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

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ClinicalTrials.gov Identifier: NCT00323414
Recruitment Status : Completed
First Posted : May 9, 2006
Last Update Posted : March 29, 2013
Information provided by (Responsible Party):

Study Description
Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Fatty Liver Drug: PUFA (Opti-EPA) Drug: Placebo Phase 2

Detailed Description:

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 CRN pathology score of 5.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Controlled Trial of Omega-3 Fatty Acids in the Treatment of Non-Alcoholic Steatohepatitis in Patients With Type 2 Diabetes Mellitus
Study Start Date : April 2006
Primary Completion Date : December 2011
Study Completion Date : December 2011

Arms and Interventions

Arm Intervention/treatment
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
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
Placebo Comparator: B or A
Gelcaps containing corn oil as placebo 6 capsules 3 capsules by mouth 2 x per day for 48 weeks
Drug: Placebo
Placebo gelcaps containing cornoil 6 capsules-3 capsules by mouth 2x per day x 48 weeks

Outcome Measures

Primary Outcome Measures :
  1. The change in histology score at 48 weeks [ Time Frame: 48 weeks ]

Secondary Outcome Measures :
  1. 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 ]
  2. Serum liver chemistries [ Time Frame: 48 weeks ]
  3. Hepatic expression of the genes [ Time Frame: 48 weeks ]
  4. Serum cytokines [ Time Frame: 48 weeks ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.
Contacts and Locations

Information from the National Library of Medicine

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): NCT00323414

United States, Ohio
MetroHealth Medical Center
Cleveland, Ohio, United States, 44109
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Principal Investigator: Arthur J. McCullough, M.D. MetroHealth Medical Center
Principal Investigator: Srinivasan Dasarathy, M.D. The Cleveland Clinic
More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT00323414     History of Changes
Other Study ID Numbers: DK61732
First Posted: May 9, 2006    Key Record Dates
Last Update Posted: March 29, 2013
Last Verified: March 2013

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
Fatty Liver
Insulin resistance
Metabolic syndrome
Nonalcoholic fatty liver disease
Nonalcoholic steatohepatitis
Type 2 Diabetes Mellitus

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Fatty Liver
Non-alcoholic Fatty Liver Disease
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Liver Diseases
Digestive System Diseases