title: Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design.
abstract: BACKGROUND
  Non-alcoholic steatohepatitis (NASH) is often accompanied by liver fibrosis, which can progress to cirrhosis; C-C chemokine receptors type 2 and 5 (CCR2/CCR5), which mediate interactions driving inflammation and fibrosis, are promising treatment targets. Cenicriviroc (CVC), a dual-CCR2/CCR5 antagonist, has potent anti-inflammatory and antifibrotic activity in animal models; in HIV-positive subjects it reduced soluble CD14 levels, aspartate aminotransferase-to-platelet count ratio index, and non-invasive hepatic fibrosis risk scores; favorable tolerability was demonstrated in ~600 subjects. Efficacy and safety of CVC 150 mg for treating NASH with liver fibrosis are being evaluated over 2 years (primary endpoint at Year 1 [Y1]).
  
  
  METHODS
  Phase 2b, randomized, double-blind, placebo-controlled, multinational study (CENTAUR; NCT02217475). Adults with histological evidence of NASH, non-alcoholic fatty liver disease activity score (NAS) ≥ 4, and liver fibrosis (stages 1-3 NASH clinical research network system) enrolled. Subjects have increased risk of progression to cirrhosis due to ≥1 characteristic: type 2 diabetes; body mass index > 25 kg/m(2) with ≥1 feature of metabolic syndrome; bridging fibrosis and/or NAS ≥ 5. Liver biopsy evaluation at Screening, Y1, and Year 2 (Y2).
  
  
  OBJECTIVE
  Assess histologic improvement (≥2-point in NAS with ≥1-point improvement in >1 category) without worsening of fibrosis at Y1 (primary); evaluate complete NASH resolution without worsening of fibrosis at Y2 (key secondary).
  
  
  CONCLUSIONS
  CENTAUR is the first prospective study evaluating an oral agent exclusively enrolling subjects with NASH and liver fibrosis, with increased risk of developing cirrhosis. It will compare shorter versus longer CVC treatment and assess correlations between decreased inflammation and fibrosis.
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, NY, USA. Electronic address: scott.friedman@mssm.edu.
authors.forename: Scott
authors.initials: S
authors.lastname: Friedman
authors.affiliation: Department of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Sanyal
authors.affiliation: Center for Liver Diseases at Inova Fairfax Hospital, Falls Church, VA, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Goodman
authors.affiliation: Tobira Therapeutics, Inc., South San Francisco, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lefebvre
authors.affiliation: Tobira Therapeutics, Inc., South San Francisco, CA, USA.
authors.forename: Mildred
authors.initials: M
authors.lastname: Gottwald
authors.affiliation: Tobira Therapeutics, Inc., South San Francisco, CA, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Fischer
authors.affiliation: Institute of Cardiometabolism and Nutrition (ICAN), Hôpital la Pitié Salpêtrière and Université Pierre et Marie Curie, Paris, France.
authors.forename: Vlad
authors.initials: V
authors.lastname: Ratziu
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D065100:CCR5 Receptor Antagonists / Q000627:therapeutic use*; D002985:Clinical Protocols; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000150:complications*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000188:drug therapy*; D011446:Prospective Studies; D012107:Research Design; D013454:Sulfoxides; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D065100:CCR5 Receptor Antagonists; D007093:Imidazoles; D013454:Sulfoxides; C506967:cenicriviroc
keywords: Cenicriviroc; Liver fibrosis; Metabolic syndrome; Non-alcoholic fatty liver; Non-alcoholic steatohepatitis; Type 2 diabetes mellitus