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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT01265498
First received: December 21, 2010
Last updated: October 29, 2013
Last verified: October 2013
  Purpose

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).


Condition Intervention Phase
Nonalcoholic Fatty Liver Disease (NAFLD)
Nonalcoholic Steatohepatitis (NASH)
Drug: obeticholic acid
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis (NASH) Treatment (FLINT) Trial

Resource links provided by NLM:


Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:
  • Hepatic histological improvement in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]

    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


Secondary Outcome Measures:
  • NASH diagnosis [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Change from definite or indeterminate NASH to not-NASH

  • Fibrosis score [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Decrease in fibrosis score

  • Hepatocellular ballooning score [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Change in hepatocellular ballooning score assessed by a centrally read pathology group.

  • Change in hepatic fat fraction determined by magnetic resonance imaging (MRI) [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Change in hepatic fat fraction determined by MRI

  • Change in fasting markers of insulin resistance [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Changes in hepatic and adipose insulin sensitivity as measured by HOMA-IR and adipo-IR index respectively

  • Change in serum aminotransferase and gamma-glutamyl transpeptidase (GGT) levels [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Change in serum aminotransferase and gamma-glutamyl transpeptidase (GGT) levels

  • Change in bile acid levels [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Changes in levels of bile acids and bile acid metabolites (e.g., 7alpha-hydroxy-4-cholesten-3-one)

  • Change in health related quality of life (HR-QoL) scores [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Change in health related quality of life (HR-QoL) scores

  • Changes in fasting glucose and 2 hour glucose during glucose tolerance testing [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Changes in fasting glucose and 2 hour glucose during glucose tolerance testing

  • Change in weight, body mass index, waist circumference, waist-hip ratio, and blood pressure [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Change in weight, body mass index, waist circumference, waist-hip ratio, and blood pressure

  • Changes in total cholesterol, LDL cholesterol, HDL cholesterol, and serum triglycerides [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Changes in total cholesterol, LDL cholesterol, HDL cholesterol, and serum triglycerides levels

  • Improvement in CK-18 derived fragments in blood. [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    Improvement in CK-18 derived fragments in blood measured using a specific enzyme-linked immunosorbent assay.


Other Outcome Measures:
  • Vanguard analysis of change in serum alanine aminotransferase (ALT) [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
    Approximately 65 weeks after the first patient is randomized, an interim analysis for efficacy and safety for 25-40% of participants who have completed 24 weeks of follow-up. Our pre-specified interim criterion for efficacy for continuing the FLINT trial beyond the vanguard phase is based on serum ALT: the criterion for continuation will be considered met if the upper 95% confidence limit on the between-group mean difference in mean changes from baseline to the 24 week measure of ALT, comparing the obeticholic acid versus placebo groups, is at least a 20% net reduction in serum ALT from the overall baseline mean ALT. The analysis will also include detailed safety data, as required by the DSMB, to determine whether any emergent safety issues are present.

  • Interim efficacy analysis of primary histological outcome measure [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]
    One planned interim analysis of the primary histological outcome measure. O'Brien-Fleming statistical stopping guidelines for efficacy will be applied. This interim efficacy analysis will occur when approximately 50% (140 of the 280 patients) have completed both baseline and 72 week biopsies. Based on the Lan-DeMets method for group sequential trials using O'Brien-Fleming boundaries (Reboussin et al., 2000), the levels of significance for the interim and final analyses will be alpha=0.00305 and alpha=0.049, respectively.


Enrollment: 283
Study Start Date: March 2011
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Obeticholic acid
obeticholic acid
Drug: obeticholic acid
25 mg daily for 72 weeks
Other Name: farnesoid X receptor (FXR) ligand obeticholic acid (OCA)
Placebo Comparator: Placebo
Placebo
Drug: placebo
placebo capsule, 25 mg daily for 72 weeks
Other Name: Placebo for obeticholic acid

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01265498

Locations
United States, California
University of California, San Diego
San Diego, California, United States, 92103
University of California, San Francisco
San Francisco, California, United States, 94143
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 46202
United States, Missouri
St. Louis University
St. Louis, Missouri, United States, 63104
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Case Western Reserve University
Cleveland, Ohio, United States, 44109
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
United States, Washington
Virginia Mason Medical Center
Seattle, Washington, United States, 98101
Sponsors and Collaborators
Investigators
Study Director: Edward Doo, MD National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT01265498     History of Changes
Other Study ID Numbers: NASH-FLINT (IND)
Study First Received: December 21, 2010
Last Updated: October 29, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
Farnesoid X Receptor
FXR
Nonalcoholic fatty liver disease
Nonalcoholic steatohepatitis
NAFLD
NASH
obeticholic acid

Additional relevant MeSH terms:
Fatty Liver
Liver Diseases
Digestive System Diseases

ClinicalTrials.gov processed this record on July 31, 2014