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

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ClinicalTrials.gov Identifier: NCT01265498
Recruitment Status : Completed
First Posted : December 23, 2010
Results First Posted : August 21, 2015
Last Update Posted : April 6, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

December 21, 2010
December 23, 2010
June 26, 2015
August 21, 2015
April 6, 2018
March 2011
January 2014   (Final data collection date for primary outcome measure)
Hepatic Histological Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) [ Time Frame: baseline to 72 weeks ]

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:

  1. No worsening in fibrosis; and
  2. A decrease in NAFLD Activity Score (NAS) of at least 2 points
Hepatic histological improvement in NAFLD Activity Score (NAS) [ Time Frame: 72 weeks ]

Centrally scored histological improvement in NAFLD from baseline to the end of 72 weeks of treatment, where improvement is defined as:

  1. No worsening in fibrosis; and
  2. A decrease in NAFLD Activity Score (NAS) of at least 2 points
Complete list of historical versions of study NCT01265498 on ClinicalTrials.gov Archive Site
  • Resolution of NASH Diagnosis [ Time Frame: baseline to 72 weeks ]
    Resolution of definite nonalcoholic steatohepatitis. Resolution defined as either not NAFLD, or NAFLD but not non-alcoholic steatohepatitis on week 72 biopsy
  • Fibrosis: Patient With Improvement [ Time Frame: baseline to 72 weeks ]
    Patients with improvement in fibrosis score. Fibrosis was assessed on a scale of 0-4, with higher scores showing more severe fibrosis.
  • Fibrosis: Change in Score [ Time Frame: baseline to 72 weeks ]
    Change in fibrosis score. Fibrosis was assessed on a scale of 0-4, with higher scores showing more severe fibrosis.
  • Total NAFLD Activity Score: Change in Score [ Time Frame: baseline to 72 weeks ]
    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]).
  • Hepatocellular Ballooning: Patients With Improvement [ Time Frame: baseline to 72 weeks ]
    Patients with improvement in hepatocellular ballooning score. Hepatocellular ballooning was assessed on a scale of 0-2, with higher scores showing more severe ballooning.
  • Hepatocellular Ballooning: Change in Score [ Time Frame: baseline to 72 weeks ]
    Change in hepatocellular ballooning score. Hepatocellular ballooning was assessed on a scale of 0-2, with higher scores showing more severe ballooning.
  • Steatosis: Patients With Improvement [ Time Frame: baseline to 72 weeks ]
    Patients with improvement in steatosis score. Steatosis was assessed on a scale of 0-3, with higher scores showing more severe steatosis.
  • Steatosis: Change in Score [ Time Frame: baseline to 72 weeks ]
    Change in steatosis score. Steatosis was assessed on a scale of 0-3, with higher scores showing more severe steatosis.
  • Lobular Inflammation: Patients With Improvement [ Time Frame: baseline to 72 weeks ]
    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.
  • Lobular Inflammation: Change in Score [ Time Frame: baseline to 72 weeks ]
    Change in lobular inflammation score. Lobular inflammation was assessed on a scale of 0-3, with higher scores showing more severe lobular inflammation.
  • Portal Inflammation: Patients With Improvement [ Time Frame: baseline to 72 weeks ]
    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.
  • Portal Inflammation: Change in Score [ Time Frame: baseline to 72 weeks ]
    Change in portal inflammation score. Portal inflammation was assessed on a scale of 0-3, with higher scores showing more severe portal inflammation.
  • Change in Alanine Aminotransferase [ Time Frame: baseline to 72 weeks ]
  • Change in Asparate Aminotransferase [ Time Frame: baseline to 72 weeks ]
  • Change in Alkaline Phosphatase [ Time Frame: baseline to 72 weeks ]
  • Change in γ-glutamyl Transpeptidase [ Time Frame: baseline to 72 weeks ]
  • Change in Total Bilirubin [ Time Frame: baseline to 72 weeks ]
  • Change in Total Cholesterol [ Time Frame: baseline to 72 weeks ]
  • Change in HDL Cholesterol [ Time Frame: baseline to 72 weeks ]
  • Change in LDL Cholesterol [ Time Frame: baseline to 72 weeks ]
  • Change in Triglycerides [ Time Frame: baseline to 72 weeks ]
  • Change in Haemoglobin [ Time Frame: baseline to 72 weeks ]
  • Change in Haematocrit [ Time Frame: baseline to 72 weeks ]
  • Change in Mean Corpuscular Volume [ Time Frame: baseline to 72 weeks ]
  • Change in White Blood Cell Count [ Time Frame: baseline to 72 weeks ]
  • Change in Platelet Count [ Time Frame: baseline to 72 weeks ]
  • Change in Bicarbonate [ Time Frame: baseline to 72 weeks ]
  • Change in Calcium [ Time Frame: baseline to 72 weeks ]
  • Change in Phosphate [ Time Frame: baseline to 72 weeks ]
  • Change in Creatinine [ Time Frame: baseline to 72 weeks ]
  • Change in Uric Acid [ Time Frame: baseline to 72 weeks ]
  • Change in Albumin [ Time Frame: baseline to 72 weeks ]
  • Change in Total Protein [ Time Frame: baseline to 72 weeks ]
  • Change in Prothrombin Time [ Time Frame: baseline to 72 weeks ]
  • Change in International Normalised Ratio [ Time Frame: baseline to 72 weeks ]
  • Change in Fasting Serum Glucose [ Time Frame: baseline to 72 weeks ]
  • Change in Insulin [ Time Frame: baseline to 72 weeks ]
  • Change in HOMA-IR [ Time Frame: baseline to 72 weeks ]
  • Change in Glycated Haemoglobin A1c [ Time Frame: baseline to 72 weeks ]
  • Change in Weight [ Time Frame: baseline to 72 weeks ]
  • Change in Body-mass Index [ Time Frame: baseline to 72 weeks ]
  • Change in Waist Circumference [ Time Frame: baseline to 72 weeks ]
  • Change in Waist-to-hip Ratio [ Time Frame: baseline to 72 weeks ]
  • Change in Systolic Blood Pressure [ Time Frame: baseline to 72 weeks ]
  • Change in Diastolic Blood Pressure [ Time Frame: baseline to 72 weeks ]
  • Change in SF-36 Quality of Life Physical Component Summary [ Time Frame: baseline to 72 weeks ]
    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.
  • Change in SF-36 Quality of Life Mental Component Summary [ Time Frame: baseline to 72 weeks ]
    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.
Not Provided
Not Provided
Not Provided
 
The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in NASH Treatment Trial(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).
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.
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
  • Nonalcoholic Fatty Liver Disease (NAFLD)
  • Nonalcoholic Steatohepatitis (NASH)
  • Drug: obeticholic acid
    25 mg daily for 72 weeks
    Other Name: farnesoid X receptor (FXR) ligand obeticholic acid (OCA)
  • Drug: placebo
    placebo capsule, 25 mg daily for 72 weeks
    Other Name: Placebo for obeticholic acid
  • Active Comparator: Obeticholic acid
    obeticholic acid
    Intervention: Drug: obeticholic acid
  • Placebo Comparator: Placebo
    Placebo
    Intervention: Drug: placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
283
280
September 2014
January 2014   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01265498
NASH-FLINT (IND)
U01DK061730 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Not Provided
Study Director: Edward Doo, MD National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
July 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP