Clinical trial NCT00323414: Polyunsaturated Fatty Acids (PUFA) in Diabetic Fatty Liver
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fatty Liver
Keywords: PUFA
NASH
Fatty Liver
Insulin resistance
Metabolic syndrome
Nonalcoholic fatty liver disease
Nonalcoholic steatohepatitis
Type 2 Diabetes Mellitus
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
First posted: 2006-05-09
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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 Clinical Research Network pathology score of 5.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Improvement of >= 2 Points in NAFLD Activity Score (NAS)
timeFrame: 48 weeks
Secondary outcomes:
measure: Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) Values
timeFrame: 48 weeks
measure: Aspartate Amino Transferase (AST) Levels
timeFrame: 48 weeks
measure: Alanine Amino Transferase (ALT) Levels
timeFrame: 48 weeks
measure: Blood Glucose Levels
timeFrame: 48 weeks
measure: HbA1C Levels
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
Study officials:
affiliation: MetroHealth Medical Center
name: Arthur J. McCullough, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: Srinivasan Dasarathy, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1016/s1542-3565(04)00014-x.
citation: Dasarathy S, Dasarathy J, Khiyami A, Yerian L, Hawkins C, Sargent R, McCullough AJ. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol. 2015 Feb;49(2):137-44. doi: 10.1097/MCG.0000000000000099.