The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in NASH Treatment Trial(FLINT)

Study Overview
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Brief Summary
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Administration of the farnesoid X receptor (FXR) ligand obeticholic acid (OCA) for 72 weeks to subjects with biopsy evidence of nonalcoholic steatohepatitis (NASH) will result in improvement in their liver disease as measured by changes in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS).

Detailed Description
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To evaluate whether treatment with obeticholic acid, 25 mg daily for 72 weeks compared to treatment with placebo, improves the severity of nonalcoholic fatty liver disease (NAFLD) as determined from hepatic histology.

Official Title
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The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis (NASH) Treatment (FLINT) Trial

Conditions
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Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: obeticholic acid
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older as of the initial screening interview and provision of consent Histologic evidence of definite or probable nonalcoholic steatohepatitis (NASH) based upon a liver biopsy obtained no more than 90 days prior to randomization and a nonalcoholic fatty liver disease activity score (NAS) of 4 or greater with at least 1 in each component of the NAS score (steatosis scored 0-3, ballooning degeneration scored 0-2, and lobular inflammation scored 0-3). Exclusion Criteria: Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 grams per day in females and more than 30 grams per day in males, on average) Inability to reliably quantify alcohol consumption based upon local study physician judgment Use of drugs historically associated with nonalcoholic fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) for more than 2 weeks in the year prior to randomization Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y gastric bypass) Uncontrolled diabetes defined as Hemoglobin A1c 9.5% or higher within 60 days prior to enrollment Presence of cirrhosis on liver biopsy A platelet count below 100,000/mm3 Clinical evidence of hepatic decompensation as defined by the presence of any of the following abnormalities: Serum albumin less than 3.2 grams/deciliter (g/dL) International Normalized Ratio(INR)greater than 1.3 Direct bilirubin greater than 1.3 milligrams per deciliter (mg/dL) History of esophageal varices, ascites or hepatic encephalopathy Evidence of other forms of chronic liver disease: Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) Hepatitis C as defined by presence of hepatitis C virus (HCV) ribonucleic acid (RNA) or positive hepatitis C antibody (anti-HCV) Evidence of ongoing autoimmune liver disease as defined by compatible liver histology Primary biliary cirrhosis as defined by the presence of at least 2 of these criteria (i) Biochemical evidence of cholestasis based mainly on alkaline phosphatase elevation (ii)Presence of anti-mitochondrial antibody (AMA) (iii)Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts Primary sclerosing cholangitis Wilson's disease as defined by ceruloplasmin below the limits of normal and compatible liver histology Alpha-1-antitrypsin(A1AT) deficiency as defined by diagnostic features in liver histology (confirmed by alpha-1 antitrypsin level less than normal; exclusion at the discretion of the study physician) History of hemochromatosis or iron overload as defined by presence of 3+ or 4+ stainable iron on liver biopsy Drug-induced liver disease as defined on the basis of typical exposure and history Known bile duct obstruction Suspected or proven liver cancer Any other type of liver disease other than nonalcoholic steatohepatitis (NASH) Serum alanine aminotransferase (ALT) greater than 300 units per liter (U/L) Serum creatinine of 2.0 mg/dL or greater Use of ursodeoxycholic acid (Ursodiol, Urso) within 90 days prior to enrollment Inability to safely obtain a liver biopsy History of biliary diversion Known positivity for Human Immunodeficiency Virus (HIV) infection Active, serious medical disease with likely life expectancy less than 5 years Active substance abuse including inhaled or injection drugs in the year prior to screening Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use effective birth control during the trial, breast feeding Participation in an investigational new drug (IND) trial in the 30 days before randomization Any other condition which, in the opinion of the investigator, would impede compliance or hinder completion of the study Failure to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Obeticholic acid<br>obeticholic acid | Drug: obeticholic acid<br>* 25 mg daily for 72 weeks<br>* Other names: farnesoid X receptor (FXR) ligand obeticholic acid (OCA);|
| Placebo Comparator: Placebo<br>Placebo | Drug: placebo<br>* placebo capsule, 25 mg daily for 72 weeks<br>* Other names: Placebo for obeticholic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic Histological Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) | Centrally scored histological improvement in nonalcoholic fatty liver disease (NAFLD) from baseline to the end of 72 weeks of treatment, where improvement is defined as: No worsening in fibrosis; and A decrease in NAFLD Activity Score (NAS) of at least 2 points | baseline to 72 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resolution of NASH Diagnosis | Resolution of definite nonalcoholic steatohepatitis. Resolution defined as either not NAFLD, or NAFLD but not non-alcoholic steatohepatitis on week 72 biopsy | baseline to 72 weeks | 
