 I型高脂蛋白血症(T1HLP，又称家族性乳糜斑综合征或FCS)是一种罕见的 常染色体隐性代谢性疾病的特征是由于缺乏 脂蛋白脂肪酶或相关蛋白质。这些患者的治疗像传统的甘油三酯一样具有挑战性- 降压药物，如贝特类和鱼油，是无效的。然而，极低脂肪的饮食是有帮助的， 尽管饮食依从性良好，但一些患者仍有严重的高甘油三酯血症和复发。 可能危及生命的胰腺炎。迫切需要开发新的治疗方案来治疗 这些患者目前还没有FDA批准的药物。我们最新的初步数据来自 奥利司他(一种肠道脂肪酶抑制剂)的随机、开放标签、四周期、两序列临床试验 (“奥利司他”和“停用奥利司他”为期3个月)，两名年轻男性(11岁和9岁)的交叉研究设计， T1HLP显示空腹血清甘油三酯降低了50%以上，副作用很小。然而， 奥利司他治疗儿童和成人T1HLP的长期疗效和安全性尚不清楚。 长期服用奥利司他的潜在并发症包括脂溶维生素缺乏，脂肪泻， 高草酸尿性肾结石与粪便微生物区系改变。 因此，我们希望研究奥利司他降低高脂血症患者血清甘油三酯水平的长期疗效和安全性。 T1HLP患者。我们计划招募28名T1HLP(空腹血清甘油三酯≥1,000 mg/dL)患者参加 随机、双盲、安慰剂对照、开放标签扩展的交叉试验。在放映之后 评估后，将建议受试者摄入极低脂肪的饮食(≤占总脂肪能量的15%) 研究的整个持续时间。在8周的基准期之后，他们将被随机分配到安慰剂组 或奥利司他治疗24周(第1期)。在第一阶段之后，所有患者将进入开放标签扩展 (2)口服奥利司他，疗程24周，共48周。在过去一周内 基线阶段，阶段1，在阶段2的24周时，患者将进入住院临床 研究组连续4天测定血清脂蛋白和化学板，脂溶 维生素水平，24小时尿草酸和结石风险概况，矿物质平衡，72小时粪便脂肪，粪便微生物区系， 肝甘油三酯、肝脾体积，并将完成胃肠道和生活质量调查问卷。 主要终点将是空腹血清甘油三酯。次要终点变量将是载脂蛋白 B-48水平、肝脏脂肪含量和体积。安全性将通过测量脂溶维生素水平、身体 体重、生活质量、胃肠道症状、草酸尿、粪便脂肪排泄和粪便微生物区系。 广义线性混合模型将用于统计比较。我们的数据将决定长期 奥利司他治疗T1HLP和奥利司他的安全性和有效性可能成为AS 在这些患者中作为极低脂肪饮食的补充。

Abstract Type I hyperlipoproteinemia (T1HLP, also known as familial chylomicronemia syndrome or FCS) is a rare, autosomal recessive metabolic disorder characterized by extreme hypertriglyceridemia due to a deficiency of lipoprotein lipase or related proteins. Treatment of these patients is challenging as conventional triglyceride- lowering medications, such as fibrates and fish oil, are ineffective. An extremely 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. There is a pressing need for developing novel therapeutic options for these patients, as currently, there is no FDA approved medication. Our recent preliminary data from a randomized, open-label, clinical trial of orlistat (an inhibitor of intestinal lipase) with a four-period, two- sequence (“orlistat” and “off orlistat” for 3 months), crossover study design in two young males (11 and 9 years old) with T1HLP revealed more than 50% reduction in fasting serum triglycerides with only minimal side effects. However, the long-term efficacy and safety of orlistat therapy for children and adults with T1HLP remains unknown. Potential complications of long-term orlistat use include deficiencies in fat soluble vitamins, steatorrhea, hyperoxaluric nephrolithiasis, and alteration in fecal microbiota. Therefore, we wish to study the long-term efficacy and safety of orlistat for reducing serum triglyceride levels in patients with T1HLP. We plan to enroll 28 patients with T1HLP (fasting serum triglycerides ≥ 1,000 mg/dL) in a randomized, double-blind, placebo-controlled, cross-over trial with an open-label extension. After a screening evaluation, the subjects will be advised to consume an extremely low fat diet (≤15% of total energy from fat) for the entire duration of the study. After the baseline period of 8 weeks, they will be randomly assigned to placebo or orlistat for the duration of 24 weeks (Phase 1). After Phase 1, all patients will enter an open-label extension (Phase 2) and receive orlistat for a period of 24 weeks for a total duration of 48 weeks. During the last week of Baseline Period, Phase 1, and at 24 weeks of Phase 2, patients will be admitted to the in-patient Clinical Research Unit for 4 days to measure serum lipoproteins and chemistry panel for 3 consecutive days, fat-soluble vitamin levels, 24 hour urine oxalate and stone risk profile, mineral balance, 72 hour fecal fat, fecal microbiota, hepatic triglyceride, liver and spleen volume, and will complete gastrointestinal and quality of life questionnaires. The primary endpoint will be fasting serum triglycerides. The secondary endpoint variables will be apolipoprotein B-48 levels, liver fat content and volume. Safety will be assessed by measuring fat soluble vitamins levels, body weight, quality of life, gastrointestinal symptoms, oxalic aciduria, fecal fat excretion and fecal microbiota. Generalized linear mixed models will be used for statistical comparisons. Our data will determine long-term safety and efficacy of orlistat therapy for patients with T1HLP and orlistat may become the first line therapy as an adjunct to extremely low fat diet in these patients.