Low Dose Thyroid Hormone, Mitochondrial Fatty Acid Oxidation, and Treatment of Nonalcoholic Steatohepatitis (NASH)

低剂量甲状腺激素、线粒体脂肪酸氧化和非酒精性脂肪性肝炎 (NASH) 的治疗

• 批准号: 10483713
• 负责人: JAMAL A IBDAH
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483713
• 关键词: Adverse event; Animals; Biogenesis; Biopsy; Biopsy Specimen; Cell Culture Techniques; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Control Groups; Controlled Clinical Trials; Cultured Cells; Data; Diagnosis; Dose; Double-Blind Method; Energy Intake; Enzymes; Epidemic; Fatty acid glycerol esters; Fibrosis; Gene Expression; Goals; Health; Histologic; In Vitro; Life Style Modification; Link; Liver; Liver Fibrosis; Liver Mitochondria; Malignant neoplasm of liver; Measurement; Measures; Mediating; Military Personnel; Mitochondria; Multienzyme Complexes; Mus; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Obesity; Outcome; PINK1 gene; PPAR alpha; Pathologic; Patients; Physical activity; Placebo Control; Placebos; Population; Prevalence; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Probability; Proteins; Public Health; Quality Control; Randomized; Recommendation; SIRT1 gene; Testing; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Titrations; United States; Veterans; active method; chronic liver disease; clinically relevant; comparison control; diet and exercise; effective therapy; efficacy evaluation; end stage liver disease; fatty acid oxidation; human data; human subject; imaging study; improved; in vivo; liver biopsy; long chain fatty acid; military veteran; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; placebo group; power analysis; pre-clinical; primary outcome; recruit; secondary outcome; standard care; success; treatment group; treatment response; treatment strategy; trend

Nonalcoholic steatohepatitis (NASH) is an aggressive part of the pathological spectrum of nonalcoholic fatty liver disease (NAFLD) that has evolved into a world-wide epidemic and is the most common chronic liver disease in the United States. NASH is strongly linked to obesity, and type 2 diabetes mellitus and may progress to cirrhosis and liver cancer. Disturbingly, prevalence rates of NASH appear to be greater in the Veteran population compared with the general US population. Thus, the burden of NASH is substantial to Veterans. Despite the recognition of NASH as a major public health problem, only lifestyle modifications aimed at increasing physical activity and reducing caloric intake are currently recommended as treatments with limited success. Thus, there is a great need for effective therapy of NASH. The goal of this study is to test whether low dose thyroid hormone administered to Veterans with biopsy-proven NASH, at a titrated dose that will maintain thyroid function within normal range, can result in histological improvement of NASH, measured by significant reduction in nonalcoholic fatty liver disease score (NAS). The hypothesis is that low dose thyroid hormone causes histological improvement in NASH by increasing mitochondrial FAO in the liver mediated by an increase in mitochondrial trifunctional protein (MTP), the key enzyme in FAO cycle. The preliminary clinical studies in human subjects, including Veterans, support reduced FAO in NASH. In addition, preclinical in vivo animal studies and in vitro cell culture studies support that low dose thyroid hormone can effectively increase mitochondrial fatty acid oxidation and rescue NAFLD. In a randomized double-blinded placebo-controlled clinical trial, Veterans with normal thyroid levels and biopsy-proven NASH will be recruited and randomized to receive 52 weeks of either active treatment (low dose levothyroxine) or placebo control to accomplish the following Specific Aims. 1) To determine the efficacy of low dose thyroid hormone in improving NASH histological features. To accomplish this aim, NAS will be measured in pre- and post-liver biopsy samples. 2) To determine the effect of low dose thyroid hormone on mitochondrial FAO, MTP, and mitochondrial health markers in the liver compared to control. To accomplish this aim, mitochondrial FAO and the expression of genes supporting mitochondrial health will be measured in the pre- and post-liver biopsy samples. The primary clinical outcome is histological improvement in NASH measured by improvement in NAS and the secondary clinical outcome is improvement in fibrosis stage. The mechanistic outcomes include improvements in mitochondrial FAO, MTP, and quality markers. This project will be conducted in two stages. In stage 1 (proof- of-concept, 2 years), 32 Veterans with biopsy-proven NASH will be recruited and randomized to either the active treatment or placebo groups (16/group). At the end of the second year, interim analysis will be performed based on criteria that will include conditional power analysis for early efficacy to determine the probability that the full study will yield a statistically significant finding in the primary outcome (histological improvement in NASH) in the clinically relevant direction. Other milestones include trend in the secondary outcome, adverse events, and feasibility. The outcome from the proof-of-concept stage will guide the Go or No-Go decision to stage 2 for continuation of the study with recruitment of additional Veterans for a full 6-year clinical trial (total recruitment of 128 Veterans with biopsy-proven NASH: 64/active treatment group and 64/placebo control group). This project will exert a sustained and powerful impact in the field by providing new information and strategies for treatment of NASH that will be highly relevant and impactful to the health of the Veteran population.

