Treatment for Non-Alcoholic Fatty Liver With Different Doses of Vitamin E

Phase 2

Completed

Conditions: Fatty Liver

Interventions: Drug: Vitamin E 800 IU/d
Drug: Vitamin E 200 IU/d
Drug: Vitamin E 400 IU/d
Behavioral: Diet and Exercise

Registration Number: NCT01792115

Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Brief Summary: Background:

* Non-alcoholic fatty liver disease (NAFLD) is an excess accumulation of fat in the liver cells. It is associated with obesity, high blood pressure, high cholesterol, and diabetes. Some people with NAFLD only have excess fat in the liver. However, other people may develop a worse form of NAFLD with liver injury and scarring. This form, called non-alcoholic steatohepatitis (NASH), can lead to liver failure, liver cancer, and death. Not much is known about why some people develop NASH and others do not.

* Lifestyle changes such as diet, exercise, and weight loss can decrease the liver damage in NAFLD. Some studies show that vitamin E can also help treat NAFLD. The dose of vitamin E used in these studies is almost 40 times the recommended amount of vitamin E intake from food. It is unclear whether a lower dose could achieve the same effect. Researchers also want to study how vitamin E works at different doses to treat NAFLD.

Objectives:

* To find out the most effective dose of vitamin E to treat NAFLD.

* To gain a better understanding of how NAFLD and NASH develop, and predict who will respond to treatment.

Eligibility:

- Individuals at least 18 years of age with suggestion of non-alcoholic fatty liver disease.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.

* For the first 12 weeks of the study, participants will meet with a nutritionist. They will have personalized diet and exercise plans. Treatment will be monitored with diaries and questionnaires to fill out at home. Participants will also wear a pedometer to measure physical activity.

* After the 12-week period, participants will have a full physical examination with the following tests:

* Blood tests

* Glucose tolerance tests

* Imaging studies (DEXA scan and magnetic resonance imaging)

* Liver and fatty tissue biopsy

* Two weeks after the tests, participants will start vitamin E treatment. They will take up to two pills a day, taken with fat-containing foods.

* 4 weeks after starting treatment they will have a repeat full evaluation with imaging tests, blood work, and liver and fat biopsies.

* Participants who are taking vitamin E will take it for up to 120 weeks. They will have monitoring visits every 8 to 12 weeks. At the end of 120 weeks, they will have another full evaluation, with imaging tests, blood work, and liver and fat biopsies.

Detailed Description: Non-alcoholic fatty liver disease (NAFLD) is the most common cause for liver test abnormalities in the western world, and an increasingly rising cause for liver-related morbidity and mortality. Vitamin E, a fat-soluble anti-oxidant was recently found to be an effective treatment for NAFLD; however, its mechanism of action is unclear. In a controlled clinical trial vitamin E treatment was shown to significantly reduce the hepatic fat burden, suggesting mechanisms other than reducing oxidative stress are involved. Furthermore, the optimal dose of vitamin E to treat NAFLD is unknown.

We propose a phase IIa study to determine the optimal dose of vitamin E and its mechanism and site of action. In this study we aim to enroll up to 90 patients with NAFLD. Initially, all patients will undergo 12 weeks of intensive lifestyle modification. Following that, all patients will be randomized to treatment with 3 different doses of natural vitamin E (rrr- -tocopherol at 200, 400 or 800 IU/d) for 24 weeks. The primary end points for efficacy are normalization of liver enzymes and reduction in liver fat contents by magnetic resonance spectroscopy. Patients will undergo liver and adipose tissue biopsies before vitamin E treatment and after 4 weeks of therapy, and the biopsy samples will be used to measure changes in gene expression and markers of oxidative stress. This will be coupled with extensive phenotyping before and after treatment using serological, radiological and dynamic endocrine testing and is aimed at finding the dose-response characteristics of vitamin E in NAFLD, and allowing us to understand the mechanism of its action.

After 24 weeks of randomized treatment, all patients will be switched to a dose of 800 IU/ml and will continue treatment for up to 30 months, at the end of which another liver biopsy will be performed. From this phase we will assess the effects of dose increase of vitamin E on liver enzymes and fat content, and will determine the effect of long-term treatment on histological outcome.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vit E 200 IU/d	Diet and Exercise	Subjects randomized to vitamin E 200 IU/day for 24 weeks; invited to optional extension of open- label vitamin E 800 IU /day for up to 120 weeks following the initial 24 week period.
Vitamin E 800	Vitamin E 800 IU/d	Subjects randomized to vitamin E 800 IU /day for 24 weeks; invited to optional extension of open- label vitamin E 800 IU /day for up to 120 weeks following the initial 24 week period.
Vit E 200 IU/d	Vitamin E 200 IU/d	Subjects randomized to vitamin E 200 IU/day for 24 weeks; invited to optional extension of open- label vitamin E 800 IU /day for up to 120 weeks following the initial 24 week period.
Vitamin E 400	Vitamin E 400 IU/d	Subjects randomized to vitamin E 400 IU/day for 24 weeks; invited to optional extension of open- label vitamin E 800 IU/day for up to 120 weeks following the initial 24 week period.
Vitamin E 400	Diet and Exercise	Subjects randomized to vitamin E 400 IU/day for 24 weeks; invited to optional extension of open- label vitamin E 800 IU/day for up to 120 weeks following the initial 24 week period.
Vitamin E 800	Diet and Exercise	Subjects randomized to vitamin E 800 IU /day for 24 weeks; invited to optional extension of open- label vitamin E 800 IU /day for up to 120 weeks following the initial 24 week period.

Primary Outcome Measures

Name	Time	Method
Biochemical: Number of Patients With Normal Transaminases at End of Treatment.	24 weeks	Biochemical response defined as number of patients with normal transaminases AST \<=32 or ALT \<=35 U/L at end of treatment.
Physiological: Absolute Change in Liver Fat	Baseline and 24 weeks	Physiological response defined as absolute change in liver fat measured by 1H-MRS

Secondary Outcome Measures

Name	Time	Method
Percent Change in ALT	Baseline and 24 weeks	Percent change in ALT by week 24
Percent Change in Liver Fat	Baseline and 24 weeks	Percent change in liver fat by week 24
Absolute Change in ALT	Baseline and 24 weeks	Absolute Change in ALT \[u/l\] by week 24
Absolute Change in GGT	Baseline and 24 weeks	Change in GGT by week 24 (U/L)
Absolute Change in AST	Baseline and 24 weeks	Absolute Change in AST \[u/l\] by week 24
Percent Change in AST	Baseline and 24 weeks	Percent change in AST by week 24