| Fibrosis: Patient With Improvement | Patients with improvement in fibrosis score. Fibrosis was assessed on a scale of 0-4, with higher scores showing more severe fibrosis. | baseline to 72 weeks | 
| Fibrosis: Change in Score | Change in fibrosis score. Fibrosis was assessed on a scale of 0-4, with higher scores showing more severe fibrosis. | baseline to 72 weeks | 
| Total NAFLD Activity Score: Change in Score | NAFLD activity score was assessed on a scale of 0-8, with higher scores showing more severe disease (the components of this measure are steatosis [assessed on a scale of 0-3], lobular inflammation [assessed on a scale of 0-3], and hepatocellular ballooning [assessed on a scale of 0-2]). | baseline to 72 weeks | 
| Hepatocellular Ballooning: Patients With Improvement | Patients with improvement in hepatocellular ballooning score. Hepatocellular ballooning was assessed on a scale of 0-2, with higher scores showing more severe ballooning. | baseline to 72 weeks | 
| Hepatocellular Ballooning: Change in Score | Change in hepatocellular ballooning score. Hepatocellular ballooning was assessed on a scale of 0-2, with higher scores showing more severe ballooning. | baseline to 72 weeks | 
| Steatosis: Patients With Improvement | Patients with improvement in steatosis score. Steatosis was assessed on a scale of 0-3, with higher scores showing more severe steatosis. | baseline to 72 weeks | 
| Steatosis: Change in Score | Change in steatosis score. Steatosis was assessed on a scale of 0-3, with higher scores showing more severe steatosis. | baseline to 72 weeks | 
| Lobular Inflammation: Patients With Improvement | Patients with improvement in lobular inflammation score. Lobular inflammation was assessed on a scale of 0-3, with higher scores showing more severe lobular inflammation. | baseline to 72 weeks | 
| Lobular Inflammation: Change in Score | Change in lobular inflammation score. Lobular inflammation was assessed on a scale of 0-3, with higher scores showing more severe lobular inflammation. | baseline to 72 weeks | 
| Portal Inflammation: Patients With Improvement | Patients with improvement in portal inflammation score. Portal inflammation was assessed on a scale of 0-2, with higher scores showing more severe portal inflammation. | baseline to 72 weeks | 
| Portal Inflammation: Change in Score | Change in portal inflammation score. Portal inflammation was assessed on a scale of 0-3, with higher scores showing more severe portal inflammation. | baseline to 72 weeks | 
| Change in Alanine Aminotransferase |  | baseline to 72 weeks | 
| Change in Asparate Aminotransferase |  | baseline to 72 weeks | 
| Change in Alkaline Phosphatase |  | baseline to 72 weeks | 
| Change in γ-glutamyl Transpeptidase |  | baseline to 72 weeks | 
| Change in Total Bilirubin |  | baseline to 72 weeks | 
| Change in Total Cholesterol |  | baseline to 72 weeks | 
| Change in HDL Cholesterol |  | baseline to 72 weeks | 
| Change in LDL Cholesterol |  | baseline to 72 weeks | 
| Change in Triglycerides |  | baseline to 72 weeks | 
| Change in Haemoglobin |  | baseline to 72 weeks | 
| Change in Haematocrit |  | baseline to 72 weeks | 
| Change in Mean Corpuscular Volume |  | baseline to 72 weeks | 
| Change in White Blood Cell Count |  | baseline to 72 weeks | 
| Change in Platelet Count |  | baseline to 72 weeks | 
| Change in Bicarbonate |  | baseline to 72 weeks | 
| Change in Calcium |  | baseline to 72 weeks | 
| Change in Phosphate |  | baseline to 72 weeks | 
| Change in Creatinine |  | baseline to 72 weeks | 
| Change in Uric Acid |  | baseline to 72 weeks | 
| Change in Albumin |  | baseline to 72 weeks | 
| Change in Total Protein |  | baseline to 72 weeks | 
| Change in Prothrombin Time |  | baseline to 72 weeks | 
| Change in International Normalised Ratio |  | baseline to 72 weeks | 
| Change in Fasting Serum Glucose |  | baseline to 72 weeks | 
| Change in Insulin |  | baseline to 72 weeks | 
| Change in HOMA-IR |  | baseline to 72 weeks | 
| Change in Glycated Haemoglobin A1c |  | baseline to 72 weeks | 
| Change in Weight |  | baseline to 72 weeks | 
| Change in Body-mass Index |  | baseline to 72 weeks | 
| Change in Waist Circumference |  | baseline to 72 weeks | 
| Change in Waist-to-hip Ratio |  | baseline to 72 weeks | 
| Change in Systolic Blood Pressure |  | baseline to 72 weeks | 
| Change in Diastolic Blood Pressure |  | baseline to 72 weeks | 
| Change in SF-36 Quality of Life Physical Component Summary | Short Form (36) Health Survey The SF-36 evaluates health-related quality of life in 8 domains consisting of two components: physical and mental. The score for each domain ranges from 0 to 100. Norm based scoring (based on the general US population) is used with a mean of 50 and standard deviation of 10. Higher values represent a better outcome. | baseline to 72 weeks | 
| Change in SF-36 Quality of Life Mental Component Summary | Short Form (36) Health Survey The SF-36 evaluates health-related quality of life in 8 domains consisting of two components: physical and mental. The score for each domain ranges from 0 to 100. Norm based scoring (based on the general US population) is used with a mean of 50 and standard deviation of 10. Higher values represent a better outcome. | baseline to 72 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Farnesoid X Receptor, FXR, Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, NAFLD, NASH, obeticholic acid