非酒精性脂肪性肝炎 (NASH) 是非酒精性脂肪性肝炎病理谱中的一个侵袭性部分 肝病（NAFLD）已发展成为世界范围内的流行病，是最常见的慢性肝病 疾病发生在美国。 NASH 与肥胖和 2 型糖尿病密切相关，并且可能 进展为肝硬化和肝癌。令人不安的是，NASH 的患病率似乎更高 退伍军人人口与美国普通人口的比较。因此，NASH 的负担是巨大的 退伍军人。尽管 NASH 被认为是一个主要的公共卫生问题，但只有改变生活方式才能达到目标 目前推荐的治疗方法是增加体力活动和减少热量摄入 成功有限。因此，非常需要NASH的有效治疗。这项研究的目的是测试 是否向经活检证明患有 NASH 的退伍军人施用低剂量甲状腺激素，滴定剂量 将甲状腺功能维持在正常范围内，可导致 NASH 的组织学改善（经测量） 通过显着降低非酒精性脂肪肝疾病评分（NAS）。假设是低剂量甲状腺 激素通过增加肝脏中线粒体FAO介导的NASH组织学改善 线粒体三功能蛋白 (MTP) 的增加，这是FAO循环中的关键酶。初步临床 对包括退伍军人在内的人类受试者的研究支持减少 NASH 中的粮农组织。此外，临床前体内 动物研究和体外细胞培养研究支持低剂量甲状腺激素可有效增加 线粒体脂肪酸氧化和拯救 NAFLD。在一项随机双盲安慰剂对照研究中 临床试验中，甲状腺水平正常且活检证实 NASH 的退伍军人将被招募并随机分组 接受 52 周的积极治疗（低剂量左旋甲状腺素）或安慰剂对照以实现 遵循具体目标。 1) 确定低剂量甲状腺激素改善 NASH 的功效 组织学特征。为了实现这一目标，将在肝活检样本中测量 NAS。 2） 确定低剂量甲状腺激素对线粒体FAO、MTP和线粒体健康的影响 与对照相比，肝脏中的标记物。为了实现这一目标，线粒体FAO和表达 支持线粒体健康的基因将在肝活检样本中进行测量。初级 临床结果是 NASH 的组织学改善，通过 NAS 的改善和继发性症状的改善来衡量 临床结果是纤维化阶段的改善。机械结果包括以下方面的改进： 线粒体FAO、MTP 和质量标记。该项目将分两个阶段进行。在第一阶段（证明- 概念阶段，2 年），将招募 32 名经活检证明患有 NASH 的退伍军人，并随机分配到 积极治疗组或安慰剂组（16/组）。第二年年底，将进行中期分析 执行的标准包括早期疗效的条件功效分析，以确定 完整的研究将在主要结果（组织学 NASH 的改善）在临床相关方向。其他里程碑包括中学的趋势 结果、不良事件和可行性。概念验证阶段的结果将指导 Go 或 决定不进入第二阶段，继续研究并招募额外的退伍军人进行为期六年的研究 临床试验（总共招募了 128 名经活检证实 NASH 的退伍军人：64 名/积极治疗组和 64/安慰剂对照组）。该项目将通过提供新的领域，在该领域产生持续而强大的影响。 NASH 治疗的信息和策略对人们的健康具有高度相关性和影响力 退伍军人人口。