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

NCT01002547 | Completed Phase 4 Results DMC

• 4 other identifiers: CLIN-015-08FHSC20090401HVA-ORD#GRANT00508571610-2011
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Nonalcoholic Steatohepatitis

Keywords

steatohepatitis; type 2 diabetes; fatty liver

Outcome Measures

Primary Outcomes (1)

• Liver Histology (Kleiner's et al Criteria, Hepatology 2005)

  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.

  18 months

Secondary Outcomes (16)

• Number of Participants With Resolution of NASH Without Worsening of Fibrosis

  Month 18

• Mean Individual Histological Scores

  Month 18

• Individual Histological Scores

  Month 18

• Liver Fat by Magnetic Resonance Imaging and Spectroscopy (MRS).

  Month 18

• Weight

  Month 18

Study Arms (3)

Arm 1

PLACEBO COMPARATOR

Diabetic with proven NASH by biopsy

Drug: pioglitazone-placebo; Drug: Vitamin E-placebo

Arm 2

ACTIVE COMPARATOR

Diabetic with proven NASH by biopsy

Drug: pioglitazone; Dietary Supplement: Vitamin E

Arm 3

OTHER

Diabetic with proven NASH by biopsy

Drug: pioglitazone-placebo; Dietary Supplement: Vitamin E

Interventions

pioglitazone-placebo DRUG

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.

Arm 1

pioglitazone DRUG

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.

Also known as: Actos

Arm 2

Vitamin E DIETARY_SUPPLEMENT

All participants will receive vitamin E 400 IU orally twice daily.

Arm 2

Vitamin E-placebo DRUG

Placebo of vitamin E will be given to arm 3.

Arm 1

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (2)

North Florida/South Georgia Veterans Health System, Gainesville, FL

Gainesville, Florida, 32608, United States

Location

South Texas Health Care System, San Antonio, TX

San Antonio, Texas, 78229, United States

Location

Related Publications (1)

• Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, Tio F, Suman A, Orsak BK, Hecht J, Cusi K. Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial. Diabetes Care. 2019 Aug;42(8):1481-1488. doi: 10.2337/dc19-0167. Epub 2019 May 21.

  PMID: 31332029 DERIVED

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Fatty Liver; Diabetes Mellitus, Type 2

Interventions

Pioglitazone; Vitamin E

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzopyrans; Pyrans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

Relative small sample size. A larger sample size could have resulted in significantly positive results for vitamin E alone in secondary outcomes. Because of this we acknowledge that vitamin E may still be an alternative for some patients.

Results Point of Contact

• Title: Dr. Kenneth Cusi
• Organization: Malcom Randall VA Medical Center

Kenneth.Cusi@va.gov; Kenneth.Cusi@medicine.ufl.edu

352-273-8662

Study Officials

• Kenneth Cusi, PhD

  North Florida/South Georgia Veterans Health System, Gainesville, FL

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2009
• First Posted: October 27, 2009
• Study Start: June 24, 2010
• Primary Completion: September 30, 2016
• Study Completion: December 31, 2016
• Last Updated: September 11, 2018
• Results First Posted: September 11, 2018

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)