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Prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) in Hispanics With Diabetes Mellitus Type 2 (T2DM) and Role of Treatment (VA NASH)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT01002547
First received: October 23, 2009
Last updated: April 10, 2017
Last verified: April 2017
  Purpose

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.


Condition Intervention Phase
Nonalcoholic Steatohepatitis Drug: pioglitazone-placebo Drug: pioglitazone Dietary Supplement: Vitamin E Drug: Vitamin E-placebo Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator
Primary Purpose: Treatment
Official Title: NAFLD in T2DM: Prevalence in Hispanics and Role of Treatment

Resource links provided by NLM:


Further study details as provided by VA Office of Research and Development:

Primary Outcome Measures:
  • Liver Histology (Kleiner's et al criteria, Hepatology 2005) [ Time Frame: 18 months and 36 months ]

Secondary Outcome Measures:
  • Hepatic, muscle and adipose tissue insulin sensitivity (from glucose turnover measurements during the euglycemic insulin clamps; oral glucose tolerance test [Matsuda index]). [ Time Frame: 18 and 36 months ]
  • Anthropometric variables (weight, BMI, total body fat by DXA). [ Time Frame: 18 and 36 months ]
  • Liver fat by magnetic resonance imaging and spectroscopy (MRS). [ Time Frame: 18 and 36 months ]
  • Plasma biomarkers of NAFLD/NASH [ Time Frame: 18 and 36 months ]
  • Metabolic control (glucose/A1c and lipid profile) and insulin secretion/glucose tolerance (OGTT). [ Time Frame: 18 and 36 months ]
  • Hypoglycemia. [ Time Frame: during 36 month study ]
  • Bone metabolism parameters (BMD by DXA; laboratory measurements of bone metabolism). [ Time Frame: 18 and 36 months ]
  • Edema (lower extremity, congestive heart failure). [ Time Frame: during entire 36 month study ]

Enrollment: 105
Actual Study Start Date: June 24, 2010
Study Completion Date: December 31, 2016
Primary Completion Date: September 30, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Arm 1
Diabetic with proven NASH by biopsy
Drug: pioglitazone-placebo
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.
Drug: Vitamin E-placebo
Placebo of vitamin E will be given to arm 3.
Active Comparator: Arm 2
Diabetic with proven NASH by biopsy
Drug: pioglitazone
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.
Other Name: Actos
Dietary Supplement: Vitamin E
All participants will receive vitamin E 400 IU orally twice daily.
Arm 3
Diabetic with proven NASH by biopsy
Drug: pioglitazone-placebo
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.
Dietary Supplement: Vitamin E
All participants will receive vitamin E 400 IU orally twice daily.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01002547

Locations
United States, Florida
North Florida/South Georgia Veterans Health System, Gainesville, FL
Gainesville, Florida, United States, 32608
United States, Texas
South Texas Health Care System, San Antonio, TX
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
VA Office of Research and Development
Investigators
Principal Investigator: Kenneth Cusi, PhD North Florida/South Georgia Veterans Health System, Gainesville, FL
  More Information

Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT01002547     History of Changes
Other Study ID Numbers: CLIN-015-08F
HSC20090401H ( Other Identifier: IRB UTHSCSA )
VA-ORD#GRANT00508571 ( Other Grant/Funding Number: CSRD CSP )
610-2011 ( Other Identifier: University of Florida IRB-01 )
Study First Received: October 23, 2009
Last Updated: April 10, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by VA Office of Research and Development:
steatohepatitis
type 2 diabetes
fatty liver

Additional relevant MeSH terms:
Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
Vitamins
Vitamin E
Tocopherols
Tocotrienols
alpha-Tocopherol
Pioglitazone
Micronutrients
Growth Substances
Physiological Effects of Drugs
Hypoglycemic Agents
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents

ClinicalTrials.gov processed this record on July 25, 2017