Please select the eligibility criteria that correspond to the clinical trial below.
Title: Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis (NASH)
Brief Summary: To determine the role of pioglitazone in the treatment of nonalcoholic steatohepatitis (NASH) in patients with glucose intolerance or type 2 diabetes mellitus (T2DM).


Options:
A: Inclusion Criteria:

1. Be able to communicate meaningfully with the investigators and be legally competent to provide written informed consent.
2. Age range between 18 to 70 years (inclusive).
3. Female patients must be non-lactating and must either be at least one year post-menopausal, or be using adequate mechanical contraceptive precautions (i.e. intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period. Patients on oral contraceptives or an hormonal implant will be excluded (patches are acceptable as they deliver much lower estrogen systemically).
4. Participants must have the following laboratory values:

   * Hemoglobin ≥ 12 gm/dl in males, or ≥ 11 gm/dl in females,
   * WBC count ≥ 3,000/mm3
   * Neutrophil count ≥ 1,500/mm3
   * Platelets ≥ 100,000/mm3
   * Albumin ≥3.0 g/dl
   * Serum creatinine ≤ 1.8 mg/dl
   * Creatinine phosphokinase ≤ 2 times upper limit of normal
   * AST and ALT ≤ 3.0 times upper limit of normal
   * Alkaline phosphatase ≤ 2.5 times upper limit of normal
5. A diagnosis of NASH by liver biopsy performed within the past 6 months,

Exclusion Criteria:

1. Any cause of chronic liver disease other than NASH (such as -but not restricted to- alcohol or drug abuse, medication, chronic hepatitis B or C, autoimmune, hemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency).
2. Any clinical evidence or history of ascitis, bleeding varices, or spontaneous encephalopathy.
3. Current history of alcohol abuse (alcohol consumption greater than 20 grams of ethanol per day).
4. Prior surgical procedures to include gastroplasty, jejuno-ileal or jejunocolic bypass.
5. Prior exposure to organic solvents such as carbon tetrachloride.
6. Total parenteral nutrition (TPN) within the past 6 months.
7. Subjects with type 1 diabetes mellitus.
8. Patients on chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for 4 weeks before entry into the study. Patients on estrogens or other hormonal replacement therapy, tamoxifen, raloxifene, oral glucocorticoids or chloroquine will be excluded.
9. Patients with a history of clinically significant heart disease (New York Heart Classification greater than grade II), peripheral vascular disease (history of claudication), or diagnosed pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation).
10. Patients with severe osteoporosis.
B: Inclusion Criteria:

1. Be able to communicate meaningfully with the Investigator and be legally competent to provide written informed consent.
2. Patients must have an age range between 21 to 70 years (inclusive).
3. NASH confirmed by liver biopsy.
4. Subjects must meet the criteria for impaired glucose tolerance (FPG concentration \<126 mg/dl and a two hour plasma glucose value during the oral glucose tolerance test \[OGTT\] ≥140 but \<200 mg/dl) or type 2 diabetes mellitus (FPG concentration ≥ 126 mg/dl or a two hour plasma glucose value during the OGTT ≥200 mg/dl) (62). Subjects with a FPG greater than 260 mg/dl will be excluded from the study.
5. Diabetic patients will be allowed to be on sulfonylureas or repaglinide but not on metformin, a thiazolidinedione or insulin. Patients must have been on a stable dose of allowed chronic medications for four weeks prior to entering the double-blind treatment period.
6. Female patients must be non-lactating and must either be at least two years post-menopausal, or be using adequate mechanical contraceptive precautions (i.e. intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period. Patients on oral contraceptives or an hormonal implant will be excluded.
7. All participants must have the following laboratory values:

Hemoglobin ≥ 13 gm/dl in males, or

≥ 12 gm/dl in females WBC count ≥ 3,000/mm3 Neutrophil count ≥ 1,500/mm3 Platelets ≥ 100,000/mm3 Prothrombin time within 3 seconds of control Albumin ≥3.0 g/dl Serum creatinine ≤ 1.6 mg/dl Creatinine phosphokinase ≤ 2 times upper limit of normal AST (SGOT) ≤ 2.5 times upper limit of normal ALT (SGPT) ≤ 2.5 times upper limit of normal Alkaline phosphatase ≤ 2.5 times upper limit of normal

Exclusion Criteria:

1. Any cause of chronic liver disease other than NASH (such as -but not restricted to- alcohol or drug abuse, medication, chronic hepatitis B or C, autoimmune, hemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency).
2. Any clinical evidence or history of ascitis, bleeding varices, or spontaneous encephalopathy.
3. No past (for at least for 1 year) or current history of alcohol abuse (alcohol consumption greater than one drink per day).
4. Prior surgical procedures to include gastroplasty, jejuno-ileal or jejunocolic bypass.
5. Prior exposure to organic solvents such as carbon tetrachloride.
6. Total parenteral nutrition (TPN) within the past 6 months.
7. Diabetics with a FPG greater than 260 mg/dl on initial visit.
8. Diabetics who are taking metformin, a thiazolidinedione or insulin.
9. Subjects with type 1 diabetes mellitus.
10. Patients on chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for 4 weeks before entry into the study. Patients on estrogens or other hormonal replacement therapy, tamoxifen, raloxifene, oral glucocorticoids or chloroquine will be excluded.
11. Patients with a history of clinically significant heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation), will not be studied.
C: Inclusion Criteria

1. Ages 40 years or greater at the time of randomization.
2. Ischemic stroke or TIA no less than 14 days and no more than 6 months before randomization
3. Documentation of insulin resistance as defined by a value over 3.0 on the Homeostasis Model Assessment of insulin sensitivity (HOMA).
4. Both ability and willingness to provide informed consent.
5. Presence of none of the exclusion criteria.

Exclusion Criteria

Permanent Exclusions

1. Severely disabling stroke as indicated by an inability to participate in scheduled follow-up activities.
2. Persons whose ischemic stroke or TIA was related to structural cardiac lesion, significant head trauma, proximal arterial dissection or medical instrumentation.
3. Diabetes mellitus as defined by recent use of medication for diabetes as an out-patient (\*see note below) or two fasting plasma blood sugars \> 126 mg/dL.
4. HgbA1c \> 7.0%.
5. Irreversible medical conditions likely to affect short-term survival or ability to participate in the study protocol. These include:

   * Cancer or other chronic disease with poor prognosis (predicted survival of less than four years).
   * Severe neurologic or psychiatric disease that would complicate the evaluation of study outcomes (e.g., dementia or schizophrenia).
6. History of intolerance to any thiazolidinedione.
7. Pregnancy or desire to become pregnant.
8. Oral contraceptive use.
9. Ongoing use of oral corticosteroids.
10. History of heart failure
11. Active liver disease as defined by known liver disease accompanied by cirrhosis, significant cholestasis, portal hypertension, hepatic encephalopathy, hepatic synthetic dysfunction, or expected significant loss of liver function over the course of the study.
12. History of bladder cancer.
13. Current participation in a conflicting clinical trial. A conflicting clinical trial is defined as a trial with any of following:

    * Intervention that is known to affect the incidence of stroke or myocardial infarction.
    * Intervention that is an experimental drug.
    * Outcome that includes stroke or myocardial infarction.
    * Exclusion for participation in another trial.

Temporary Exclusions Persons with temporary exclusions may be enrolled as soon as the exclusion has resolved.

1. Alanine aminotransferase (ALT) \>2.5 times the upper limit of normal.
2. Hemoglobin \<8.5 g/dl.
3. Moderate or severe pitting edema of the feet or legs (IRIS grade 3 or 4).
4. Carotid surgery or carotid stenting procedure scheduled (delay randomization until 2 weeks following procedure).
D: Inclusion Criteria:

* Men and women
* All ethnic groups
* 18 years of age and older
* Impaired glucose tolerance by glucose tolerance test (fasting glucose 95-125 mg/dl and 2 hr glucose of 140-199 mg/dl)
* At least one of the following:

  * One or more components of the insulin resistance syndrome (HDL \< 40 mg/dl in females and \<35 mg/dl in males, fasting triglycerides \> 150 mg/dl, blood pressure \> 135/85 mmHg, BMI \> 24 kg/m2, waist circumference \> 102 cm in men and \> 88 cm in women)
  * One or more first degree relatives with type 2 diabetes
  * History of gestational diabetes
  * Polycystic ovarian disease
  * Minority ethnic background (Mexican American, African American, Asian and Pacific Islanders, Native American)

Exclusion Criteria:

* Type 2 diabetes
* Previously treated with thiazolidinediones (ever) or metformin (within one year)
* Previously treated with a sulfonylurea, a meglitinide, an alpha glucosidase inhibitor for more than a week within last year or within the 3 months prior to randomization
* Previously treated with insulin (other than during pregnancy) for more than one week within the last year or within the 3 months prior to randomization
* Cardiovascular disease
* Hospitalization for treatment of heart disease or stroke in past 6 months
* New York Heart Association Functional Class \> 2
* Left bundle branch block or third degree AV block
* Aortic stenosis
* SBP \> 180 mmHg or DBP \> 105 mmHg
* Renal disease
* Anemia
* Hepatitis
* GI diseases (pancreatitis, inflammatory bowel disease)
* Recent or significant abdominal surgery
* Advanced pulmonary disease
* Chronic infections
* Weight loss \> 10% in past 6 months
* Pregnancy and childbearing
* Major psychiatric disorders
* Excessive alcohol intake
* Thiazide use \> 25 mg per day
* Non-selective beta blockers
* Niacin
* Systemic glucocorticoids
* Weight loss or weight gain medication
* Thyroid disease-suboptimally treated
* Active endocrine diseases (Cushing's, acromegaly)
* Plasma triglycerides over 400 mg/dl (despite treatment)
* History bladder cancer
* Hematuria

Answer: B