Please select the eligibility criteria that correspond to the clinical trial below.
Title: The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis (NASH) Treatment (FLINT) Trial
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).


Options:
A: Inclusion Criteria:

* In a single-center study, 63 patients (32 males and 31 females) diagnosed with nonalcoholic fatty liver disease were recruited from the outpatient clinic and evaluated for the study.

Exclusion Criteria:

* Patients with history of unstable angina, MI, CVA or major surgery within the six months preceding entrance to the study.
* Patients with unbalanced endocrine disease or any disease that might affect absorption of medications.
* Patients with plasma creatinine \> 1.5 mg/dl, and electrolyte abnormalities.
B: Inclusion Criteria:

* Histologically proven NAFLD less than 18 months prior to inclusion. For those with pure steatosis, ALAT or aspartate aminotransferase (ASAT) must be elevated above the upper limits of normal, and impaired glucose tolerance or diabetes mellitus type 2 must be present.
* Body weight within +/- 5 kg compared with the weight at the time of biopsy.

Exclusion Criteria:

* Treatment for more than 1 week with metformin or glitazones the last 6 months before inclusion.
* Treatment with insulin.
* Hypersensitivity to metformin.
* Treatment with cimetidine.
* Heart failure requiring pharmacological treatment.
* Coronary heart disease (New York Heart Association \[NYHA\] class 3 or 4).
* Chronic obstructive lung disease (moderate or severe).
* Breast-feeding or pregnant.
* Metabolic acidosis.
* Renal failure (male \[♂\]: creatinine \> 135 micromol/L, female \[♀\] \> 110 micromol/L).
* Average alcohol consumption \> 24 g/day the last year.
* Serum ALAT or serum ASAT \> 5 x upper limit of normal (ULN) at screening.
* Cirrhosis.
* Platelets \< 100 000.
* Haemochromatosis.
* Alfa-1-antitrypsin-deficiency.
* Wilson's disease.
* Thyroid dysfunction (0.2 mU/L \< thyroid stimulating hormone \[TSH\] \< 5.0 mU/L).
* Chronic infection with hepatitis B or C virus or HIV.
* Autoimmune hepatitis (antinuclear antibodies \[ANA\] \> 1/256 or smooth muscle antibodies \[SMA\] \> 1/128).
* Primary biliary cirrhosis (antimitochondrial antibodies \[AMA\] \> 1/64).
* Primary sclerosing cholangitis.
* Previous participation in another clinical trial the last 6 months.
* Legal incapability.
C: Inclusion Criteria:

* Patients with histologically proven NAFLD or NASH based on a biopsy performed during the preceding 18 months fulfilling the following criteria:

  * At least 15% of hepatocytes showing steatosis,with Fibrosis of not more than stage 3, with at most bridging fibrosis.

Patients with a NAFLD activity score 0-2 will be considered to have NAFLD. Biopsies with an activity score of 3 or more will be considered NASH.

* Triglycerides concentration in the liver of 6% or more as measured by NMRS.
* At least two elevated serum ALT levels in the previous six months, with latest test within 2 months of trial.
* Normal or only slightly impaired synthetic liver function (serum albumin \>3.5gm%, INR 0.8-1.3)
* Male or female aged 18-75 years.
* Negative pregnancy test at study entry for females of child bearing potential.
* Females of child bearing potential practicing reliable contraception throughout the study period.
* Signature of the written informed consent

Exclusion Criteria:

* Evidence of cirrhosis on liver biopsy.
* Evidence of fibrosis of more than stage 3 on liver biopsy.
* Patient with liver disease due to acute or chronic hepatitis A, B,C, HIV, and all other liver diseases affecting liver function. Patients with cysts, hemangiomas, or similar abnormalities, are accepted.
* BMI \> 35 or \>130 kg body weight
* Any other concomitant, significant: metabolic, infectious, inflammatory, neoplastic, or other non-liver disease.
* Various concomitant diseases requiring chronic steroid administration.
* Use of warfarin, metformin, thiaglitazones, insulin or current steroid therapy of more than 3 days.
* Use of other investigational agents \< 30 days prior to the study.
* Pregnancy
* Daily alcohol intake \> 10gm/day.
* Patients with symptoms of significant mental illness. Inability to cooperate or communicate with the investigator, who are unlikely to comply with the study requirements, or who are unable to give informed consent.
* Performance status: WHO performance status ≥4.
D: 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

Answer: D