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

Study Overview
=================
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.

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

Conditions
-----------------
Non Alcoholic Steatohepatitis (NASH)

Intervention / Treatment
-----------------
* Drug: Obeticholic Acid
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. 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). 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. Stable body weight. Exclusion Criteria: Model for End-stage Liver Disease (MELD) score >12 ALT ≥10× ULN HbA1c >9.5% Total bilirubin >1.5 mg/dL 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) History of liver transplant, or current placement on a liver transplant list Current or history of significant alcohol consumption Prior or planned ileal resection, or prior or planned bariatric surgery Histological presence of cirrhosis History of biliary diversion Known positivity for human immunodeficiency virus infection. Acute cholecystitis or acute biliary obstruction. BMI >45 kg/m2

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 mg Obeticholic Acid<br>10 mg Obeticholic Acid daily for the remainder of the study | Drug: Obeticholic Acid<br> <br> |
| Experimental: 25 mg Obeticholic Acid<br>25 mg Obeticholic Acid daily for the remainder of the study | Drug: Obeticholic Acid<br> <br> |
| Placebo Comparator: Placebo<br>One tablet daily for the remainder of the study | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Measurements at Baseline and 18 months | 
| 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) | 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. | Time to accrue a pre-specified number of adjudicated events, End of Study, estimated to be 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effect of Obeticholic Acid compared to placebo on liver histology in NASH | 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 | 18 month Interim Analysis | 
| To evaluate the effect of Obeticholic Acid compared to placebo on liver histology in NASH | 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 | End of Study, estimated to be 7 years | 
| To evaluate the effect of Obeticholic Acid compared to placebo on liver biochemistry and markers of liver function |  | 18 months and End of Study, estimated to be 7 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non Alcoholic Steatohepatitis, fatty liver disease, NASH