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Polyunsaturated Fatty Acids (PUFA) in the Treatment of Non-Alcoholic Steatohepatitis (NASH) in Patients With Type 2 Diabetes Mellitus (PUFA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT00323414
First received: May 5, 2006
Last updated: March 28, 2013
Last verified: March 2013

May 5, 2006
March 28, 2013
April 2006
December 2011   (final data collection date for primary outcome measure)
The change in histology score at 48 weeks [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
The primary outcome will be the change in histology score at 48 weeks.
Complete list of historical versions of study NCT00323414 on ClinicalTrials.gov Archive Site
  • Secondary outcomes will include: insulin sensitivity and resistance calculated from the homeostasis model assessment (HOMA) and insulin sensitivity index (ISI) using standard formulae [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Serum liver chemistries [ Time Frame: 48 weeks ]
  • Hepatic expression of the genes [ Time Frame: 48 weeks ]
  • Serum cytokines [ Time Frame: 48 weeks ]
  • Secondary outcomes will include:
  • insulin sensitivity and resistance calculated from the HOMA and ISI indexes using standard formulae.
  • Serum liver chemistries
  • Hepatic expression of the genes
  • Serum cytokines
Not Provided
Not Provided
 
Polyunsaturated Fatty Acids (PUFA) in the Treatment of Non-Alcoholic Steatohepatitis (NASH) in Patients With Type 2 Diabetes Mellitus (PUFA)
Randomized Controlled Trial of Omega-3 Fatty Acids in the Treatment of Non-Alcoholic Steatohepatitis in Patients With Type 2 Diabetes Mellitus

Non-alcoholic steatohepatitis (NASH), the most severe form of liver injury in the spectrum of non-alcoholic fatty liver disease (NAFLD), has emerged as the major cause of chronic liver disease in developed countries. Among adults in the United States, the prevalence is between 5.7% and 17%. These rates are expected to increase concurrent with the epidemics of obesity and type 2 diabetes mellitus, which are the major risk factors for NAFLD and NASH. In addition to its high prevalence, NASH is also a progressive fibrotic disease that advances to cirrhosis and liver related death in 20% and 12% of patients, respectively. Among NASH patients with cirrhosis, 40% have liver related death. Diabetics are particularly prone to experience these poor outcomes. No therapy has been proven effective for patients with NASH.

The purpose of this study is to find out whether treatment with polyunsaturated fatty acids (eicosapentaenoic acid [EPA] combined with docosahexaenoic acid [DHA] called Opti-EPA) improves NASH compared to treatment with placebo pills. The placebo pills will contain corn oil and will be contained in a capsule, but have no medical effect on the body. The investigators will determine improvement in NASH from microscopic changes in the subject's liver tissue during 48 weeks of treatment. This means that the subject will need to have a liver biopsy before and after the treatment.

Omega-3 fatty acids are a form of polyunsaturated fats, one of the four basic types of fat that the body gets from food. (Cholesterol, saturated fat, and monounsaturated fat are the others.) One's body does not make this type of fat; it comes from food sources. These fats are found in foods like cold water fish (tuna, salmon, and mackerel), and vegetable products like flaxseed oil and walnuts.

Research shows that polyunsaturated fats are good for people. Studies have shown that it is good for heart health by playing a role in keeping blood cholesterol levels low, keeping irregular heart rhythms stable, and reducing blood pressure.

The drug being studied, Opti-EPA, is a nutritional supplement. They do not have to be reviewed by the Food and Drug Administration (FDA) like medicines do. Opti-EPA is considered experimental in this study. This means that the United States Food and Drug Administration (FDA) has not approved it for use in people with nonalcoholic fatty liver disease.

Although there is no proven effective treatment of NASH, dietary supplementation with long chain omega-3 polyunsaturated fatty acids (PUFA's) may be beneficial. This suggestion is based on three previously reported observations: first, patients with NASH consume less PUFAs and more saturated fats than subjects without NASH. Second, PUFAs are beneficial in patients with hypertension and hypertriglyceridemia. Third, PUFAs decrease lipid peroxidation and ameliorate hepatic steatosis in animal models of NAFLD.

We therefore hypothesize that the administration of these PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) will reduce hepatic fat content, inflammation and hepatic injury in patients with type 2 diabetes mellitus who have NASH.

Aims

To determine in patients with type 2 diabetes mellitus who have NASH if dietary supplementation with purified omega-3 fatty acids (EPA and DHA) will:

  1. Decrease the histologic severity of NASH.
  2. Alter the expression of genes important in the pathways of hepatic lipid synthesis and oxidation.

Study design:

Patients who meet the inclusion criteria will be randomized to receive omega-3 fatty acids or placebo. Stratified randomization will be done based on the NASH CRN pathology score of 5.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Fatty Liver
  • Drug: PUFA (Opti-EPA)
    EPA:DHA (360 mg EPA and 240 DHA in each capsule) 6 capsules-3 capsules by mouth 2 x per day x 48 weeks
  • Drug: Placebo
    Placebo gelcaps containing cornoil 6 capsules-3 capsules by mouth 2x per day x 48 weeks
  • Experimental: A or B
    Purified EPA:DHA (360 mg EPA and 240 mg DHA) 6 gelcaps 3 capsules by mouth 2x per day x 48 weeks
    Intervention: Drug: PUFA (Opti-EPA)
  • Placebo Comparator: B or A
    Gelcaps containing corn oil as placebo 6 capsules 3 capsules by mouth 2 x per day for 48 weeks
    Intervention: Drug: Placebo
Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2004 Mar;2(3):262-5. Erratum in: Clin Gastroenterol Hepatol. 2004 Jun;2(6):522.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
32
December 2011
December 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Adult patients (age >18 years)
  • Have type 2 diabetes mellitus with good control of blood sugar (hemoglobin A1c [HbA1c] <7.5%) and will have been on a stable regimen of anti-diabetic agents for more than 4 months.
  • NASH established on liver biopsy done within 6 months prior to inclusion in the study as determined by established histologic criteria

Exclusion Criteria:

  • Cirrhosis of the liver
  • End stage target organ damage in diabetes mellitus: advanced renal failure (serum creatinine > 2.0 mg/dl) with or without dialysis, severe neuropathy, or advanced peripheral vascular disease.
  • Any organ dysfunction with anticipated life expectancy of less than 2 years
  • Co-existent etiologies for liver disease
  • Significant alcohol consumption, defined as more than 30 g per day in men and more than 20 g per day in women.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00323414
DK61732
Yes
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Not Provided
Principal Investigator: Arthur J. McCullough, M.D. MetroHealth Medical Center
Principal Investigator: Srinivasan Dasarathy, M.D. The Cleveland Clinic
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
March 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP