Please select the eligibility criteria that correspond to the clinical trial below.
Title: The Effect of Spironolactone and Vitamin E Versus Vitamin E on Serum Adipocytokines Levels in Patients With Biopsy-proven Nonalcoholic Fatty Liver Disease-A Phase II Study
Brief Summary: The primary aim of the study is the effect of spironolactone and vitamin E versus vitamin E on serum levels of adipokines 52 weeks post-treatment.


Options:
A: 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.
B: Inclusion Criteria:

* NASH on liver biopsy (within 6 months of screening visit).
* NAFLD Activity Score (NAS) ≥ 3, comprising of a minimum of 1 point from each of the individual steatosis, lobular inflammation and hepatocyte ballooning scores
* Body Mass Index (BMI) ≥ 25 at randomisation
* Type 2 Diabetes Mellitus/impaired glucose tolerance or normal glucose tolerance

Exclusion Criteria (brief):

* Insulin dependent diabetes
* Glycosylated Haemoglobin (HbA1c) \> 9.0%
* treatment with dipeptidyl peptidase 4 (DPP-IV) inhibitors, Glucagon-like Peptides (GLP) 1 analogues, thiazolidinediones (TZDs)
* Past Medical History of Acute (or chronic) pancreatitis/pancreatic carcinoma, weight loss surgery, liver transplantation, Medullary thyroid cancer, hepatocellular carcinoma (HCC), Multiple Endocrine Neoplasia (MEN) syndrome, malignancy (within last 3 years, exception of treated skin malignancy)
* Other liver aetiologies (i.e. drug-induced, viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, haemochromatosis, alpha 1 anti-trypsin deficiency, Wilsons disease)
* concomitant or recent use of orlistat, prednisolone,
* Refusal or lacks capacity to give informed consent to participate in the trial
* Participation in any clinical trial of an investigational therapy or agent within 3 months of randomisation
* Patient (or carer) deemed not competent at using the correct site and technique for subcutaneous injection of the trial treatment (containing dummy drug on practice) at visit 2
* NAS\<3
* Child's B or C cirrhosis
* Abnormal clinical examination of thyroid (i.e. unexplained goitre or palpable nodules)
* Liver enzymes \> 10 x upper limit of normal
* Average alcohol consumption per week \> 21 units (210g) male, \>14 units (140g) female within the last 5 years.
* \>5% weight loss since the diagnostic liver biopsy was obtained.
* Recent or concomitant use of steroids (oral), methotrexate, amiodarone, Orlistat
* Addition or significant change (as judged by the chief investigator) in dose of the following drugs; Angiotensin converting enzymes (ACE)-inhibitors, Angiotensin receptor blockers (ARBs) and/or Multi-vitamins (containing Vitamin E)
* Known positivity for antibody to Human Immunodeficiency virus (HIV)
* Serum creatinine \> 150 μmol/L or currently being treated with renal replacement therapy
* Past medical history of multiple drug allergies (defined as anaphylactoid drug reactions in \>2 drug groups)
* Presence of any acute/chronic infections or illness that at the discretion of the chief investigator might compromise the patient's health and safety in the trial
* Pregnancy or breastfeeding
* Women, of child-bearing age, who are not willing to practise effective contraception (i.e. barrier, oral contraceptive pill, implanon or history hysterectomy) for the 48 week duration of the trial and for one-month after the last administration of the drug.
* Men, sexually active with women of child-bearing age, who are not willing to practise effective contraception for the 48 week duration of the trial and for one-month after the last administration of the drug.
C: 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.
D: Inclusion Criteria:

1. Age at entry at least 18 years.
2. Serum alanine (ALT) or aspartate (AST) aminotransferase activities that are above the upper limits of normal. 19 or more in women and 30 or more in men.
3. Evidence of hepatic steatosis or liver fat (\>5%) by MRI.
4. Evidence of definite or suspected NASH

   1. Evidence of (definite) steatohepatitis on liver biopsy done within the previous 12 months with a NASH activity score of at least 4 (of a total possible score of 8) including a score of at least 1 each for steatosis, hepatocellular injury and parenchymal inflammation. Histological criteria of steatohepatitis include: (1) macrovesicular steatosis, (2) acinar zone 3 hepatocellular injury (ballooning degeneration), (3) parenchymal and (4) portal inflammation. Additionally helpful, but not required, features include the presence of (5) Mallory's hyaline and (6) pericellular and/or sinusoidal fibrosis that predominantly involves zone 3. If a liver biopsy is available within the last 12 months, then a repeat biopsy may not be conducted unless there has been a considerable change in body weight that may change liver histologic parameters associated with NASH
   2. Those who are suspected of having NASH and have not undergone a liver biopsy within the last 12 months may undergo a liver biopsy as a screening liver biopsy but would qualify for randomization into either ezetimibe or placebo arms only if they meet histologic criteria of NASH.
5. Written informed consent.

Exclusion Criteria:

1. Evidence of another form of liver disease.

   1. Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg).
   2. Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum.
   3. Autoimmune hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistent with autoimmune hepatitis or previous response to immunosuppressive therapy.
   4. Autoimmune cholestatic liver disorders as defined by elevation of alkaline phosphatase and anti-mitochondrial antibody of greater than 1:80 or liver histology consistent with primary biliary cirrhosis or elevation of alkaline phosphatase and liver histology consistent with sclerosing cholangitis.
   5. Wilson disease as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilson disease.
   6. Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than normal and liver histology consistent with alpha-1-antitrypsin deficiency.
   7. Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D.
   8. Drug-induced liver disease as defined on the basis of typical exposure and history.
   9. Bile duct obstruction as shown by imaging studies.
2. History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol intake averaging greater than 10 gm/day (1 drink per day: 7 drinks per week) in the previous one year.
3. Contraindications to liver biopsy: platelet counts \< 75,000/mm3 or prothrombin time \>16 seconds or history of bleeding disorders
4. Decompensated liver disease, Child-Pugh score greater than or equal to 7 points
5. History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months.
6. Recent initiation or change of anti-diabetic drugs, including insulin, sulfonylureas, or thiazolidinediones in the previous 90 days.
7. Use of ezetimibe or other agents in the same class within the 90 days prior to randomization and/or liver biopsy.
8. Significant systemic or major illnesses other than liver disease, including congestive heart failure, coronary artery disease, cerebrovascular disease, pulmonary disease with hypoxia, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator would preclude treatment with ezetimibe and adequate follow up.
9. Positive test for anti-HIV.
10. Active substance abuse, such as alcohol, inhaled or injection drugs within the previous one year.
11. Pregnancy or inability to practice adequate contraception in women of childbearing potential.
12. Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver mass on imaging study that is suggestive of liver cancer.
13. Any other condition, which, in the opinion of the investigators would impede competence or compliance or possibility hinder completion of the study.
14. Serum creatinine \>1.5 mg/dl.
15. Contraindications to ezetimibe use :

    1. History of allergic reaction to ezetimibe
    2. patients with acute liver injury or unexplained persistent elevations in ALT \> 500 U/L
    3. Women who are pregnant or may become pregnant
    4. Nursing mothers
16. Contraindications to MRI:

    1. The subject has any contraindication to MR imaging, such as patients with pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or other conditions that would preclude proximity to a strong magnetic field.
    2. The subject has a history of extreme claustrophobia
    3. The subject cannot fit inside the MR scanner cavity

Answer: A