Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in North America (1). Hepatic steatosis (HS) is the hallmark of NAFLD (2). NAFLD may transition in sub-groups to chronic inflammation (non- alcoholic steatohepatitis, NASH), and ultimately to cirrhosis. HS is prevalent in all stages of NAFLD. 3-10% of all children in the US and 40-70% of obese children have HS (3). There are approximately 15 million obese children in the US (4), meaning that as many as 10 million youths have HS. Pediatric HS is associated with premature mortality due to type 2 diabetes (T2D), cardiovascular disease (CVD) and progressive liver disease in early adulthood (5,6). Successful treatment of pediatric HS is therefore central to long-term metabolic and cardiovascular health. Recommended options are largely limited to behavioral modifications (i.e., weight loss and exercise) and nutritional supplement with Vitamin E (3,5-7). There is no FDA-approved drug for the treatment of NAFLD in individuals of any age. We propose to perform a randomized clinical trial (RCT) in youths with HS. We will expand our previous study in which treatment with our essential amino acid (EAA)-based composition called AMS2392 reduced liver fat in adolescent females with polycystic ovary syndrome (PCOS). Specific Aim 1. We will investigate the hypothesis that 8 weeks of treatment with AMS2392 will reduce liver fat in youths with HS. We will perform a double-blind RCT in 48 male and female youths 13 to 18 years of age (Tanner stage 4 or 5) with biopsy-documented HS. Liver fat content will be measured by magnetic resonance imaging (MRI) at the outset and after the eight-week intervention. Specific Aim 2. We propose that secondary end points of liver stiffness, body composition, insulin sensitivity, and plasma concentrations of very-low density triglycerides (VLDL-TG), alanine transaminase (ALT), ApoB100, creatinine and insulin sensitivity will be improved in the group receiving AMS2392 as compared to placebo. Specific Aim 3. Adherence to protocol will be greater than 90% and there will be no adverse events in those consuming AMS2392, including no change in plasma glutathione concentration. Completion of this RCT will provide information regarding efficacy, effect size, safety and tolerance that will position us to successfully market AMS2392 as a medical nutrition product.
Public Health Relevance Statement: 8. Project Narrative We will perform a double-blind placebo randomized clinical trial (RCT) in male and female youths 13 to 17 years of age with biopsy-documented hepatic steatosis and clinically diagnosed NAFLD. Eight weeks of treatment with AMS2392 will be compared to placebo. The primary endpoint will be liver fat content as measured by magnetic resonance imaging (MRI) at the outset and after the eight-week intervention.
Project Terms: adolescent girl; Female Adolescents; ages; Age; Aging; ALT1; Alanine Aminotransferase; Alanine-2-Oxoglutarate Aminotransferase; Glutamic-Alanine Transaminase; Glutamic-Pyruvate Transaminase; Glutamic-Pyruvic Transaminase; Alanine Transaminase; ethanol use disorder; alcohol use disorder; aminoacid; Amino Acids; essential aminoacid; Essential Amino Acids; Base Composition; Behavior Therapy; Behavior Conditioning Therapy; Behavior Modification; Behavior Treatment; Behavioral Conditioning Therapy; Behavioral Modification; Behavioral Therapy; Behavioral Treatment; Conditioning Therapy; behavior intervention; behavioral intervention; Biopsy; Body Composition; Cardiovascular Diseases; cardiovascular disorder; Child; 0-11 years old; Child Youth; Children (0-21); kids; youngster; Clinical Trials; Creatinine; Non-Insulin-Dependent Diabetes Mellitus; Adult-Onset Diabetes Mellitus; Ketosis-Resistant Diabetes Mellitus; Maturity-Onset Diabetes Mellitus; NIDDM; Non-Insulin Dependent Diabetes; Noninsulin Dependent Diabetes; Noninsulin Dependent Diabetes Mellitus; Slow-Onset Diabetes Mellitus; Stable Diabetes Mellitus; T2 DM; T2D; T2DM; Type 2 Diabetes Mellitus; Type 2 diabetes; Type II Diabetes Mellitus; Type II diabetes; adult onset diabetes; ketosis resistant diabetes; maturity onset diabetes; type 2 DM; type II DM; type two diabetes; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Exercise; Experimental Designs; Fatty acid glycerol esters; Fats; Fatty Liver; Liver Steatosis; hepatic steatosis; hepatosteatosis; Female; Food; Glutathione; gamma-L-Glu-L-Cys-Gly; gamma-L-Glutamyl-L-Cysteinylglycine; Inflammation; Liver; hepatic body system; hepatic organ system; Liver diseases; Hepatic Disorder; hepatic disease; hepatopathy; liver disorder; Magnetic Resonance Imaging; MR Imaging; MR Tomography; MRI; MRIs; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Zeugmatography; male; Marketing; North America; nutrition; Placebos; Sham Treatment; sham therapy; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Polycystic Ovary Syndrome; Polycystic Ovarian Disease; Polycystic Ovarian Syndrome; Sclerocystic Ovarian Degeneration; Sclerocystic Ovary Syndrome; polycystic ovary; polycystic ovary disease; polycystic ovary disorder; Protons; H+ element; Hydrogen Ions; Puberty; Public Health; Publishing; Recommendation; Safety; Medical Societies; Triglycerides; Triacylglycerol; Vitamin E; Body Weight decreased; Weight Loss; Weight Reduction; body weight loss; wt-loss; very low density lipoprotein triglyceride; VLDL triacylglycerol; VLDL triglyceride; VLDL triglyceride lipoprotein; Measures; Youth 10-21; Youth; Crossover Studies; Cross-Over Studies; Blinded; New Drug Approvals; density; dosage; improved; Chronic; Medical; Adolescent Youth; juvenile; juvenile human; Adolescent; randomized, clinical trials; pediatric; Childhood; Individual; diet supplement; nutritional supplement; dietary supplements; Premature Mortality; Metabolic; clinical diagnosis; Protocols documentation; Protocol; success; Benefits and Risks; Positioning Attribute; Position; Adverse event; Adverse Experience; Intervention; Intervention Strategies; interventional strategy; Documentation; insulin sensitivity; caloric restricted; calorically restricted; calorie restricted; calorie restriction; Caloric Restriction; Dual-Energy X-Ray Absorptiometry; DEXA; DXA; Dual-Energy Xray Absorptiometry; Adherence; Subgroup; Magnetic Resonance Elastography; sex; Cirrhosis; cirrhotic; obesity in children; child adiposity; child obesity; childhood adiposity; childhood obesity; obese children; obesity during childhood; pediatric obesity; nonalcoholic; non-alcoholic; Consumption; 17 years of age; age 17 years; seventeen year old; seventeen years of age; 17 year old; 18 years of age; age 18 years; eighteen year old; eighteen years of age; 18 year old; treatment effect; inclusion criteria; NASH; non-alcohol induced steatohepatitis; non-alcoholic steato-hepatitis; non-alcoholic steatohepatitis; nonalcoholic steato-hepatitis; nonalcoholic steatohepatitis; early adulthood; emerging adult; cardiovascular health; Formulation; fitness program; exercise program; obese adolescents; obesity among adolescents; obesity during adolescence; obesity in adolescence; obesity in adolescents; youth adiposity; Adolescent obesity; NAFLD; non-alcohol fatty liver disease; non-alcoholic liver disease; nonalcoholic fatty liver disease; non-alcoholic fatty liver disease; weight loss programming; weight loss program; treatment guidelines; secondary end point; secondary endpoint; primary end point; primary endpoint; liver stiffness; hepatic stiffness
