Please select the eligibility criteria that correspond to the clinical trial below.
Title: Long-term Role of Pioglitazone in Non-Alcoholic Fatty Liver Disease (NAFLD) in Type 2 Diabetes Mellitus (T2DM).
Brief Summary: Obesity and Type 2 diabetes are creating a silent epidemic, Non-alcoholic fatty liver disease, which is a chronic liver disease associated with insulin resistance, impaired glucose intolerance, and hepatic fat accumulation. The thiazolidinedione pioglitazone improves glucose/lipid metabolism and histology in NASH by improving insulin resistance in the liver/peripheral/adipose tissues and reducing subclinical inflammation. The aim of this study is to assess the underlying mechanisms at the clinical and molecular level and the long-term efficacy and safety of pioglitazone in NASH in a multiethnic cohort of subjects (predominantly Hispanics, Caucasians and African-Americans - the most common ethnic groups locally) and examine the response including patients with normal glucose tolerance, impaired glucose tolerance or established type 2 diabetes mellitus (T2DM).


Options:
A: Inclusion Criteria:

* Is female and has not experienced menses for at least 5 years.
* Has a Fasting Plasma Glucose level greater than or equal to 100 and less than 126 mg/dL or a 2-hour post-oral glucose tolerance test greater than or equal to 140 and less than or equal to 199 mg/dL at Screening.
* Has a body mass index greater than or equal to 16 and less than or equal to 40 kg/m2 and weighs less than 300 pounds (approximately 136 kilograms).
* Agrees to take daily supplements of Vitamin D (a minimum of 800 IU daily) and calcium (a minimum of 1000 mg daily) during the treatment and wash-out periods.
* Has clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis \[fasted for at least 8 hours\]) within the reference range for the testing laboratory unless the results are deemed not clinically significant by the investigator or sponsor.
* Is in good health as determined by the physician (ie, via medical history and physical examination) at Screening.

Exclusion Criteria:

* Has a fasting triglyceride level greater than 500 mg/dL.
* Has a hemoglobinopathy causing anemia or interfering with glycosylated hemoglobin assays.
* Has an alanine transaminase level greater than or equal to 2.5 times the upper limit of normal, active liver disease or jaundice.
* Has Vitamin D (25-OH-D) less than 20 ng/mL.
* Has Baseline Bone Mineral Density defined as a T-score less than -2.0 at the total hip, spine, or femoral neck based on Caucasian reference values.
* Has unexplained microscopic or macroscopic hematuria confirmed by repeat testing.
* Has any of the following disorders:

  * Rheumatoid Arthritis
  * Thyroid (uncontrolled on thyroid replacement therapy), parathyroid, pituitary, nutritional, inflammatory, gastrointestinal, autoimmune, or renal or other disease known to affect bone metabolism.
  * A personal history of kidney stones.
* Has a clinical history after age 45 of wrist, hip, or leg fractures.
* Has a history of more than 1 asymptomatic vertebral deformity or any vertebral deformity attributed to osteoporosis.
* Has a known history of drug abuse (defined as illicit drug use) or a known history of alcohol abuse within 2 years of Screening.
* Has signs and/or symptoms of heart failure.
* Is currently participating in another investigational study or has participated in an investigational study within the past 30 days or 5 half lives of the investigational product, whichever is longer.
* Has any other serious disease or condition at screening or at randomization that might make it difficult to successfully manage and follow up with the subject according to the protocol.
* Has a history of cancer, other than basal cell carcinoma or Stage 1 squamous cell carcinoma of the skin that has not been in remission for at least 5 years prior to the first dose of study drug.
* Has a history of breast cancer.
* Is taking or has ever taken pioglitazone or other Thiazolidinediones.
* Has received or donated blood or blood products within 30 days preceding the Screening visit or plans to donate blood during the study.
B: Inclusion Criteria:

* Informed consent obtained
* Body Mass Index (BMI) of 30.0 kg/m\^2 or above
* Body Mass Index (BMI) of 27 kg/m\^2 or above in the presence of co-morbidities of treated or untreated dyslipidemia and/or hypertension
* Stable body weight
* Preceding failed dietary effort

Exclusion Criteria:

* Known type 1 or type 2 diabetes
* Glycosylated haemoglobin (HbA1c) of 6.5 % or above (Screening visit 1) or FPG of 126 mg/dL (7 mmol/L) or above (Screening visit 2) or 2 hour post-challenge (OGTT) plasma glucose of 200 mg/dL (11.1 mmol/L) or above (Screening visit 2)
* Screening calcitonin of 50 ng/L or above
* Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC)
* Personal history of non-familial medullary thyroid carcinoma
* History of acute or chronic pancreatitis
* Obesity induced by drug treatment
* Use of approved weight lowering pharmacotherapy
* Previous surgical treatment of obesity
* History of major depressive disorder or suicide attempt
* Uncontrolled hypertension (systolic blood pressure of 160 mmHg or above and/or diastolic blood pressure of 100 mmHg or above)
C: 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.
D: 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).

Answer: C