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

NCT01792115 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 13000213-DK-0002
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Fatty Liver

Keywords

Fatty Liver; Alpha-Tocopherol; Vitamin E; Non-Alcoholic Steatohepatitis

Outcome Measures

Primary Outcomes (2)

• Biochemical: Number of Patients With Normal Transaminases at End of Treatment.

  Biochemical response defined as number of patients with normal transaminases AST \<=32 or ALT \<=35 U/L at end of treatment.

  24 weeks

• Physiological: Absolute Change in Liver Fat

  Physiological response defined as absolute change in liver fat measured by 1H-MRS

  Baseline and 24 weeks

Secondary Outcomes (6)

• Absolute Change in AST

  Baseline and 24 weeks

• Percent Change in AST

  Baseline and 24 weeks

• Absolute Change in ALT

  Baseline and 24 weeks

• Percent Change in ALT

  Baseline and 24 weeks

• Absolute Change in GGT

  Baseline and 24 weeks

Study Arms (3)

Vit E 200 IU/d

ACTIVE COMPARATOR

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.

Drug: Vitamin E 200 IU/d; Behavioral: Diet and Exercise

Vitamin E 400

ACTIVE COMPARATOR

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.

Drug: Vitamin E 400 IU/d; Behavioral: Diet and Exercise

Vitamin E 800

ACTIVE COMPARATOR

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.

Drug: Vitamin E 800 IU/d; Behavioral: Diet and Exercise

Interventions

Vitamin E 200 IU/d DRUG

Supplement-low dose

Vit E 200 IU/d

Vitamin E 400 IU/d DRUG

Supplement-intermediate dose

Vitamin E 400

Vitamin E 800 IU/d DRUG

Supplement High Dose

Vitamin E 800

Diet and Exercise BEHAVIORAL

Diet and Exercise for all Arms of the study at baseline

Vit E 200 IU/d; Vitamin E 400; Vitamin E 800

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical suspicion of NAFLD, defined by the presence of at least two of the following criteria:
• Suggestion of liver fat by an imaging study (ultrasound, CT scan, MRI or MR spectroscopy) performed in the 6 months prior to enrollment.
• Elevated aminotransferase levels (ALT \> 31 U/L for men or \> 19 U/L for women, or AST \> 30 U/L) on at least two occasions in the 6 months preceding enrollment.
• Presence of the metabolic syndrome, defined according to the modified AHA/NCEP criteria as the presence of at least three of:
• Abdominal obesity, defined as waist circumference \> 102 cm for men or \> 88 cm for women
• Elevated triglycerides (\> 150 mg/dL) or the use of medication to lower triglycerides
• Reduced HDL cholesterol (\< 40 mg/DL for men or \< 50 mg/dL for women)
• Elevated blood pressure (\> 135/80 mmHg) or use of medication for hypertension
• Elevated fasting glucose levels (\> 100 mg/dL) or use of anti-diabetic medication
• Estimated average alcohol consumption \< 30 g/d for men or \< 20 g/d for women in the 6 months prior to enrollment and no binge-drinking behavior.
• Age \> 18 years at enrollment
• Willingness to participate in the study

You may not qualify if:

• Chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who were treated successfully for HCV and achieved sustained virological response can be eligible for enrollment \> 18 months after treatment cessation. Patients who are inactive carriers of HBV (HBV DNA \< 1000 copies/mL, HBeAg negative, Anti HDV negative) for at least 12 months prior to enrollment are also eligible. Patients receiving antiviral therapy are ineligible.
• Concomitant liver disease such as autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson s disease, alpha-1 antitrypsin deficiency.
• Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen
• Uncontrolled hypo- or hyperthyroidism.
• Decompensated advanced liver disease, defined as direct bilirubin \> 0.5 g/dL, PT \> 18, albumin \< 3 g/dL, or history of ascites, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis or liver transplant.
• Active coronary artery disease, defined as persistent angina pectoris, reversible ischemia on cardiac stress test or imaging, or the presence of significant coronary artery disease on imaging or catheterization. Patients with coronary artery disease that was treated by angioplasty or bypass surgery may be eligible if they have no evidence of active disease \>= 1 year after intervention, can safely stop antiplatelet and anticoagulant medications before the performance of invasive procedures, and have adequate ventricular function as assessed by echocardiography or cardiology consultation. These patients will require cardiology consultation and clearance prior to enrollment.
• Congestive heart failure.
• Chronic kidney disease, with creatinine clearance \< 60 ml/h.
• Uncontrolled diabetes mellitus. Patients may be enrolled if they have been on stable therapy with any anti-diabetic agent for at least 3 months prior to enrollment, are not foreseen by the physician treating their diabetes to require antidiabetic medication or dose changes during the trial and have an HbA1c \<= 7.5% on enrollment.
• Treatment with vitamin E. Patients who are currently taking vitamin E as a supplement will be requested to stop for at least 3 months before becoming eligible for enrollment. Patients who are taking vitamin E for a medical indication other than NAFLD will not be eligible.
• Contraindication to or inability to undergo a liver biopsy.
• Patients who had a liver biopsy performed \<= 2 years before enrollment, unless they are willing to undergo all of the trial biopsies, knowing that these biopsies are purely for research and are not clinically indicated. This will be clearly documented in the patients charts prior to enrollment.
• Patients with coagulopathy (PT/PTT values that are prolonged \>= 3 seconds from the upper limit of the normal, including treatment with oral and parenteral anticoagulants), thrombocytopenia (\<70,000), or platelet dysfunction will not be enrolled because of potential increase in risk of bleeding with vitamin E treatment. Antiplatelet agents taken for cardiovascular prevention will not exclude patients, unless they cannot be stopped safely for the performance of a liver biopsy.
• Maldigestion or malabsorption that can interfere with absorption of vitamin E including: steatorrhea of all causes, chronic pancreatitis, cystic fibrosis, short bowel syndrome, severe cholestasis, orlistat treatment and similar conditions
• Inability to swallow vitamin E capsules

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Podszun MC, Alawad AS, Lingala S, Morris N, Huang WCA, Rotman Y. Development of Subtle Iron Deficiency During Vitamin E Treatment For Metabolic Dysfunction-Associated Steatotic Liver Disease. J Diet Suppl. 2025;22(2):284-299. doi: 10.1080/19390211.2025.2465414. Epub 2025 Feb 17.

  PMID: 39960325 DERIVED

• Podszun MC, Alawad AS, Lingala S, Morris N, Huang WA, Yang S, Schoenfeld M, Rolt A, Ouwerkerk R, Valdez K, Umarova R, Ma Y, Fatima SZ, Lin DD, Mahajan LS, Samala N, Violet PC, Levine M, Shamburek R, Gharib AM, Kleiner DE, Garraffo HM, Cai H, Walter PJ, Rotman Y. Vitamin E treatment in NAFLD patients demonstrates that oxidative stress drives steatosis through upregulation of de-novo lipogenesis. Redox Biol. 2020 Oct;37:101710. doi: 10.1016/j.redox.2020.101710. Epub 2020 Sep 1.

  PMID: 32920226 DERIVED

• Podszun MC, Chung JY, Ylaya K, Kleiner DE, Hewitt SM, Rotman Y. 4-HNE Immunohistochemistry and Image Analysis for Detection of Lipid Peroxidation in Human Liver Samples Using Vitamin E Treatment in NAFLD as a Proof of Concept. J Histochem Cytochem. 2020 Sep;68(9):635-643. doi: 10.1369/0022155420946402.

  PMID: 32867573 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Fatty Liver; Non-alcoholic Fatty Liver Disease

Interventions

Vitamin E; Diet; Exercise

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Results Point of Contact

• Title: Dr. Yaron Rotman
• Organization: NIDDK

rotmanyaron@mail.nih.gov

301-451-6553

Study Officials

• Yaron Rotman, M.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2013
• First Posted: February 15, 2013
• Study Start: May 1, 2013
• Primary Completion: August 30, 2019
• Study Completion: August 30, 2019
• Last Updated: November 4, 2020
• Results First Posted: October 19, 2020

Record last verified: 2020-03-05

Locations

US (1)