REGENERATE: Design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis

Contemp Clin Trials. 2019 Sep:84:105803. doi: 10.1016/j.cct.2019.06.017. Epub 2019 Jun 29.


Background: Nonalcoholic steatohepatitis (NASH) is a chronic, progressive, and severe form of nonalcoholic fatty liver disease. In FLINT, obeticholic acid (OCA) treatment improved multiple histological NASH features. The design and endpoints of REGENERATE, an ongoing phase 3 study, further evaluate OCA treatment in patients with fibrosis due to NASH.

Aims: The Month 18 interim analysis assesses the effect of OCA on liver histology, defined as improvement of fibrosis by ≥1 stage with no worsening of NASH or resolution of NASH with no worsening of fibrosis. The end-of-study analyses evaluate the effect of OCA on mortality, liver-related clinical outcomes, and long-term safety.

Methods: REGENERATE is a pivotal, long-term study of ~2400 patients with NASH, including ~2100 patients with stage 2 or 3 liver fibrosis. Additionally, ~300 patients with stage 1 fibrosis and ≥1 accompanying comorbidity are included to gather information on the safety of OCA and liver disease progression. Patients are randomised 1:1:1 to receive placebo or OCA (10 or 25 mg). A liver biopsy evaluation occurs at screening, Months 18 and 48, and end of study. The duration of the study is dependent upon accrual of a predetermined number of clinical outcome events.

Conclusions: REGENERATE is designed in conjunction with regulatory authorities to support regulatory approvals in NASH. This robust phase 3 study assesses the effect of OCA on liver histology as a surrogate for transplant-free survival and liver-related outcomes, including progression to cirrhosis and mortality, and will ultimately assess clinical benefit through specific evaluation of these outcomes.

Clinical trial registration: with the identifier NCT02548351.

Keywords: Farnesoid X receptor; NASH; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Obeticholic acid.

Publication types

  • Clinical Trial Protocol
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chenodeoxycholic Acid* / administration & dosage
  • Chenodeoxycholic Acid* / adverse effects
  • Chenodeoxycholic Acid* / analogs & derivatives
  • Chenodeoxycholic Acid* / therapeutic use
  • Clinical Trials, Phase III as Topic
  • Dose-Response Relationship, Drug
  • Health Resources / statistics & numerical data
  • Health Services / statistics & numerical data
  • Humans
  • Liver Cirrhosis* / drug therapy
  • Liver Cirrhosis* / etiology
  • Liver Cirrhosis* / pathology
  • Liver Transplantation / statistics & numerical data
  • Longitudinal Studies
  • Multicenter Studies as Topic
  • Non-alcoholic Fatty Liver Disease* / complications
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Randomized Controlled Trials as Topic


  • Chenodeoxycholic Acid
  • obeticholic acid

Associated data