Prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) in Hispanics With Diabetes Mellitus Type 2 (T2DM) and Role of Treatment (VA NASH)
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ClinicalTrials.gov Identifier: NCT01002547 |
Recruitment Status :
Completed
First Posted : October 27, 2009
Results First Posted : September 11, 2018
Last Update Posted : September 11, 2018
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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 or disease | Intervention/treatment | Phase |
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Nonalcoholic Steatohepatitis | Drug: pioglitazone-placebo Drug: pioglitazone Dietary Supplement: Vitamin E Drug: Vitamin E-placebo | Phase 4 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 105 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Triple (Participant, Care Provider, Investigator) |
Primary Purpose: | Treatment |
Official Title: | NAFLD in T2DM: Prevalence in Hispanics and Role of Treatment |
Actual Study Start Date : | June 24, 2010 |
Actual Primary Completion Date : | September 30, 2016 |
Actual Study Completion Date : | December 31, 2016 |
Arm | Intervention/treatment |
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Placebo Comparator: Arm 1
Diabetic with proven NASH by biopsy
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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
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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
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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. |
- Liver Histology (Kleiner's et al Criteria, Hepatology 2005) [ Time Frame: 18 months ]
Number of patients with reduction of at least 2 points in the nonalcoholic fatty liver disease activity score (NAS) (with reduction in at least 2 different histological categories) without worsening of fibrosis. NAS is the sum of the separate scores for steatosis (0-3), hepatocellular ballooning (0-2) and lobular inflammation (0-3), and ranges from 0-8 .
The scoring system is based on the following grading:
Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis.
- Number of Participants With Resolution of NASH Without Worsening of Fibrosis [ Time Frame: Month 18 ]Resolution of NASH was defined as absence of NASH after 18 months of therapy in patients with definite NASH (presence of zone 3 accentuation of macrovesicular steatosis of any grade, hepatocellular ballooning of any degree, and lobular inflammatory infiltrates of any amount) at baseline.
- Mean Individual Histological Scores [ Time Frame: Month 18 ]
Mean change in individual scores compared to baseline. Steatosis range 0-3, where: 0 = <5% fat; 1 = 5-33% fat; 2 = >33-66% fat; 3 = >66% fat.
Lobular Inflammation, range 0-3, where: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x.
Hepatocyte Ballooning, range 0-2, where: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning.
Fibrosis stage, range 0-4, where: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis.
- Individual Histological Scores [ Time Frame: Month 18 ]
Number of patients with improvement of at least 1 grade in each of the histological parameters.
Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x.
Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning.
Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis.
- Liver Fat by Magnetic Resonance Imaging and Spectroscopy (MRS). [ Time Frame: Month 18 ]Change from baseline in intrahepatic triglyceride content after 18 months of therapy
- Weight [ Time Frame: Month 18 ]Change from baseline in weight
- Body Mass Index [ Time Frame: Month 18 ]Weight (in kg) / (Height [in m] x Height [in m])
- Total Body Fat by DEXA [ Time Frame: Month 18 ]Change from baseline in total body fat by DEX after 18 months of therapy
- Plasma AST [ Time Frame: Month 18 ]Change from baseline in plasma AST after 18 months of therapy
- Plasma ALT [ Time Frame: Month 18 ]Change from baseline in plasma ALT after 18 months of therapy
- Fasting Plasma Glucose [ Time Frame: Month 18 ]Change from baseline after 18 months of therapy
- Fasting Plasma Insulin [ Time Frame: Month 18 ]Change from baseline after 18 months of therapy
- Matsuda Index [ Time Frame: Month 18 ]This is a method for assessing insulin resistance (IR) based on measurements of glucose and insulin during the oral glucose tolerance test. The formula used is = (10000/(SQRT(fasting plasma glucose * fasting plasma insulin * ((fasting plasma glucose * 15 + glucose at minute 30 * 30 + glucose at minute 60 * 30 + glucose at minute 90 * 30 + glucose at minute 120 * 15)/120)*((fasting plasma insulin * 15 + insulin at minute 30 * 30 + insulin at minute 60 * 30 + insulin at minute 90 * 30 + insulin at minute 120 * 15)/120))), with a lower value representing worse insulin resistance.
- Total Cholesterol [ Time Frame: Month 18 ]Change from baseline in plasma total cholesterol after 18 months of therapy
- Triglycerides [ Time Frame: Month 18 ]Change from baseline in plasma triglycerides after 18 months of therapy
- HDL-cholesterol [ Time Frame: Month 18 ]Change from baseline in plasma HDL-cholesterol after 18 months of therapy
- LDL-cholesterol [ Time Frame: Month 18 ]Change from baseline in plasma LDL-cholesterol after 18 months of therapy
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Ages Eligible for Study: | 18 Years to 70 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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.
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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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01002547
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 |
Principal Investigator: | Kenneth Cusi, PhD | North Florida/South Georgia Veterans Health System, Gainesville, FL |
Responsible Party: | VA Office of Research and Development |
ClinicalTrials.gov Identifier: | NCT01002547 |
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 ) |
First Posted: | October 27, 2009 Key Record Dates |
Results First Posted: | September 11, 2018 |
Last Update Posted: | September 11, 2018 |
Last Verified: | August 2018 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
steatohepatitis type 2 diabetes fatty liver |
Fatty Liver Non-alcoholic Fatty Liver Disease Liver Diseases Digestive System Diseases Vitamins Vitamin E Tocopherols Tocotrienols |
alpha-Tocopherol Pioglitazone Micronutrients Physiological Effects of Drugs Hypoglycemic Agents Antioxidants Molecular Mechanisms of Pharmacological Action Protective Agents |