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Fatty LiverPhase 2NCT01792115

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

A Phase 2 study testing Vitamin E 200 IU/d, Vitamin E 400 IU/d and Vitamin E 800 IU/d in people with Fatty Liver, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Fatty Liver
What is being tested?
Vitamin E 200 IU/d, Vitamin E 400 IU/d and Vitamin E 800 IU/d
Could I receive a placebo?
No, everyone receives an active treatment
How many people
22 participants
Where
1 siteUnited States
Study dates
1 May 2013to 30 Aug 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 13Show fewer
  • 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

Who cannot join

  • 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.
Show all 20Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

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.
Read more

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.
Read the 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.

Conditions
Fatty Liver
Being tested
Vitamin E 200 IU/d, Vitamin E 400 IU/d, Vitamin E 800 IU/d, Diet and Exercise
Keywords
Fatty Liver, Alpha-Tocopherol, Vitamin E, Non-Alcoholic Steatohepatitis
Medical subject headings
Fatty Liver, Non-alcoholic Fatty Liver Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Vitamin E 200 IU/dDrug

    Supplement-low dose

  • Vitamin E 400 IU/dDrug

    Supplement-intermediate dose

  • Vitamin E 800 IU/dDrug

    Supplement High Dose

  • Diet and ExerciseBehavioural

    Diet and Exercise for all Arms of the study at baseline

Study groups in NCT01792115
Study groupRoleWhat they receive
Vit E 200 IU/dActive comparatorSubjects 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.
Receives: Drug: Vitamin E 200 IU/d; Behavioral: Diet and Exercise
Vitamin E 400Active comparatorSubjects 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.
Receives: Drug: Vitamin E 400 IU/d; Behavioral: Diet and Exercise
Vitamin E 800Active comparatorSubjects 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.
Receives: Drug: Vitamin E 800 IU/d; Behavioral: Diet and Exercise

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 24 weeks

  2. Physiological: Absolute Change in Liver Fat

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

    Measured: Baseline and 24 weeks

Secondary outcomes (6)

  1. Absolute Change in AST

    Absolute Change in AST [u/l] by week 24

    Measured: Baseline and 24 weeks

  2. Percent Change in AST

    Percent change in AST by week 24

    Measured: Baseline and 24 weeks

  3. Absolute Change in ALT

    Absolute Change in ALT [u/l] by week 24

    Measured: Baseline and 24 weeks

  4. Percent Change in ALT

    Percent change in ALT by week 24

    Measured: Baseline and 24 weeks

  5. Absolute Change in GGT

    Change in GGT by week 24 (U/L)

    Measured: Baseline and 24 weeks

  6. Percent Change in Liver Fat

    Percent change in liver fat by week 24

    Measured: Baseline and 24 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Feb 2013 (estimated)
  2. Study start1 May 2013
  3. Primary completion30 Aug 2019
  4. Study completion30 Aug 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
22 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01792115
Sponsor's protocol ID
130002
Other IDs
13-DK-0002
Status last verified
5 Mar 2020
First submitted
13 Feb 2013
Last updated
4 Nov 2020
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 39960325

  • 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.

    PubMed 32920226

  • 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.

    PubMed 32867573

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vitamin E 200 IU/d, Vitamin E 400 IU/d and Vitamin E 800 IU/d in people with Fatty Liver, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Biochemical: Number of Patients With Normal Transaminases at End of Treatment. (time frame: 24 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01792115, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2020.

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