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Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design.
Contemp Clin Trials 2016; 47:356-65CC

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]).

DESIGN

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).

OBJECTIVES

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).

DISCUSSION

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+Show Affiliations

Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, NY, USA. Electronic address: scott.friedman@mssm.edu.Department of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA.Center for Liver Diseases at Inova Fairfax Hospital, Falls Church, VA, USA.Tobira Therapeutics, Inc., South San Francisco, CA, USA.Tobira Therapeutics, Inc., South San Francisco, CA, USA.Tobira Therapeutics, Inc., South San Francisco, CA, USA.Institute of Cardiometabolism and Nutrition (ICAN), Hôpital la Pitié Salpêtrière and Université Pierre et Marie Curie, Paris, France.

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26944023

Citation

Friedman, Scott, et al. "Efficacy and Safety Study of Cenicriviroc for the Treatment of Non-alcoholic Steatohepatitis in Adult Subjects With Liver Fibrosis: CENTAUR Phase 2b Study Design." Contemporary Clinical Trials, vol. 47, 2016, pp. 356-65.
Friedman S, Sanyal A, Goodman Z, et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp Clin Trials. 2016;47:356-65.
Friedman, S., Sanyal, A., Goodman, Z., Lefebvre, E., Gottwald, M., Fischer, L., & Ratziu, V. (2016). Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemporary Clinical Trials, 47, pp. 356-65. doi:10.1016/j.cct.2016.02.012.
Friedman S, et al. Efficacy and Safety Study of Cenicriviroc for the Treatment of Non-alcoholic Steatohepatitis in Adult Subjects With Liver Fibrosis: CENTAUR Phase 2b Study Design. Contemp Clin Trials. 2016;47:356-65. PubMed PMID: 26944023.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. AU - Friedman,Scott, AU - Sanyal,Arun, AU - Goodman,Zachary, AU - Lefebvre,Eric, AU - Gottwald,Mildred, AU - Fischer,Laurent, AU - Ratziu,Vlad, Y1 - 2016/03/02/ PY - 2015/12/11/received PY - 2016/02/25/revised PY - 2016/02/28/accepted PY - 2016/3/6/entrez PY - 2016/3/6/pubmed PY - 2017/1/4/medline KW - Cenicriviroc KW - Liver fibrosis KW - Metabolic syndrome KW - Non-alcoholic fatty liver KW - Non-alcoholic steatohepatitis KW - Type 2 diabetes mellitus SP - 356 EP - 65 JF - Contemporary clinical trials JO - Contemp Clin Trials VL - 47 N2 - 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]). DESIGN: 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). OBJECTIVES: 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). DISCUSSION: 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. SN - 1559-2030 UR - https://www.unboundmedicine.com/medline/citation/26944023/Efficacy_and_safety_study_of_cenicriviroc_for_the_treatment_of_non_alcoholic_steatohepatitis_in_adult_subjects_with_liver_fibrosis:_CENTAUR_Phase_2b_study_design_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1551-7144(16)30026-X DB - PRIME DP - Unbound Medicine ER -