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

奥利司他治疗 1 型高脂蛋白血症的长期疗效和安全性：一项随机、双盲、安慰剂对照试验

• 批准号: 10570530
• 负责人: Abhimanyu Garg
• 金额: $ 55.06万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570530
• 关键词: 9 year old; Admission activity; Adult; Apolipoproteins; Atherosclerosis; Body Weight; Chemistry; Child; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Consumption; Coronary heart disease; Cross-Over Studies; Cross-Over Trials; Data; Dependovirus; Development; Diabetes Mellitus; Diagnosis; Dietary Fats; Disease; Docosahexaenoic Acids; Double-Blind Method; Eicosapentaenoic Acid; Enrollment; Equilibrium; Evaluation; Excretory function; Familial Hypercholesterolemia; Familial Lipoprotein Lipase Deficiency; Fasting; Fat-Restricted Diet; Fat-Soluble Vitamin; Fatty acid glycerol esters; Fibrates; Fish Oils; Hepatic; Hepatosplenomegaly; Hour; Hyperlipoproteinemia; Hypertriglyceridemia; Inpatients; Intestines; Life; Lipase; Lipoproteins; Liver; Longitudinal Studies; Loss of Heterozygosity; Low-Density Lipoproteins; Marketing; Measures; Metabolic Diseases; Minerals; Modeling; Morbidity - disease rate; Nephrolithiasis; Nicotinic Acids; Omega-3 Fatty Acids; Outcome; Oxalates; Pancreas; Patients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Plasmapheresis; Prevalence; Procedures; Proteins; Quality of life; Questionnaires; Randomized; Recurrence; Reporting; Research Design; Research Personnel; Risk; Safety; Serum; Spleen; Steatorrhea; Stomach; Syndrome; Testing; Thrombocytopenia; Time; Toxic effect; Triglycerides; United States Food and Drug Administration; Urine; Variant; Xanthomas; absorption; acute pancreatitis; apolipoprotein B-48; autosome; chronic pancreatitis; diacylglycerol O-acyltransferase; dietary; double-blind placebo controlled trial; early childhood; effective therapy; fecal microbiota; gastrointestinal; gastrointestinal symptom; gene therapy; infancy; inhibitor; lipoprotein lipase; loss of function; male; man; microsomal triglyceride transfer protein; mortality; novel therapeutics; older women; open label; orlistat; prevent; primary endpoint; screening; secondary endpoint; side effect; trial design

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.

抽象的 I 型高脂蛋白血症（T1HLP，也称为家族性乳糜微粒血症综合征或 FCS）是一种罕见的、 常染色体隐性遗传代谢病，其特征是由于缺乏甘油三酯而导致极度高甘油三酯血症 脂蛋白脂肪酶或相关蛋白的治疗与传统的甘油三酯治疗一样具有挑战性。 然而，降脂药物（例如贝特类药物和鱼油）无效。 尽管饮食依从性良好，但一些患者仍然患有严重的高甘油三酯血症并反复发作 胰腺炎可能危及生命，迫切需要开发新的治疗方案。 对于这些患者，目前还没有 FDA 批准的药物治疗。 奥利司他（肠脂肪酶抑制剂）的四周期、两序列随机、开放标签临床试验 （“奥利司他”和“停用奥利司他”3个月），针对两名年轻男性（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，且副作用极小。 奥利司他治疗儿童和成人 T1HLP 的长期疗效和安全性仍不清楚。 长期使用奥利司他的潜在并发症包括脂溶性维生素缺乏、脂肪泻、 高草酸尿症肾结石和粪便微生物群的改变。 因此，我们希望研究奥利司他降低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 患者（空腹血清甘油三酯≥ 1,000 mg/dL）。 筛选后进行开放标签延伸的随机、双盲、安慰剂对照、交叉试验。 评估时，将建议受试者食用极低脂肪饮食（≤脂肪总能量的15%） 在 8 周的基线期后，他们将被随机分配到安慰剂组。 或奥利司他持续 24 周（第 1 阶段），第 1 阶段后，所有患者将进入开放标签延期。 （第 2 阶段）并在最后一周接收或列出 24 周，总持续时间为 48 周。 基线期、第 1 阶段和第 2 阶段第 24 周时，患者将被送往住院临床 研究单位4天测量血清脂蛋白和化学板连续3天，脂溶性 维生素水平、24 小时尿液草酸盐和结石风险概况、矿物质平衡、72 小时粪便脂肪、粪便微生物群、 肝甘油三酯、肝脏和脾脏体积，并将完成胃肠道和生活质量调查问卷。 主要终点是空腹血清甘油三酯，次要终点变量是载脂蛋白。 通过测量体内脂溶性维生素水平来评估 B-48 水平、肝脏脂肪含量和体积。 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群。 广义线性混合模型将用于统计比较。我们的数据将确定长期。 奥利司他治疗 T1HLP 患者的安全性和有效性，奥利司他可能成为一线治疗 这些患者极低脂肪饮食的辅助手段。