Vlad Ratziu1, Arun J Sanyal2, Rohit Loomba3, Mary Rinella4, Stephen Harrison5, Quentin M Anstee6, Zachary Goodman7, Pierre Bedossa8, Leigh MacConell9, Reshma Shringarpure9, Amrik Shah9, Zobair Younossi7. 1. Sorbonne Université, Hôpital Pitié - Salpêtrière, 91-105 Boulevard de l'Hôpital, 75013 Paris, France. Electronic address: vlad.ratziu@inserm.fr. 2. Department of Internal Medicine, Virginia Commonwealth University, 1101 E Marshall St, Richmond, VA, USA. 3. University of California, San Diego, 9500 Gilman Dr, La Jolla, CA, USA. 4. Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, 676 N Saint Clair St, Chicago, IL, USA. 5. Pinnacle Clinical Research Center, 5109 Medical Dr. Ste 200, San Antonio, TX 78229, United States. 6. Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. 7. Betty and Guy Beatty Center for Integrated Research, Inova Health System, Claude Moore Health Education and Research Building, 3300 Gallows Rd, Falls Church, VA, USA. 8. Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, INSERM UMR 1149-CRI, Université Denis Diderot Paris-7, 46 rue Henri Huchard, 75018 Clichy, France. 9. Intercept Pharmaceuticals, 4760 Eastgate Mall, San Diego, CA, USA.
Abstract
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: ClinicalTrials.gov with the identifier NCT02548351.
RCT Entities:
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: ClinicalTrials.gov with the identifier NCT02548351.
Authors: Mohammed Eslam; Shiv K Sarin; Vincent Wai-Sun Wong; Jian-Gao Fan; Takumi Kawaguchi; Sang Hoon Ahn; Ming-Hua Zheng; Gamal Shiha; Yusuf Yilmaz; Rino Gani; Shahinul Alam; Yock Young Dan; Jia-Horng Kao; Saeed Hamid; Ian Homer Cua; Wah-Kheong Chan; Diana Payawal; Soek-Siam Tan; Tawesak Tanwandee; Leon A Adams; Manoj Kumar; Masao Omata; Jacob George Journal: Hepatol Int Date: 2020-10-01 Impact factor: 6.047