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

• ClinicalTrials.gov Identifier: NCT01792115
• Recruitment Status: Completed
• First Posted: February 15, 2013
• Results First Posted: October 19, 2020
• Last Update Posted: November 4, 2020
• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Fatty Liver	Drug: Vitamin E 200 IU/d; Drug: Vitamin E 400 IU/d; Drug: Vitamin E 800 IU/d; Behavioral: Diet and Exercise	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Treatment for Non-Alcoholic Fatty Liver With Different Doses of Vitamin E
• Actual Study Start Date: May 1, 2013
• Actual Primary Completion Date: August 30, 2019
• Actual Study Completion Date: August 30, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Vit 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.	Drug: Vitamin E 200 IU/d; Supplement-low dose; Behavioral: Diet and Exercise; Diet and Exercise for all Arms of the study at baseline
Active Comparator: Vitamin E 400; 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; Supplement-intermediate dose; Behavioral: Diet and Exercise; Diet and Exercise for all Arms of the study at baseline
Active Comparator: Vitamin E 800; 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; Supplement High Dose; Behavioral: Diet and Exercise; Diet and Exercise for all Arms of the study at baseline

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Absolute Change in AST [ Time Frame: Baseline and 24 weeks ]
   Absolute Change in AST [u/l] by week 24
2. Percent Change in AST [ Time Frame: Baseline and 24 weeks ]
   Percent change in AST by week 24
3. Absolute Change in ALT [ Time Frame: Baseline and 24 weeks ]
   Absolute Change in ALT [u/l] by week 24
4. Percent Change in ALT [ Time Frame: Baseline and 24 weeks ]
   Percent change in ALT by week 24
5. Absolute Change in GGT [ Time Frame: Baseline and 24 weeks ]
   Change in GGT by week 24 (U/L)
6. Percent Change in Liver Fat [ Time Frame: Baseline and 24 weeks ]
   Percent change in liver fat by week 24

Eligibility Criteria

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

Criteria

• INCLUSION CRITERIA:

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

    • For the purpose of inclusion, the presence of overt diabetes mellitus type 2 will be considered equivalent to the presence of the metabolic syndrome, even if the other criteria are absent.
• 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

EXCLUSION CRITERIA:

• 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.
• Presence of definite or probable drug-induced liver injury. In the case of lipid-lowering, anti-hypertensive or anti-diabetic medications that are suspected to cause elevation of aminotransferases, patients will be eligible if treatment is associated with stable enzyme levels for at least 6 months and inclusion criteria 1a. and 1c. are both present.
• 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
• Allergy to vitamin E
• Alcohol or substance abuse within the past 12 months. Patients will be required to have an AUDIT score of 7 or less18, and drink no more than 14 drinks/week (for men) or 7 drinks/week (for women).
• For women of childbearing age, pregnancy or inability (or unwillingness) to practice contraception for the duration of the study or breast feeding.
• Inability to understand and give informed consent for participation.

Contacts and Locations

Locations

United States, Maryland

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Yaron Rotman, M.D.; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  Study Documents (Full-Text)

Documents provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):

Study Protocol and Statistical Analysis Plan  [PDF] July 7, 2020

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT01792115
• Other Study ID Numbers: 130002; 13-DK-0002 ( Other Identifier: NIH Clinical Center )
• First Posted: February 15, 2013
• Results First Posted: October 19, 2020
• Last Update Posted: November 4, 2020
• Last Verified: March 5, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):

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

Additional relevant MeSH terms:

Fatty Liver; Non-alcoholic Fatty Liver Disease; Liver Diseases; Digestive System Diseases; Vitamins; Vitamin E; Tocopherols; Tocotrienols; alpha-Tocopherol; Micronutrients; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents