Anti-LPS antibody for Pediatric Nonalcoholic Fatty Liver Disease

抗 LPS 抗体治疗小儿非酒精性脂肪肝

基本信息

批准号：
9168600
负责人：
MIRIAM B. VOS
金额：
$ 23.4万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9168600
关键词：
Address Adult Adverse effects Affect Age Alcoholic Hepatitis Antibodies Australia Biopsy Blood Canada Caring Cattle Child Child health care Childhood Chronic Clinic Clinical Clinical Research Clinical Trials Colostrum Controlled Clinical Trials Data Decision Making Double-Blind Method Effectiveness Endotoxemia Enrollment Enzymes Escherichia coli Exposure to FDA approved Feces Future Goals Health Healthcare Hepatic Histology Immune Response Genes Immune response Immunoglobulin G Individual Inflammation Insulin Resistance Letters Life Style Lipids Lipopolysaccharides Liver Liver diseases Measurement Medical Milk Mission Monitor Mucous Membrane Multicenter Trials National Institute of Child Health and Human Development Obesity Participant Patients Permeability Placebo Control Placebos Population Positioning Attribute Powder dose form Quality of life Randomized Recruitment Activity Regulatory T-Lymphocyte Research Design Research Personnel Resolution Ribosomal RNA Risk Role Safety Sample Size Subgroup System Target Populations Testing Therapeutic Traveler&apos s diarrhea United States United States National Institutes of Health Universities Vaccinated blood lipid chronic liver disease cytokine design gut microbiome improved insulin sensitivity liver inflammation liver transplantation medical food member metabolomics microbial microbiome non-alcoholic fatty liver nonalcoholic steatohepatitis novel therapeutics pathogenic bacteria phase 1 study phase 2 study phase III trial pregnant prevent primary outcome response secondary outcome standard of care transcriptomics treatment strategy treatment trial

项目摘要

Project Summary Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects 10-30% of children in the United States. NAFLD is surprisingly aggressive in children and there is currently no approved therapy for it. Because the onset of NAFLD is often in young children (8-12 years), any potential therapeutic for NAFLD will need to be almost risk-free. In this proposal, we seek to study IMM-124E, a medical product that was initially developed for traveler’s diarrhea and has been available over the counter in Australia for years. IMM-124E is a hyperimmune bovine colostrum manufactured by drying the cow’s first milk and packaging it into caplets. This hyperimmune “milk powder” is enriched with IgG against E. coli bacterial products (LPS) by vaccinating the pregnant cow. Because altered microbiome, increased gut permeability, and increased LPS have been shown to be important in the mechanism of NAFLD, IMM-124E has logical support for efficacy in NAFLD. Phase I studies in adults have shown improved insulin resistance, liver enzymes, and promotion of regulatory T-cells. This proposal is designed to test IMM-124E in a small phase II study in children with NAFLD in order to assess preliminary efficacy and safety endpoints and to improve understanding of the mechanisms. This will be accomplished through two aims in a 12 week double-blind, randomized, placebo-controlled clinical trial in children with NAFLD. Aim 1 will determine if 3 months of treatment with IMM-124E in combination with lifestyle changes (standard of care (SOC)) results in greater improvement in 1) hepatic lipid and inflammation, 2) insulin sensitivity, 3) blood lipids, in children with NAFLD, compared to placebo with SOC as well as monitor safety related endpoints. Aim 2 will define mechanisms of action-related endpoints including: stool microbiome, metabolomics, LPS and transcriptomics of innate immune response genes and correlate these with changes in clinical measurements. The proposal leverages state-of-the art platforms at Emory University including high throughput, high resolution metabolomics and established centers for microbiome and transcriptomics to accomplish the mechanism studies. Additionally, we have the clinical population to quickly enroll children into this trial. This proposal addresses the mission of the NIH NCCIH and NICHD by rigorously investigating a complementary treatment with the potential to improve health for large numbers of children. If successful, these studies would support designing a future large scale phase III trial. These studies will enhance our understanding of the role of the gut in pediatric NAFLD and if positive, will result in a low risk, low side effect, high yield therapeutic for pediatric NAFLD.

项目概要非酒精性脂肪肝 (NAFLD) 是一种慢性肝病，影响美国 10-30% 的儿童 NAFLD 对儿童具有惊人的侵袭性，目前尚无批准的治疗方法。 NAFLD 的发病通常是幼儿（8-12 岁），因此任何潜在的 NAFLD 治疗方法都需要在本提案中，我们寻求研究最初开发的医疗产品 IMM-124E。 IMM-124E 是一种用于治疗旅行者腹泻的药物，多年来一直在澳大利亚柜台销售。通过干燥牛初乳并将其包装成囊片而制成的超免疫牛初乳。超免疫“奶粉”通过接种疫苗，富含针对大肠杆菌细菌产物 (LPS) 的 IgG 因为微生物群的改变、肠道通透性的增加和脂多糖的增加已被证明 IMM-124E 在 NAFLD 的发病机制中发挥着重要作用，为 NAFLD 的疗效提供了逻辑支持。成人中的胰岛素抵抗、肝酶和调节性 T 细胞的促进作用得到改善。该提案旨在在 NAFLD 儿童的一项小型 II 期研究中测试 IMM-124E，以评估初步的功效和安全性终点，并提高对机制的理解。通过一项为期 12 周的双盲、随机、安慰剂对照临床试验的两个目标来实现目标 1 将确定是否将 IMM-124E 联合治疗 3 个月。生活方式的改变（护理标准 (SOC)）可显着改善 1) 肝脂和炎症， 2) 胰岛素敏感性，3) 血脂，与带有 SOC 和监测仪的安慰剂相比，NAFLD 儿童目标 2 将定义与行动相关的终点机制，包括：粪便微生物组、先天免疫反应基因的代谢组学、LPS 和转录组学，并将这些与该提案利用了埃默里大学最先进的平台，包括高水平的平台。通量、高分辨率代谢组学以及已建立的微生物组和转录组学中心此外，我们还拥有可以快速招募儿童的临床人群。这项试验通过严格调查来体现 NIH NCCIH 和 NICHD 的使命。如果成功的话，这些补充治疗有可能改善大量儿童的健康。研究将支持设计未来的大规模 III 期试验，这些研究将增强我们的理解。肠道在儿科 NAFLD 中的作用，如果呈阳性，将导致低风险、低副作用、高产量治疗小儿 NAFLD。