@article{77ed38788b384eefb8d3704ea377a1d9,
title = "CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients",
abstract = "Background & Aims: Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. Methods: This randomized, double-blind, placebo-controlled, phase 2 study began with a 5-week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16-week double-blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy-confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. Results: At Week 4, all OCA groups had an increase from baseline in mean low-density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. Conclusions: The CONTROL study showed that OCA-induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956).",
keywords = "atorvastatin, lipoproteins, nonalcoholic fatty liver disease, obeticholic acid",
author = "Pockros, {Paul J.} and Michael Fuchs and Bradley Freilich and Eugene Schiff and Anita Kohli and Lawitz, {Eric J.} and Hellstern, {Paul A.} and Janet Owens-Grillo and {Van Biene}, Courtney and Reshma Shringarpure and Leigh MacConell and David Shapiro and Cohen, {David E.}",
note = "Funding Information: The CONTROL study was sponsored by Intercept Pharmaceuticals. Professional writing and editorial services were provided by Carolyn Green, PhD, MedLogix Communications, and were funded by Intercept Pharmaceuticals. Content was directed by the authors who were involved in data analyses, interpretation, review and approval of this manuscript. Funding Information: PJP has received grants and personal fees from Intercept Pharmaceuticals. MF has received grants from Intercept Pharmaceuticals, Genfit, Conatus Pharmaceuticals, Gilead Sciences, Allergan, Galectin Therapeutics, Novartis, Bristol‐Myers Squibb, and HepQuant. BF has received grants from Intercept Pharmaceuticals. ES has received grants from Bristol‐Myers Squibb, Conatus Pharmaceuticals, Genfit, Intercept Pharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Shire, Tobira Therapeutics, and Zydus Pharmaceuticals USA, and served as a scientific advisory board member for Gilead Sciences, and receives royalties from Wiley. EJL has received grants from Allergan, Akcea Therapeutics, Bristol‐Myers Squibb, Boehringer Ingelheim, Bird Rock Bio, Conatus Pharmaceuticals, Enanta Pharmaceuticals, Exalenz Bioscience, Durect Corporation, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal Pharmaceuticals, Novartis, Octeta Therapeutics, and Zydus Pharmaceuticals USA. JOG was an employee and stock shareholder for and has received grants from Intercept Pharmaceuticals. DEC has received consulting and scientific advisory board fees from Intercept Pharmaceuticals, scientific advisory fees from Acquist Therapeutics/Relburn Metabolomics, Merk, and Gemphire Therapeutics, data safety monitoring board fees from Alnylam Pharmaceuticals/Medpace, Esperion Therapeutics/ICON, and Aegerion Pharmaceuticals, consulting fees from Surrozen, Amgen, and SPRIM, and a research grant from Sanofi. RS, LM and DS are employees and stock shareholders for Intercept Pharmaceuticals. All other authors declare no competing interests. ",
year = "2019",
month = nov,
day = "1",
doi = "10.1111/liv.14209",
language = "English (US)",
volume = "39",
pages = "2082--2093",
journal = "Liver International",
issn = "1478-3223",
publisher = "Wiley-Blackwell",
number = "11",
}