Please select the eligibility criteria that correspond to the clinical trial below.
Title: Double Blind, Randomized, Placebo Controlled Trial With Metformin in Non-Alcoholic Fatty Liver Disease (NAFLD)
Brief Summary: The study evaluates the use of the antidiabetic medicine metformin in nonalcoholic fatty liver disease.


Options:
A: Inclusion Criteria:

* Males or females (females must be either of non-child bearing potential or using an efficient double contraception). For male participants, contraceptive measures must be taken during the study, either by the male participant or his female partner.
* Body Mass Index ≤ 45 kg/m².
* Patients agree to have one liver biopsy during the screening period for diagnostic purpose (if no historical biopsy within 6 months before randomization is available) and one at the end of the treatment period for assessment of the treatment effects.
* For hypertensive patients, hypertension must be controlled by stable dose of anti-hypertensive medication for at least 2 months prior to screening (and the stable dose can be maintained throughout the study).
* Patients treated with vitamin E (\>400IU/d), or Polyunsaturated fatty acids (\>2g/day)or Ursodeoxycholic acid can be included if drugs are stopped at least 3 months prior to diagnostic liver biopsy and up to the end of the study.
* Histological confirmation of steatohepatitis on a diagnostic liver biopsy. Histological diagnostic is confirmed by central reading of the slides (steatosis \> 5% + lobular inflammation, any grade + ballooning, any amount).
* For patients with Type 2 Diabetes, glycemia must be controlled (Glycosylated Haemoglobin A1c ≤8.5%). If glycemia is controlled by anti-diabetic drugs, qualitative change is not permitted within 6 months prior to randomization and should be avoided during the study. Treatments with metformin, Dipeptidyl Peptidase 4 inhibitors, Glucagon-like peptide-1 agonists, sulfamides, insulin are authorized. Sulfamides and insulin are permitted if glycemia is self-monitored by the patient.

Exclusion Criteria:

* Known heart failure (Grade I to IV of New York Heart Association classification).
* Weight loss of more than 5% within 6 months prior to randomization.
* History of bariatric surgery.
* Uncontrolled Blood Pressure.
* Type 1 diabetes patients.
* Patients who had an acute cardiovascular episode within the 6 months prior to screening, or with a history of coronary angioplasty, history of stroke, Transient Ischemic Attack, Coronary Heart Disease.
* Compensated and uncompensated cirrhosis. Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are excluded.
* Known alcohol and/or any other drug abuse or dependence in the last five years.
* Pregnant or lactating females.
* Other well documented causes of chronic liver disease
* Known intolerance or contra-indication to the list of excipients of GFT505.
* Evidence of any other unstable or, untreated clinically significant immunological, neoplastic, endocrine, haematological, gastrointestinal, neurological or psychiatric disorder.
* Positive HBsAg (Hepatitis B Surface Antigen), Positive anti-HIV, positive HCV-RNA (Hepatitis C Virus).
* Uncontrolled hypothyroidism defined as Thyroid Stimulating Hormone \> 2X the upper limit of normal (ULN). Thyroid dysfunction controlled for at least 6 months prior to screening is permitted.
* Significant renal disease, including nephritic syndrome, chronic renal failure (defined as creatinine clearance \< 60 mL/mn and serum creatinine \>180 μmol/L).
* Unexplained serum creatine phosphokinase (CPK) \> 3X the upper limit of normal (ULN). Patients with a reason for CPK elevation may have the measurement repeated prior to randomization; a CPK retest \> 3X ULN leads to exclusion.
B: Inclusion Criteria:

* Type 2 diabetes, defined by the American Diabetes Association (ADA), as one of the following criteria:
* Symptoms of diabetes plus casual plasma glucose concentration \>200 mg/dL (11.1 mmol/L) or
* Fasting plasma glucose \>126 mg/dL (7.0 mmol/L) or
* 2-hour post-load glucose \>200 mg/dL (11.1 mmol/L) during a 75 g oral glucose tolerance test (GTT).
* Presumed NAFLD, defined by one of the following criteria:
* Alanine aminotransferase (ALT) ≥47 U/L for females and ≥56 U/L for males
* Aspartate aminotransferase (AST) ≥47 U/L for females and ≥60 U/L for males
* Enlarged liver (demonstrated by ultrasound or other imaging technique)
* Diagnostic histological findings shown on prior biopsy (in the last 5 years).

Exclusion Criteria:

* Bilirubin \>2 × ULN
* ALT \>155 U/L for females and \>185 U/L for males.
* AST \>155 U/L for females and \>200 U/L for males.
* Patients taking any antidiabetic medications, with the exception of metformin and sulfonylureas. If the HbA1c is \<11%, patients may be enrolled who have been withdrawn from all other diabetic medications as specified in the protocol, at the discretion of the Principal Investigator.
C: Inclusion Criteria:

* Bright liver on ultrasound imaging and increased liver function tests for at least 6 months before liver biopsy
* Biopsy-proven NAFLD (either NAFL or NASH) according to NAFLD Activity Score (NAS)

Exclusion Criteria:

* Ethanol consumption more than 20 g/day
* Known intolerance to spironolactone or vitamin E
* History of liver disease (chronic viral hepatitis, autoimmune hepatitis, drug-induced liver disease, primary biliary cirrhosis, hemochromatosis, Wilson's disease and α1-antitrypsin deficiency)
* Previous exposure to hepatotoxic drugs
* Spironolactone or vitamin E administration within one year before screening
* Type I Diabetes Mellitus
* Pancreatitis
* Uncontrolled hypothyroidism or hyperthyroidism
* Adrenal Insufficiency
* Renal Failure
* Cancer
* Pregnancy

Exclusion criteria were generally the same as those proposed for PIVENS trial design with two modifications: a) known intolerance to spironolactone as an exclusion criterion and b) the inclusion of patients with T2DM not receiving thiazolidinediones or insulin.
D: 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.

Answer: D