Collaborative Clinical Research in Nonalcoholic Steatohepatitis

项目总结 本申请是对RFA-DK-18-505的响应，这是一个有限的竞争机会，以 继续支持NASH临床研究网络(NASH CRN)的临床中心。虽然 在我们对这种疾病的了解上已经取得了重大进展，有许多临床上重要的 知识差距仍然存在，NASH CRN将在下一个供资周期弥补这一差距。为了满足 RFA-DK-18-505的研究目标，我们在下一次资助中提出了以下具体目标 期间：具体目标1：成功完成以下正在进行的多中心研究：(A)NAFLD 数据库2，成人(n=2240)和儿童(n=949)经活检证实为非酒精性脂肪肝的纵向数据库，(B) Stop-NAFLD(n=110)：氯沙坦治疗儿童肝活检的随机、安慰剂对照、双盲试验 已证实的非酒精性脂肪肝，以及(C)Vatiquone的随机、安慰剂对照、双盲试验 组织学特征为NAFLD的成人；具体目标2：成功完成正在进行的辅助治疗 和转化性研究在本资助期内由印第安纳大学临床中心发起；具体目标3： 我们的中心假设是FADS1基因变异对儿童NAFLD非常重要。(A)至 经肝活检证实的儿童FADS1基因变异与肝组织学关系的研究 NAFLD。在美国多个临床中心登记的1200多名经活检证实患有NAFLD的儿童中 在美国，我们将研究FADS1单倍型与肝脏之间的基因-表型相关性 儿童非酒精性脂肪肝的组织学研究。(B)检验FADS1基因可预测对疾病的反应的假设 EPA/DHA治疗儿童NAFLD我们将通过进行一项临床研究来检验这一假设 25例FADS1低活性单倍型(单倍型A/A18)纯合子的NAFLD儿童和25例 正常活动单倍型(单倍型D/D18)纯合子的NAFLD儿童将服用鱼油 (2-3克体重)，每天口服，连续16周。大鼠红细胞EPA/DHA的浓缩 补充鱼油是药效学的终点，而肝脏脂肪和血清的变化 转氨酶是疗效的终点。具体目的4：评价一种新的PPARα/γ激动剂， Saroglitazar，用于成人NASH。Saroglitazar是一种非常有吸引力的进一步试验的药物，因为 PPARα/γ激动剂在改善NASH和稳健的临床前和早期临床和安全数据方面的理论基础。在……里面 这项随机对照试验，160名符合NASH预定义资格的成年人将获得 沙格列他(每天4毫克口服)或安慰剂，疗程72周。主要的疗效终点是改善 中央审查的肝脏组织学，定义为NAFLD活动评分(NAS)至少下降2分 不会加重纤维化。

PROJECT SUMMARY This application is submitted in response to the RFA-DK-18-505 which is a limited competition opportunity to continue the support for the clinical centers of the NASH Clinical Research Network (NASH CRN). Although significant progress has been made in our understanding of this disease, numerous clinically important knowledge gaps remain which will be addressed by the NASH CRN during the next funding cycle. To meet the research objectives of the RFA-DK-18-505, we propose the following specific aims during the next funding period: Specific Aim 1: To successfully complete the following ongoing multicenter studies: (a) NAFLD Database 2, a longitudinal database of adults (n=2240) and children (n=949) with biopsy proven NAFLD, (b) STOP-NAFLD (n=110), a randomized, placebo-controlled, double-blind trial of losartan in children with biopsy proven NAFLD, and (c) VANISH (n=90), a randomized, placebo-controlled, double-blind trial of vatiquinone in adults with histologically characterized NAFLD; Specific Aim 2: To successfully complete ongoing ancillary and translational studies initiated during the current funding period by the IU Clinical Center; Specific Aim 3: Our central hypothesis is that FADS1 genetic variation is highly important for pediatric NAFLD. (A) To investigate the relationship between FADS1 genetic variation and liver histology in children with biopsy proven NAFLD. In more than 1,200 children with biopsy-proven NAFLD enrolled at multiple clinical centers in the United States, we will examine the genotype-phenotype correlation between FADS1 haplotype and liver histology in pediatric NAFLD. (B) To test the hypothesis that FADS1 genotype predicts the response to EPA/DHA treatment in children with NAFLD. We will test this hypothesis by conducting a clinical study in which 25 children with NAFLD who are homozygote for FADS1 low-activity haplotype (haplotype A/A18) and 25 children with NAFLD who are homozygote for normal-activity haplotype (haplotype D/D18) will receive fish oil (2-3 grams weight based) orally every day for 16 weeks. The EPA/DHA enrichment of erythrocytes following fish oil supplementation is the pharmacodynamic endpoint whereas changes in hepatic fat and serum aminotransferases are the efficacy endpoints. Specific Aim 4: To evaluate a novel PPAR α/γ agonist, saroglitazar, in adults with NASH. Saroglitazar is a highly attractive agent for further testing due to strong rationale for PPARα/γ agonism in improving NASH and robust preclinical and early clinical and safety data. In this randomized controlled trial, 160 adults with NASH meeting predefined eligibility will receive either saroglitazar (4 mg orally daily) or placebo for 72 weeks. The primary efficacy endpoint is improvement in centrally reviewed liver histology, defined as a decrease in NAFLD activity score (NAS) by at least 2 points without worsening of fibrosis.