No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 triaL

Arun J. Sanyal, Manal F. Abdelmalek, Ayako Suzuki, Oscar Cummings, Mario Chojkier

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

Background & Aims 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.

Original languageEnglish
JournalGastroenterology
Volume147
Issue number2
DOIs
StatePublished - 2014

Fingerprint

Eicosapentaenoic Acid
Placebos
Fibrosis
Inflammation
Insulin Resistance
Triglycerides
Non-alcoholic Fatty Liver Disease
eicosapentaenoic acid ethyl ester
Keratin-18
Lipogenesis
Hypertriglyceridemia
Liver
Adiponectin
Omega-3 Fatty Acids
Hyaluronic Acid
North America
Unsaturated Fatty Acids
C-Reactive Protein
Randomized Controlled Trials
Biopsy

Keywords

  • Ethyl All-Cis-5,8,11,14,17-Eicosapentaenoate
  • Metabolic Syndrome
  • Triglycerides

ASJC Scopus subject areas

  • Gastroenterology

Cite this

No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 triaL. / Sanyal, Arun J.; Abdelmalek, Manal F.; Suzuki, Ayako; Cummings, Oscar; Chojkier, Mario.

In: Gastroenterology, Vol. 147, No. 2, 2014.

Research output: Contribution to journalArticle

Sanyal, Arun J. ; Abdelmalek, Manal F. ; Suzuki, Ayako ; Cummings, Oscar ; Chojkier, Mario. / No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 triaL. In: Gastroenterology. 2014 ; Vol. 147, No. 2.
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abstract = "Background & Aims 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.",
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N2 - Background & Aims 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.

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