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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02548351
Recruitment Status : Recruiting
First Posted : September 14, 2015
Last Update Posted : January 24, 2018
Information provided by (Responsible Party):
Intercept Pharmaceuticals

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.

Condition or disease Intervention/treatment Phase
Non Alcoholic Steatohepatitis (NASH) Drug: Obeticholic Acid Drug: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2370 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: 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
Study Start Date : September 2015
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : October 2022

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

Primary Outcome Measures :
  1. 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.

  2. 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, hepatocellular carcinoma (HCC), 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.

Secondary Outcome Measures :
  1. To evaluate the effect of Obeticholic Acid compared to placebo on liver histology in NASH [ Time Frame: Measurements at Baseline and 18 months up to 7 years ]
    • Improvement of fibrosis and NASH as a composite endpoint
    • Resolution of fibrosis

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 with a score of at least 1 for each and a combined score of 4 or greater out of a possible 8 points according to NASH CRN criteria.
  2. Histologic evidence of fibrosis stage 2 (perisinusoidal and portal/periportal) or stage 3 (bridging fibrosis) as defined by the NASH CRN scoring of fibrosis, or

    Histologic evidence of fibrosis stage 1a or stage 1b (mild or moderate, zone 3 perisinusoidal) as defined by the NASH CRN scoring of fibrosis if accompanied by ≥1 of the following risk factors:

    • Obesity (BMI ≥30 kg/m2)
    • Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria (hemoglobin A1c [HbA1c] ≥6.5%, fasting plasma glucose ≥126 mg/dL, 2-hour plasma glucose ≥200 mg/dL during oral glucose tolerance test, or random plasma glucose ≥200 mg/dL)
    • 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 (ie, not varying by >10% for at least 3 months) before Day 1.
  5. Age ≥18 years.
  6. Female subjects of childbearing potential must use ≥1 effective method of contraception during the study and until 30 days following the last dose of investigational product. Effective methods of contraception are considered to be those listed below:

    • Barrier method, ie, condom (male or female) with spermicide or diaphragm with spermicide
    • Intrauterine device
    • Vasectomy (partner)
    • Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection)
    • Abstinence (defined as refraining from heterosexual intercourse).
  7. Must provide written informed consent and agree to comply with the study protocol.

Exclusion Criteria:

  1. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year before Screening (significant alcohol consumption is defined as more than 2 units/day for females and more than 4 units/day for males, on average).
  2. Prior (at any point) or planned (during the study period) ileal resection, or prior (within 5 years before Screening) or planned (during the study period) bariatric surgery (eg, gastric bands, gastroplasty, roux-en-Y gastric bypass).
  3. HbA1c >9.5% within 60 days before Day 1.
  4. Evidence of other forms of known chronic liver disease including:

    • Positive test result at Screening for hepatitis B surface antigen (hBsAg)
    • Active hepatitis C virus (HCV) infection (positive for HCV ribonucleic acid [RNA] at Screening) or history of positive HCV RNA test result
    • PBC, PSC, autoimmune hepatitis, or overlap syndrome
    • Alcoholic liver disease
    • Wilson's disease, hemochromatosis, or iron overload
    • Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver histology (confirmed by A1AT level below the lower limit of normal [LLN] or exclusion at the Investigator's discretion)
    • Prior known drug-induced liver injury within 5 years before Day 1
    • Known or suspected HCC
    • History of liver transplant, current placement on a liver transplant list, or MELD score >12.
  5. Histological presence of cirrhosis.
  6. Total bilirubin >1.5 mg/dL (subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN).
  7. Conjugated bilirubin ≥1.5 ULN.
  8. AST or ALT ≥10× ULN, international normalized ratio (INR) >1.5, or serum creatinine ≥1.5 mg/dL.
  9. Creatine phosphokinase >5x ULN.
  10. Platelet count <100 000/mm3.
  11. LDL ≥190 mg/dL and already on a stable dose of statin and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for ≥30 days at Screening.
  12. Inability to safely undergo a liver biopsy.
  13. History of biliary diversion.
  14. Known positivity for human immunodeficiency virus infection.
  15. Subjects with recent history (within 1 year of Day 1) of significant atherosclerotic cardiovascular disease (myocardial infarction, unstable angina, acute coronary syndrome, cerebrovascular accident [stroke], cerebrovascular ischemia, transient ischemic attack, or peripheral vascular disease requiring intervention). Such subjects may be identified by different means, including but not limited to, an abnormal ECG, a history or planned cardiovascular intervention such as coronary revascularization (eg, percutaneous coronary intervention or coronary artery bypass graft), coronary angioplasty, stenting, carotid atherectomy, or placement of a cardiac pacemaker or defibrillator.

    • Controlled hypertension without other recent manifestations of significant atherosclerotic cardiovascular disease and placement of cardiac pacemaker or defibrillator for reasons other than atherosclerotic cardiovascular disease (eg, for treatment of atrial fibrillation subsequent to nodal ablation) is not exclusionary.

  16. Other medical conditions that may diminish life expectancy to <2 years, including known cancers (except carcinomas in situ or other stable, relatively benign carcinomas).
  17. Known substance abuse in the year before Screening.
  18. Pregnancy, planned pregnancy, potential for pregnancy (ie, unwillingness to use effective birth control during the study), or current or planned breast feeding.
  19. Participated in a clinical research study with any investigational product being evaluated for the treatment of diabetes, weight loss, or NASH in the 6 months before Day 1.
  20. Received any investigational product not being evaluated for the treatment of diabetes, weight loss, or NASH from Screening to Day 1, within 30 days before Day 1, or within 5 half-lives of the compound (whichever was longer) before Day 1.
  21. Previous exposure to OCA.
  22. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study, is uncertain.
  23. History of known or suspected clinically significant hypersensitivity to OCA or any of its components.
  24. Any other condition that, in the opinion of the Investigator, would impede compliance or hinder completion of the study.
  25. Acute cholecystitis or acute biliary obstruction.
  26. BMI >45 kg/m2 with at least 1 of the following comorbidities:

    • Hypertension with blood pressure ≥140/90 mmHg if <60 years, ≥150/90 mmHg if ≥60 years, or on antihypertensive medication
    • Hyperlipidemia defined as LDL cholesterol ≥160 mg/dL, total cholesterol ≥200 mg/dL, or on lipid lowering medication
    • Type 2 diabetes per 2013 American Diabetes Association criteria

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02548351

Contact: Szecho Lin, B.S. 858 832 4509

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Sponsors and Collaborators
Intercept Pharmaceuticals
Study Director: David Shapiro, MD Intercept Pharmaceuticals

Responsible Party: Intercept Pharmaceuticals Identifier: NCT02548351     History of Changes
Other Study ID Numbers: 747-303
First Posted: September 14, 2015    Key Record Dates
Last Update Posted: January 24, 2018
Last Verified: January 2018

Keywords provided by Intercept Pharmaceuticals:
Non Alcoholic Steatohepatitis, fatty liver disease, NASH

Additional relevant MeSH terms:
Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
Chenodeoxycholic Acid
Gastrointestinal Agents