Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment (REGENERATE)

• ClinicalTrials.gov Identifier: NCT02548351
• Recruitment Status: Active, not recruiting
• First Posted: September 14, 2015
• Last Update Posted: April 18, 2023
• Sponsor: Intercept Pharmaceuticals
• Information provided by (Responsible Party): Intercept Pharmaceuticals

Tracking Information

• First Submitted Date: September 1, 2015
• First Posted Date: September 14, 2015
• Last Update Posted Date: April 18, 2023
• Actual Study Start Date: September 22, 2015
• Estimated Primary Completion Date: September 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2019)

• To evaluate the effect of Obeticholic Acid compared to placebo on liver histology in non-cirrhotic nonalcoholic steatohepatitis (NASH) subjects with stage 2 or 3 fibrosis by assessing the following primary endpoints [ Time Frame: Measurements at Baseline and 18 months ]
  Primary endpoints include:

  • The proportion of Obeticholic Acid treated patients relative to placebo achieving at least one stage of liver fibrosis improvement with no worsening of NASH, or
  • The proportion of Obeticholic Acid treated patients relative to placebo achieving NASH resolution with no worsening of liver fibrosis.
• To evaluate the effect of Obeticholic Acid compared to placebo on all-cause mortality and liver-related clinical outcomes as measured by the time to first occurrence of any of the listed adjudicated events (clinical outcomes composite endpoint) [ Time Frame: Time to accrue a pre-specified number of adjudicated events, End of Study, estimated to be 7 years ]
  Primary endpoint events include: Death (all cause), model of end stage liver disease (MELD) score ≥15, liver transplant, ascites requiring medical intervention, histological progression to cirrhosis, hospitalization (as defined by a stay of ≥24 hours) for onset of: variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis.

Original Primary Outcome Measures (submitted: September 10, 2015)

• Clinical outcomes composite endpoint of any of the listed adjudicated events [ Time Frame: Time to accrue a pre-specified number of adjudicated events, estimated to be 5 years ]
  Primary endpoint events include: Death (all cause), model of end stage liver disease (MELD) score ≥15, liver transplant, hepatocellular carcinoma (HCC), ascites, histological progression to cirrhosis, hospitalization (as defined by a stay of ≥24 hours) for onset of: variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis.
• Evaluate the effect of Obeticholic Acid compared to placebo on fibrosis stage in non-cirrhotic nonalcoholic steatohepatitis (NASH) subjects with stage 2 or 3 fibrosis by assessing the following co-primary endpoints [ Time Frame: Samples will be measured at Baseline and every 6 months up to 5 years ]
  Co-primary endpoints include

  • The proportion of Obeticholic Acid treated patients relative to placebo achieving at least one stage of liver fibrosis improvement with no worsening of NASH
  • The proportion of Obeticholic Acid treated patients relative to placebo achieving NASH resolution with no worsening of liver fibrosis.

Current Secondary Outcome Measures (submitted: January 29, 2019)

• To evaluate the effect of Obeticholic Acid compared to placebo on liver histology in NASH [ Time Frame: 18 month Interim Analysis ]
  • Improvement of fibrosis by at lease 1 stage AND/OR resolution of NASH, without worsening of either
  • No worsening of fibrosis AND no worsening of NASH
  • Improvement in each histological feature of NASH by at least 1 point
  • Improvement of fibrosis by at least 2 stages
  • Improvement in NAS by at least 2 points with no worsening of fibrosis
  • Improvement of fibrosis and resolution of NASH as a composite endpoint and as defined by both endpoints being met in the same subject
  • Resolution of fibrosis
  • Histological progression to cirrhosis
• To evaluate the effect of Obeticholic Acid compared to placebo on liver histology in NASH [ Time Frame: End of Study, estimated to be 7 years ]
  • Improvement in fibrosis by at least 1 stage with no worsening of NASH
  • NASH resolution with no worsening of fibrosis
  • Improvement of fibrosis by at lease 1 stage AND/OR resolution of NASH, without worsening of either
  • No worsening of fibrosis AND no worsening of NASH
  • Improvement in each histological feature of NASH by at least 1 point
  • Improvement of fibrosis by at least 2 stages
  • Improvement in NAS by at least 2 points with no worsening of fibrosis
  • Improvement of fibrosis and resolution of NASH as a composite endpoint and as defined by both endpoints being met in the same subject
  • Resolution of fibrosis
• To evaluate the effect of Obeticholic Acid compared to placebo on liver biochemistry and markers of liver function [ Time Frame: 18 months and End of Study, estimated to be 7 years ]

Original Secondary Outcome Measures (submitted: September 10, 2015)

To evaluate the effect of Obeticholic Acid compared to placebo on fibrosis improvement in NASH [ Time Frame: Samples will be measured at Baseline and every 6 months up to 5 years ]

Using NASH CRN scoring criteria:

• Improvement of fibrosis and NASH as a composite endpoint and as defined by improvement in fibrosis by at least 1 stage and improvement in nonalcoholic fatty liver disease (NAFLD) activity score (NAS) by at least 2 points.
• Resolution of fibrosis
• Improvement in NAS by at least 2 points with no worsening of fibrosis

