Vitamin E Dosing Study (VEDS): A dose finding clinical trial of vitamin E for the treatment of adult NAFLD (VEDS)

General Description

The VEDS (Vitamin E Dosing Study) trial is a 200 patient, multicenter, randomized, double masked, placebo-controlled, parallel treatment groups dosing trial, designed by the NASH Clinical Research Network to determine the minimum effective dose of vitamin E (d-alpha-tocopherol) for treatment of adult NAFLD. Adults age 18 or older with FibroScan CAP>280 dB/m within 60 days prior to randomization ALT ≥ 60 U/L within 30 days of randomization are eligible for VEDS. Participants are enrolled and randomized to treatment with 133.4 mg (200 IU), 266.8 mg (400 IU), or 533.6 mg (800 IU) of vitamin E or a matching placebo once daily for 24 weeks, followed by a 24-week post-treatment follow-up period. Relative change in ALT from baseline to 24 weeks will be assessed as the primary outcome measure. Secondary outcome measures, to be assessed at 24 weeks and post-treatment (24-48 weeks), include mean change in ALT, AST, GGT, hepatic fat, and liver stiffness from baseline.

Objectives

Primary objective(s): The VEDS trial aims to determine the minimum effective dose of vitamin E (133.4 mg, 266.8 mg, or 533.6 mg) at which measures of adult NAFLD are improved, based upon relative change in alanine aminotransferase (ALT) from baseline to 24 weeks.

Secondary objective(s): The secondary objectives of the VEDS trial are to determine change in liver fat and other biomarkers over 24 weeks and to explore post-treatment (24-48 weeks) patterns of liver enzymes, CAP, and other biomarkers.

Outcome Measure

The primary outcome measure is relative change in serum alanine aminotransferase (ALT) from baseline to 24 weeks.

Secondary outcome measures assessed at 24 weeks include proportion of patients achieving normalization of ALT; mean change in ALT, AST, GGT, hepatic fat, and liver stiffness from baseline; time course and end of treatment improvement in ALT, AST, GGT, alkaline phosphatase, and C-reactive protein; time course and end of treatment improvement in change in total cholesterol, LDL cholesterol, HDL cholesterol, and serum triglycerides; change in fasting glucose levels; and change in anthropometric measurements, symptom assessment scores, and frequency of CTCAE-defined adverse events. Measures assessed post-treatment (24-48 weeks) include mean changes in ALT, AST, GGT, hepatic fat, and liver stiffness.

Criteria

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
• Serum alanine aminotransferase (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 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 (e.g., 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
• 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 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

Outcome

This study is ongoing.