Clinical trial NCT01265498: The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in NASH Treatment Trial(FLINT)
Official title: The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis (NASH) Treatment (FLINT) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nonalcoholic Fatty Liver Disease (NAFLD)
Nonalcoholic Steatohepatitis (NASH)
Keywords: Farnesoid X Receptor
FXR
Nonalcoholic fatty liver disease
Nonalcoholic steatohepatitis
NAFLD
NASH
obeticholic acid
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
First posted: 2010-12-23
Enrollment: 283
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

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 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

Primary outcomes:
measure: Hepatic Histological Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS)
timeFrame: baseline to 72 weeks
Secondary outcomes:
measure: Resolution of NASH Diagnosis
timeFrame: baseline to 72 weeks
measure: Fibrosis: Patient With Improvement
timeFrame: baseline to 72 weeks
measure: Fibrosis: Change in Score
timeFrame: baseline to 72 weeks
measure: Total NAFLD Activity Score: Change in Score
timeFrame: baseline to 72 weeks
measure: Hepatocellular Ballooning: Patients With Improvement
timeFrame: baseline to 72 weeks
measure: Hepatocellular Ballooning: Change in Score
timeFrame: baseline to 72 weeks
measure: Steatosis: Patients With Improvement
timeFrame: baseline to 72 weeks
measure: Steatosis: Change in Score
timeFrame: baseline to 72 weeks
measure: Lobular Inflammation: Patients With Improvement
timeFrame: baseline to 72 weeks
measure: Lobular Inflammation: Change in Score
timeFrame: baseline to 72 weeks
measure: Portal Inflammation: Patients With Improvement
timeFrame: baseline to 72 weeks
measure: Portal Inflammation: Change in Score
timeFrame: baseline to 72 weeks
measure: Change in Alanine Aminotransferase
timeFrame: baseline to 72 weeks
measure: Change in Asparate Aminotransferase
timeFrame: baseline to 72 weeks
measure: Change in Alkaline Phosphatase
timeFrame: baseline to 72 weeks
measure: Change in γ-glutamyl Transpeptidase
timeFrame: baseline to 72 weeks
measure: Change in Total Bilirubin
timeFrame: baseline to 72 weeks
measure: Change in Total Cholesterol
timeFrame: baseline to 72 weeks
measure: Change in HDL Cholesterol
timeFrame: baseline to 72 weeks
measure: Change in LDL Cholesterol
timeFrame: baseline to 72 weeks
measure: Change in Triglycerides
timeFrame: baseline to 72 weeks
measure: Change in Haemoglobin
timeFrame: baseline to 72 weeks
measure: Change in Haematocrit
timeFrame: baseline to 72 weeks
measure: Change in Mean Corpuscular Volume
timeFrame: baseline to 72 weeks
measure: Change in White Blood Cell Count
timeFrame: baseline to 72 weeks
measure: Change in Platelet Count
timeFrame: baseline to 72 weeks
measure: Change in Bicarbonate
timeFrame: baseline to 72 weeks
measure: Change in Calcium
timeFrame: baseline to 72 weeks
measure: Change in Phosphate
timeFrame: baseline to 72 weeks
measure: Change in Creatinine
timeFrame: baseline to 72 weeks
measure: Change in Uric Acid
timeFrame: baseline to 72 weeks
measure: Change in Albumin
timeFrame: baseline to 72 weeks
measure: Change in Total Protein
timeFrame: baseline to 72 weeks
measure: Change in Prothrombin Time
timeFrame: baseline to 72 weeks
measure: Change in International Normalised Ratio
timeFrame: baseline to 72 weeks
measure: Change in Fasting Serum Glucose
timeFrame: baseline to 72 weeks
measure: Change in Insulin
timeFrame: baseline to 72 weeks
measure: Change in HOMA-IR
timeFrame: baseline to 72 weeks
measure: Change in Glycated Haemoglobin A1c
timeFrame: baseline to 72 weeks
measure: Change in Weight
timeFrame: baseline to 72 weeks
measure: Change in Body-mass Index
timeFrame: baseline to 72 weeks
measure: Change in Waist Circumference
timeFrame: baseline to 72 weeks
measure: Change in Waist-to-hip Ratio
timeFrame: baseline to 72 weeks
measure: Change in Systolic Blood Pressure
timeFrame: baseline to 72 weeks
measure: Change in Diastolic Blood Pressure
timeFrame: baseline to 72 weeks
measure: Change in SF-36 Quality of Life Physical Component Summary
timeFrame: baseline to 72 weeks
measure: Change in SF-36 Quality of Life Mental Component Summary
timeFrame: baseline to 72 weeks
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Saint Louis
country: United States
facility: St. Louis University
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Edward Doo, MD
role: STUDY_DIRECTOR
References:
citation: 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. 2023 Feb;78(2):238-246. doi: 10.1016/j.jhep.2022.10.027. Epub 2022 Nov 8.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.