Prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) in Hispanics With Diabetes Mellitus Type 2 (T2DM) and Role of Treatment
Condition: Nonalcoholic Steatohepatitis
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: pioglitazone-placebo; pioglitazone; Vitamin E; pioglitazone-placebo; Vitamin E; Vitamin E-placebo
Intervention description: This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Depending on randomization, subjects adjudicated to placebo will be started at the same time as the active (pioglitazone) arm following completion of the baseline measurements and continued on placebo for the rest of the clinical trial.; Pioglitazone will be started on 30 mg/day, titrated to the maximal dose (45 mg/day) at two months and continued at this dose for the rest of the clinical trial.; All participants will receive vitamin E 400 IU orally twice daily.; This is a RCT in which all patients will be educated on a -500 kcal/day diet and a healthy lifestyle. Depending on randomization, subjects adjudicated to placebo will be started at the same time as the active (pioglitazone) arm following completion of the baseline measurements and continued on placebo for the rest of the clinical trial.; All participants will receive vitamin E 400 IU orally twice daily.; Placebo of vitamin E will be given to arm 3.
Intervention MeSH terms: Vitamins; Vitamin E; Tocopherols; Tocotrienols; alpha-Tocopherol; Pioglitazone
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 105.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: steatohepatitis; type 2 diabetes; fatty liver

Summary:

      Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition frequently associated
      with type 2 diabetes (T2DM) and characterized by insulin resistance and hepatic fat
      accumulation. Liver fat may range from simple steatosis to severe steatohepatitis with
      necroinflammation and variable degrees of fibrosis (nonalcoholic steatohepatitis or NASH). Up
      to 40% of patients with NAFLD develop NASH in recent series. Risk factors for progression to
      NASH are unclear, but appears to be more common and progress more rapidly in older
      individuals, and in the presence of obesity and T2DM. Because the VA population in San
      Antonio, Texas, frequently combine these risk factors for NASH it was felt that a study
      targeting this very high-risk population was needed.

      This study will establish the long-term efficacy (primary endpoint: liver histology) and
      safety of pioglitazone for the treatment of VA patients with T2DM and NASH. All patients
      diagnosed with NASH will be offered lifestyle modification/weight loss (current standard of
      care) while being randomized to pioglitazone, vitamin E or placebo for up to 3 years. We
      believe that in such a high-risk population for complications from NASH, a substantial
      benefit may be expected from early detection and treatment.

      Specifically, the arms are: a) pioglitazone + vitamin E; b) vitamin E + placebo of
      pioglitazone; c) placebo of both. Patients are randomized to one of these 3 arms, and
      followed in a double-blind fashion for up to 18 months. Patients are then offered to continue
      into an open-label phase with pioglitazone + vitamin E or vitamin E alone for another 18
      months.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Be able to communicate meaningfully with the Investigator and be legally competent to
             provide written informed consent.

          -  Subjects of both genders from within the Veterans Administration Healthcare System
             with an age range between 18 to 70 years (inclusive).

          -  Have type 2 diabetes mellitus as defined by the American Diabetes Association
             guidelines.

          -  Female volunteers 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.

          -  The following laboratory values:

               -  Hemoglobin at least 12 gm/dl in males or 11 gm/dl in females, WBC count 3,000/mm3
                  (neutrophil count 1,500/mm3) and platelets 100,000/mm3

               -  Albumin equal or greater than 3.0 g/dl

               -  Serum creatinine less than 1.8 mg/dl

               -  AST and ALT up to 3.0 times upper limit of normal and alkaline phosphatase 2.5
                  times ULN

        Exclusion Criteria:

          -  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).

          -  Any clinical evidence or history of ascitis, bleeding varices, or spontaneous
             encephalopathy.

          -  History of alcohol abuse (alcohol consumption greater than 20 grams of ethanol per
             day) or a positive AUDIT screening questionnaire.

          -  Prior surgical procedures to include gastroplasty, jejunoileal or jejunocolic bypass.

          -  Prior exposure to organic solvents such as carbon tetrachloride.

          -  Total parenteral nutrition (TPN) within the past 6 months.

          -  Subjects with type 1 diabetes mellitus.

          -  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 drugs known to cause hepatic steatosis: estrogens or other hormonal
             replacement therapy, tamoxifen, raloxifene, oral glucocorticoids, chloroquine and
             others.

          -  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).

          -  Patients with severe osteoporosis (-3.0 at the level of spine and hip).

          -  Patients who have clinically significant acute or chronic medical conditions not
             specifically written in the protocol, but that based in the investigator's clinical
             judgment he/she considers unlikely that he will be able to complete study
             participation or that such participation may be potentially detrimental to his
             well-being.