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment
• Official Title: A Phase 3, Double-Blind, Randomized, Long-Term, Placebo-Controlled, Multicenter Study Evaluating the Safety and Efficacy of Obeticholic Acid in Subjects With Nonalcoholic Steatohepatitis
• Brief Summary: The primary objectives of this study are to evaluate the effect of Obeticholic Acid treatment compared to placebo on 1) histological improvement and 2) liver-related clinical outcomes in patients with non-cirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Non Alcoholic Steatohepatitis (NASH)

Intervention

• Drug: Obeticholic Acid
• Drug: Placebo

Study Arms

• Experimental: 10 mg Obeticholic Acid
  10 mg Obeticholic Acid daily for the remainder of the study
  Intervention: Drug: Obeticholic Acid
• Experimental: 25 mg Obeticholic Acid
  25 mg Obeticholic Acid daily for the remainder of the study
  Intervention: Drug: Obeticholic Acid
• Placebo Comparator: Placebo
  One tablet daily for the remainder of the study
  Intervention: Drug: Placebo

Publications *

• Rinella ME, Dufour JF, Anstee QM, Goodman Z, Younossi Z, Harrison SA, Loomba R, Sanyal AJ, Bonacci M, Trylesinski A, Natha M, Shringarpure R, Granston T, Venugopal A, Ratziu V. Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study. J Hepatol. 2022 Mar;76(3):536-548. doi: 10.1016/j.jhep.2021.10.029. Epub 2021 Nov 15.
• Younossi ZM, Stepanova M, Nader F, Loomba R, Anstee QM, Ratziu V, Harrison S, Sanyal AJ, Schattenberg JM, Barritt AS, Noureddin M, Bonacci M, Cawkwell G, Wong B, Rinella M; RandomizEd Global Phase 3 Study to Evaluate the Impact on NASH with FibRosis of Obeticholic Acid TreatmEnt (REGENERATE) Study Investigators. Obeticholic Acid Impact on Quality of Life in Patients With Nonalcoholic Steatohepatitis: REGENERATE 18-Month Interim Analysis. Clin Gastroenterol Hepatol. 2022 Sep;20(9):2050-2058.e12. doi: 10.1016/j.cgh.2021.07.020. Epub 2021 Jul 15.
• Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, Bedossa P, Geier A, Beckebaum S, Newsome PN, Sheridan D, Sheikh MY, Trotter J, Knapple W, Lawitz E, Abdelmalek MF, Kowdley KV, Montano-Loza AJ, Boursier J, Mathurin P, Bugianesi E, Mazzella G, Olveira A, Cortez-Pinto H, Graupera I, Orr D, Gluud LL, Dufour JF, Shapiro D, Campagna J, Zaru L, MacConell L, Shringarpure R, Harrison S, Sanyal AJ; REGENERATE Study Investigators. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019 Dec 14;394(10215):2184-2196. doi: 10.1016/S0140-6736(19)33041-7. Epub 2019 Dec 5. Erratum In: Lancet. 2020 Aug 1;396(10247):312. Lancet. 2021 Jun 19;397(10292):2336.
• Ratziu V, Sanyal AJ, Loomba R, Rinella M, Harrison S, Anstee QM, Goodman Z, Bedossa P, MacConell L, Shringarpure R, Shah A, Younossi Z. 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 27, 2019): 2480
• Original Estimated Enrollment (submitted: September 10, 2015): 2500
• Estimated Study Completion Date: September 2025
• Estimated Primary Completion Date: September 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologic evidence of NASH upon central read of a liver biopsy obtained no more than 6 months before Day 1 defined by presence of all 3 key histological features of NASH according to NASH CRN criteria.

2. Histologic evidence of fibrosis stage 2 or stage 3 as defined by the NASH CRN scoring of fibrosis, or

   Histologic evidence of fibrosis stage 1a or stage 1b if accompanied by ≥1 of the following risk factors:

   • Obesity (BMI ≥30 kg/m2)
   • Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria
   • ALT >1.5× upper limit of normal (ULN).
3. For subjects with a historical biopsy, is either not taking or is on stable doses of TZDs/glitazones or vitamin E for 6 months before Day 1.
4. Stable body weight.

Exclusion Criteria:

1. Model for End-stage Liver Disease (MELD) score >12
2. ALT ≥10× ULN
3. HbA1c >9.5%
4. Total bilirubin >1.5 mg/dL
5. Evidence of other known forms of known chronic liver disease such as alcoholic liver disease, hepatitis B, hepatitis C, PBC, PSC, autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC)
6. History of liver transplant, or current placement on a liver transplant list
7. Current or history of significant alcohol consumption
8. Prior or planned ileal resection, or prior or planned bariatric surgery
9. Histological presence of cirrhosis
10. History of biliary diversion
11. Known positivity for human immunodeficiency virus infection.
12. Acute cholecystitis or acute biliary obstruction.
13. BMI >45 kg/m2

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Portugal, Puerto Rico, Serbia, Spain, Sweden, Switzerland, United Kingdom, United States
• Removed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT02548351
• Other Study ID Numbers: 747-303
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Intercept Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Intercept Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Steven Shiff, MD; Intercept Pharmaceuticals

• PRS Account: Intercept Pharmaceuticals
• Verification Date: April 2023