Vitamin E Dosing Study

Study Overview
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Brief Summary
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This is a multicenter, randomized, double masked, placebo-controlled, parallel treatment groups dosing trial of Vitamin E in adult nonalcoholic fatty liver disease (NAFLD).

Detailed Description
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Adults age 18 years or older will be enrolled for 48 weeks and treated with 200 international units (IU), 400 IU, or 800 IU of Vitamin E or matching placebo for 24 weeks. The primary objective of the study is to determine the minimum effective dose of Vitamin E (d-alpha-tocopherol) based upon relative change in alanine aminotransferase (ALT) from baseline to 24 weeks.

Official Title
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Vitamin E Dosing Study (VEDS): A Dose Finding Study of Vitamin E for the Treatment of Adult NAFLD

Conditions
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Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Vitamin E
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older as of the initial screening interview and provision of consent FibroScan CAP>280 dB/m within 60 days prior to randomization. ALT ≥ 60 U/L within 30 days of randomization Exclusion Criteria: Concurrent or prior use (within 90 days) of vitamin E supplements in excess of 40 IU/day Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more than 20 g/day ( 1.5 drinks/day) (> 10.5 drinks per week) in females and more than 30 g/day ( 2 drinks/day) (>14 drinks per week) in males, respectively. One standard drink (or one alcoholic drink equivalent) contains roughly 14 grams of pure alcohol, which is found in: 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of distilled spirits). Inability to reliably quantify alcohol consumption based upon local study physician judgment Continued use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) for more than 2 weeks in the 6 months prior to randomization Current use of anticoagulation therapy (not including antiplatelet agents such as aspirin or clopidogrel) Platelet count below 150,000 /mm3 within 90 days of randomization History of condition(s) that cause increased risk of bleeding, including hemophilia A, hemophilia B, von Willebrand disease, or other clotting factor deficiencies. Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y gastric bypass) Uncontrolled diabetes defined as HbA1c 9.5% or higher within 60 days prior to randomization Clinical evidence of hepatic decompensation as defined by the presence of any of the following abnormalities: Serum albumin less than 3.2 g/dL International Normalized Ratio (INR) greater than 1.3 Direct bilirubin greater than 1.0 mg/dL History of esophageal varices, ascites or hepatic encephalopathy Evidence of other forms of chronic liver disease: Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA Evidence of ongoing autoimmune liver disease as defined by compatible liver histology Primary biliary cirrhosis as defined by the presence of at least 2 of these criteria (i) Biochemical evidence of cholestasis based mainly on alkaline phosphatase elevation (ii) Presence of anti-mitochondrial antibody (AMA) (iii) Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts[1] Primary sclerosing cholangitis Known history of Wilson disease, alpha-1-antitrypsin liver disease, or hemochromatosis. Any other type of liver disease that is currently active other than NASH such as drug-induced liver disease, liver cancer, or bile duct obstruction. Serum alanine aminotransferase (ALT) greater than 400 U/L within 90 days of randomization Moderate or severe renal impairment (serum creatinine ≥ 2.0 mg/dL or eGFR < 60 mg/mL/1.73m2) History of biliary diversion or evidence of current biliary obstruction Known positivity for Human Immunodeficiency Virus (HIV) infection Active, serious medical disease with likely life expectancy less than 5 years Active substance abuse including inhaled or injection drugs in the year prior to screening Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use ≥ 1 effective form(s) of birth control during the trial, breast feeding Current use of medications that may impact the absorption of fat-soluble vitamins (i.e. orlistat or cholestyramine) Pre-existing history of fat malabsorption Males at high risk of prostate cancer, including: PSA >ULN at baseline History of prostate cancer Age 45 or older with a first-degree relative (father or brother) diagnosed with prostate cancer at an early age (younger than age 65). Age 40 or older with more than one first-degree relative who had prostate cancer at an early age (younger than age 65) Participation in an IND trial in the 30 days before randomization Any other condition which, in the opinion of the investigator, would impede compliance or hinder completion of the study, including inability to swallow treatment capsules Failure or inability to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multicenter, randomized, double masked, placebo-controlled, parallel treatment groups
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vitamin E, 200 IU<br>200 IU of d-alpha tocopherol (vitamin E) taken once daily with breakfast | Drug: Vitamin E<br>* Participants will be assigned to take 200 IU, 400 IU, or 800 IU of vitamin E in matching capsules daily for 24 weeks<br>* Other names: d-alpha-tocopherol;|
| Active Comparator: Vitamin E, 400 IU<br>400 IU of d-alpha tocopherol (vitamin E) taken once daily with breakfast | Drug: Vitamin E<br>* Participants will be assigned to take 200 IU, 400 IU, or 800 IU of vitamin E in matching capsules daily for 24 weeks<br>* Other names: d-alpha-tocopherol;|
| Active Comparator: Vitamin E, 800 IU<br>800 IU of d-alpha tocopherol (vitamin E) taken once daily with breakfast | Drug: Vitamin E<br>* Participants will be assigned to take 200 IU, 400 IU, or 800 IU of vitamin E in matching capsules daily for 24 weeks<br>* Other names: d-alpha-tocopherol;|
| Placebo Comparator: Placebo<br>matching placebo taken once daily with breakfast | Drug: Placebo<br>* Participants will take a placebo vitamin E capsule daily for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative change in alanine aminotransferase (ALT) from baseline to 24 weeks | ALT value in units/liter (U/L) | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving normalization of alanine aminotransferase (ALT) at 24 weeks | Normalization of ALT (U/L) is defined as a decrease in ALT to less than or equal to the ULN at the 24 week visit among participants who had an ALT value greater than ULN at baseline. Values for upper limits of normal (ULN) are defined at each clinical center per institutional guidelines. | 24 weeks | 
| Mean change in serum alanine aminotransferase (ALT) from baseline | ALT value in U/L | 24 weeks | 
| Mean change in serum aspartate aminotransferase (AST) from baseline | AST value in U/L | 24 weeks | 
| Mean change in hepatic steatosis (fat in the liver) score determined by Fibroscan® Controlled Attenuation Parameter (CAP) software function | CAP (Control Attenuation Parameter) is expressed in decibels per meter (dB/m). This value is the median of all valid measurements performed during the examination. It ranges from 100 to 400 dB/m. Higher dB/m indicates worse liver fat. 238 to 260 dB/m: 11% to 33% of liver with fatty change; 260 to 290 dB/m: 34% to 66% of liver with fatty change; 290 to 400 dB/m: at least 67% of liver with fatty change | 24 weeks | 
| Mean change in liver stiffness from baseline assessed by Fibroscan® | Fibroscan® measures stiffness in kiloPascal's (kPa) and ranges from 2 to 75. Normal range of FibroScan is between 2 to 7 kPa, and the average normal result is 5.3kPa. Higher kPa means more stiffness (scarring). | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin E, Nonalcoholic Fatty Liver Disease