title: No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial.
abstract: OBJECTIVE
  n-3 polyunsaturated fatty acids reduce insulin resistance, lipogenesis, and inflammation, which are features of nonalcoholic steatohepatitis (NASH). Ethyl-eicosapentanoic acid (EPA-E) is a synthetic polyunsaturated fatty acid that reduces hypertriglyceridemia. We report the final results of a phase 2b multicenter, prospective, double-blind, randomized, placebo-controlled trial of EPA-E for NASH.
  
  
  METHODS
  Our study, performed at 37 sites in North America, included subjects with NASH and nonalcoholic fatty liver disease (NAFLD) activity scores ≥ 4, with minimum scores of 1 for steatosis and inflammation, along with either ballooning or at least stage 1a fibrosis. A total of 243 subjects were randomly assigned to groups given placebo (n = 75), low-dosage EPA-E (1800 mg/d; n = 82), or high-dosage EPA-E (2700 mg/d; n = 86) for 12 months. Subjects were examined at 4-week intervals for 3 months, 6-week intervals for the next 3 months, and every 3 months thereafter, until 1 month after the last dose was taken. Liver biopsies were collected 2 weeks after the last dose of EPA-E or placebo. The primary efficacy end point was NAFLD activity score ≤ 3, without worsening of fibrosis; or a decrease in NAFLD activity score by ≥ 2 with contribution from >1 parameter, without worsening of fibrosis, 1 year after the last dose of EPA-E or placebo was given.
  
  
  RESULTS
  Similar proportions of subjects in each group met the primary end point (40%, 37%, and 35.9% for placebo, low-dosage, and high-dosage EPA-E, respectively). EPA-E had no significant effects on steatosis, inflammation, ballooning, or fibrosis scores. There were no significant effects on levels of liver enzymes, insulin resistance, adiponectin, keratin 18, high-sensitivity C-reactive protein, or hyaluronic acid. High-dosage EPA-E reduced levels of triglyceride (-6.5 mg/dL vs an increase of 12 mg/dL in the placebo group; P = .03). There were no treatment-related serious adverse events.
  
  
  CONCLUSIONS
  In a phase 2 trial, EPA-E had no significant effect on the histologic features of NASH. EPA-E reduced subjects' levels of triglyceride compared with placebo, without any increase in serious adverse events. Clinicaltrials.gov Number: 01154985.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia. Electronic address: asanyal@mcvh-vcu.edu.
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.affiliation: Division of Gastroenterology and Hepatology, Duke University, Durham, North Carolina.
authors.forename: Manal F
authors.initials: MF
authors.lastname: Abdelmalek
authors.affiliation: Division of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Division of Gastroenterology, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas.
authors.forename: Ayako
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, Indiana University, Bloomington, Indiana.
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Cummings
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California, San Diego, San Diego, California.
authors.forename: Mario
authors.initials: M
authors.lastname: Chojkier
mesh_terms: D001706:Biopsy; D018450:Disease Progression; D004311:Double-Blind Method; D015118:Eicosapentaenoic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005234:Fatty Liver / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D009656:North America; D011446:Prospective Studies; D012720:Severity of Illness Index; D013997:Time Factors; D017211:Treatment Failure
chemical_list: C035276:eicosapentaenoic acid ethyl ester; D015118:Eicosapentaenoic Acid
keywords: Ethyl All-Cis-5,8,11,14,17-Eicosapentaenoate; Metabolic Syndrome; Triglycerides