Polyunsaturated Fatty Acids (PUFA) in Diabetic Fatty Liver

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00323414
Recruitment Status : Completed
First Posted : May 9, 2006
Results First Posted : February 23, 2018
Last Update Posted : February 23, 2018
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

May 5, 2006
May 9, 2006
August 24, 2017
February 23, 2018
February 23, 2018
April 2006
December 2011   (Final data collection date for primary outcome measure)
Number of Participants With Improvement of >= 2 Points in NAFLD Activity Score (NAS) [ Time Frame: 48 weeks ]
The non-alcoholic fatty liver disease (NAFLD) activity score (NAS) is a score based on the liver biopsy. It represents the sum of scores for steatosis, lobular inflammation, and ballooning, and ranges from 0-8, with high scores indicating more activity.
The primary outcome will be the change in histology score at 48 weeks.
Complete list of historical versions of study NCT00323414 on Archive Site
  • Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) Values [ Time Frame: 48 weeks ]
    Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) measures insulin resistance, calculated by fasting insulin (μU/mL) multiplied by fasting glucose (mg/dL), and divided by a constant (405). A higher score indicates higher insulin resistance.
  • Aspartate Amino Transferase (AST) Levels [ Time Frame: 48 weeks ]
    Aspartate amino transferase (IU/dL) at 48 weeks
  • Alanine Amino Transferase (ALT) Levels [ Time Frame: 48 weeks ]
    Alanine amino transferase (IU/dL) ay 48 weeks
  • Blood Glucose Levels [ Time Frame: 48 weeks ]
    Fasting blood glucose
  • HbA1C Levels [ Time Frame: 48 weeks ]
    Hemoglobin A1c
  • 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 Diabetic Fatty Liver
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.


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 Clinical Research Network pathology score of 5.

Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Fatty Liver
  • Drug: Polyunsaturated fatty acid (Opti-EPA)
    Active experimental arm to patients with diabetes mellitus and non alcoholic steatohepatitis: Eicosapentaenoic acid (EPA):Docosahexaenoic acid (DHA)[360 mg EPA and 240 DHA in each capsule] 6 capsules-3 capsules by mouth 2 x per day x 48 weeks
    Other Name: Fish oil
  • Drug: Placebo
    Placebo gelcaps containing corn oil identical to the PUFA gelcaps 6 capsules-3 capsules by mouth 2x per day x 48 weeks
    Other Name: Corn oil
  • Active Comparator: Polyunsaturated fatty acid (Opti-EPA)
    Polyunsaturated fatty acid will consist of purified EPA:DHA (360 mg EPA and 240 mg DHA) 6 gelcaps-3 capsules by mouth 2x per day x 48 weeks
    Intervention: Drug: Polyunsaturated fatty acid (Opti-EPA)
  • Placebo Comparator: Placebo
    Gelcaps containing corn oil as placebo 6 capsules 3 capsules by mouth 2 x per day for 48 weeks
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
Contact information is only displayed when the study is recruiting subjects
United States
U01DK061732 ( U.S. NIH Grant/Contract )
Not Provided
Not Provided
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)
October 2017

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