CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients

Paul J. Pockros, Michael Fuchs, Bradley Freilich, Eugene R Schiff, Anita Kohli, Eric J. Lawitz, Paul A. Hellstern, Janet Owens-Grillo, Courtney Van Biene, Reshma Shringarpure, Leigh MacConell, David Shapiro, David E. Cohen

Research output: Contribution to journalArticle

4 Citations (Scopus)

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).

Original languageEnglish (US)
JournalLiver International
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Lipoproteins
Hydroxymethylglutaryl-CoA Reductase Inhibitors
LDL Cholesterol
Fibrosis
Placebos
6-ethylchenodeoxycholic acid
Non-alcoholic Fatty Liver Disease
Atorvastatin Calcium
Bile Acids and Salts
Hepatocellular Carcinoma
Cardiovascular Diseases
Lipids
Biopsy
Liver
Therapeutics

Keywords

  • atorvastatin
  • lipoproteins
  • nonalcoholic fatty liver disease
  • obeticholic acid

ASJC Scopus subject areas

  • Hepatology

Cite this

CONTROL : A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients. / Pockros, Paul J.; Fuchs, Michael; Freilich, Bradley; Schiff, Eugene R; Kohli, Anita; Lawitz, Eric J.; Hellstern, Paul A.; Owens-Grillo, Janet; Van Biene, Courtney; Shringarpure, Reshma; MacConell, Leigh; Shapiro, David; Cohen, David E.

In: Liver International, 01.01.2019.

Research output: Contribution to journalArticle

Pockros, PJ, Fuchs, M, Freilich, B, Schiff, ER, Kohli, A, Lawitz, EJ, Hellstern, PA, Owens-Grillo, J, Van Biene, C, Shringarpure, R, MacConell, L, Shapiro, D & Cohen, DE 2019, 'CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients', Liver International. https://doi.org/10.1111/liv.14209
Pockros, Paul J. ; Fuchs, Michael ; Freilich, Bradley ; Schiff, Eugene R ; Kohli, Anita ; Lawitz, Eric J. ; Hellstern, Paul A. ; Owens-Grillo, Janet ; Van Biene, Courtney ; Shringarpure, Reshma ; MacConell, Leigh ; Shapiro, David ; Cohen, David E. / CONTROL : A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients. In: Liver International. 2019.
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AU - Schiff, Eugene R

AU - Kohli, Anita

AU - Lawitz, Eric J.

AU - Hellstern, Paul A.

AU - Owens-Grillo, Janet

AU - Van Biene, Courtney

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AU - MacConell, Leigh

AU - Shapiro, David

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