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

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

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).

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis (NASH); Nonalcoholic Fatty Liver Disease (NAFLD)
• Intervention / Treatment: Drug: obeticholic acid; Drug: placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 283
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • University of California, San Diego
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • St. Louis University
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44109
      • Case Western Reserve University
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Study Director: Edward Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Shen W, Middleton MS, Cunha GM, Delgado TI, Wolfson T, Gamst A, Fowler KJ, Alazraki A, Trout AT, Ohliger MA, Shah SN, Bashir MR, Kleiner DE, Loomba R, Neuschwander-Tetri BA, Sanyal AJ, Zhou J, Sirlin CB, Lavine JE. Changes in abdominal adipose tissue depots assessed by MRI correlate with hepatic histologic improvement in non-alcoholic steatohepatitis. J Hepatol. 2022 Nov 8:S0168-8278(22)03284-6. doi: 10.1016/j.jhep.2022.10.027. Online ahead of print.
• Vilar-Gomez E, Gawrieh S, Liang T, McIntyre AD, Hegele RA, Chalasani N. Interrogation of selected genes influencing serum LDL-Cholesterol levels in patients with well characterized NAFLD. J Clin Lipidol. 2021 Mar-Apr;15(2):275-291. doi: 10.1016/j.jacl.2020.12.010. Epub 2020 Dec 27.
• Loomba R, Neuschwander-Tetri BA, Sanyal A, Chalasani N, Diehl AM, Terrault N, Kowdley K, Dasarathy S, Kleiner D, Behling C, Lavine J, Van Natta M, Middleton M, Tonascia J, Sirlin C; NASH Clinical Research Network. Multicenter Validation of Association Between Decline in MRI-PDFF and Histologic Response in NASH. Hepatology. 2020 Oct;72(4):1219-1229. doi: 10.1002/hep.31121. Epub 2020 Oct 9.
• Siddiqui MS, Van Natta ML, Connelly MA, Vuppalanchi R, Neuschwander-Tetri BA, Tonascia J, Guy C, Loomba R, Dasarathy S, Wattacheril J, Chalasani N, Sanyal AJ; NASH CRN. Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J Hepatol. 2020 Jan;72(1):25-33. doi: 10.1016/j.jhep.2019.10.006. Epub 2019 Oct 18.
• Chalasani N, Abdelmalek MF, Loomba R, Kowdley KV, McCullough AJ, Dasarathy S, Neuschwander-Tetri BA, Terrault N, Ferguson B, Shringarpure R, Shapiro D, Sanyal AJ. Relationship between three commonly used non-invasive fibrosis biomarkers and improvement in fibrosis stage in patients with non-alcoholic steatohepatitis. Liver Int. 2019 May;39(5):924-932. doi: 10.1111/liv.13974. Epub 2019 Feb 21.
• Hameed B, Terrault NA, Gill RM, Loomba R, Chalasani N, Hoofnagle JH, Van Natta ML; NASH CRN. Clinical and metabolic effects associated with weight changes and obeticholic acid in non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2018 Mar;47(5):645-656. doi: 10.1111/apt.14492. Epub 2018 Jan 14.
• Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015 Mar 14;385(9972):956-65. doi: 10.1016/S0140-6736(14)61933-4. Epub 2014 Nov 7. Erratum In: Lancet. 2015 Mar 14;385(9972):946. Lancet. 2016 Apr 16;387(10028):1618.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: December 21, 2010
• First Submitted That Met QC Criteria: December 21, 2010
• First Posted (Estimate): December 23, 2010

Study Record Updates

• Last Update Posted (Actual): April 6, 2018
• Last Update Submitted That Met QC Criteria: March 12, 2018
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: NAFLD; NASH; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; obeticholic acid; FXR; Farnesoid X Receptor
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Gastrointestinal Agents; Cathartics; Chenodeoxycholic Acid
• Other Study ID Numbers: NASH-FLINT (IND); U01DK061730 (U.S. NIH Grant/Contract)