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

Nonalcoholic Steatohepatitis (NASH) Clinical Trial

— FLINT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01265498
• Other study ID #: NASH-FLINT (IND)
• Secondary ID: U01DK061730
• Status: Completed
• Phase: Phase 2
• First received: December 21, 2010
• Last updated: March 12, 2018
• Start date: March 2011
• Est. completion date: September 2014

Study information

• Verified date: July 2015
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 283
• Est. completion date: September 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Fatty Liver Disease (NAFLD)
• Nonalcoholic Steatohepatitis (NASH)

Intervention

Drug:
• obeticholic acid
25 mg daily for 72 weeks
• placebo
placebo capsule, 25 mg daily for 72 weeks

Locations

Country	Name	City	State
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Indiana University	Indianapolis	Indiana
United States	Virginia Commonwealth University	Richmond	Virginia
United States	St. Louis University	Saint Louis	Missouri
United States	University of California, San Diego	San Diego	California
United States	University of California, San Francisco	San Francisco	California
United States	Virginia Mason Medical Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in Alanine Aminotransferase		baseline to 72 weeks
Secondary	Change in Asparate Aminotransferase		baseline to 72 weeks
Secondary	Change in Alkaline Phosphatase		baseline to 72 weeks
Secondary	Change in ?-glutamyl Transpeptidase		baseline to 72 weeks
Secondary	Change in Total Bilirubin		baseline to 72 weeks
Secondary	Change in Total Cholesterol		baseline to 72 weeks
Secondary	Change in HDL Cholesterol		baseline to 72 weeks
Secondary	Change in LDL Cholesterol		baseline to 72 weeks
Secondary	Change in Triglycerides		baseline to 72 weeks
Secondary	Change in Haemoglobin		baseline to 72 weeks
Secondary	Change in Haematocrit		baseline to 72 weeks
Secondary	Change in Mean Corpuscular Volume		baseline to 72 weeks
Secondary	Change in White Blood Cell Count		baseline to 72 weeks
Secondary	Change in Platelet Count		baseline to 72 weeks
Secondary	Change in Bicarbonate		baseline to 72 weeks
Secondary	Change in Calcium		baseline to 72 weeks
Secondary	Change in Phosphate		baseline to 72 weeks
Secondary	Change in Creatinine		baseline to 72 weeks
Secondary	Change in Uric Acid		baseline to 72 weeks
Secondary	Change in Albumin		baseline to 72 weeks
Secondary	Change in Total Protein		baseline to 72 weeks
Secondary	Change in Prothrombin Time		baseline to 72 weeks
Secondary	Change in International Normalised Ratio		baseline to 72 weeks
Secondary	Change in Fasting Serum Glucose		baseline to 72 weeks
Secondary	Change in Insulin		baseline to 72 weeks
Secondary	Change in HOMA-IR		baseline to 72 weeks
Secondary	Change in Glycated Haemoglobin A1c		baseline to 72 weeks
Secondary	Change in Weight		baseline to 72 weeks
Secondary	Change in Body-mass Index		baseline to 72 weeks
Secondary	Change in Waist Circumference		baseline to 72 weeks
Secondary	Change in Waist-to-hip Ratio		baseline to 72 weeks
Secondary	Change in Systolic Blood Pressure		baseline to 72 weeks
Secondary	Change in Diastolic Blood Pressure		baseline to 72 weeks
Secondary	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
Secondary	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

External Links

•   Nonalcoholic Steatohepatitis Clinical Research Network
•   The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)