Vitamin E Dosing Study (VEDS)

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

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

Study Overview

• Status: Recruiting
• Conditions: Nonalcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: Vitamin E; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Laura Miriel, BS; Email: lmiriel1@jhu.edu
• Study Contact Backup: Name: Emily Mitchell, MS, MBA; Phone Number: 410-955-8183; Email: esharke5@jhu.edu

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92103
      • Recruiting
      • University of California, San Diego
      • Contact: Egbert Madamba; Phone Number: 858-246-1394; Email: emadamba@ucsd.edu
      • Contact: Lisa Richards; Email: lrichards@ucsd.edu
      • Principal Investigator: Rohit Loomba, MD
    • Los Angeles, California, United States, 90089
      • Recruiting
      • University of Southern California
      • Contact: Christy Rico; Phone Number: 323-442-1100; Email: christy.rico@med.usc.edu
      • Contact: Daisy Olvera; Phone Number: (323) 442-0535; Email: daisy.olvera@med.usc.edu
      • Principal Investigator: Norah Terrault, MD, MPH
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
      • Contact: Rae Davis; Phone Number: 415-514-3274; Email: rayshawnda.davis@ucsf.edu
      • Contact: Remi Awe; Phone Number: (415) 502-2906; Email: remilekun.awe@ucsf.edu
      • Principal Investigator: Norah Terrault, MD
      • Sub-Investigator: Bilal Hameed, MD
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana University- Adults
      • Contact: Lisa Garrison, BSN; Phone Number: 317-278-3206; Email: ljgarris@iu.edu
      • Contact: Regina Webster; Phone Number: (317) 278-3584; Email: reginaw@iu.edu
      • Principal Investigator: Naga Chalasani, MD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Not yet recruiting
      • St. Louis University
      • Contact: Theresa Cattoor, RN; Phone Number: 314-977-9355; Email: theresa.cattooor@health.slu.edu
      • Principal Investigator: Brent Tetri, MD
      • Contact: Page Puricelli; Phone Number: (314) 977-9336; Email: paige.puricelli@health.slu.edu
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University Medical Center
      • Contact: Dawn Piercy; Phone Number: (919) 684-0129; Email: dawn.piercy@duke.edu
      • Sub-Investigator: Anna Mae Diehl, MD
      • Contact: Mariko Kopping; Phone Number: 919-684-4798; Email: mariko.kopping@duke.edu
      • Principal Investigator: Ayako Suzuki, MD
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic Foundation
      • Principal Investigator: Srinivasan Dasarathy, MD
      • Contact: Rahul Yerrapothu; Phone Number: 216-445-4863; Email: yerrapr@ccf.org
      • Contact: Annette Bellar; Phone Number: (216) 636-5247; Email: bellara@ccf.org
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Recruiting
      • Virginia Commonwealth University
      • Contact: Sherry Boyett; Phone Number: 804-828-5434; Email: slboyett@vcu.edu
      • Principal Investigator: Arun J Sanyal, MD
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Liver Institute Northwest
      • Principal Investigator: Kris Kowdley, MD
      • Contact: John Castillo; Phone Number: 206-524-0749; Email: jcastillo@liverinstitutenw.org
      • Contact: Keerat Kaur; Phone Number: (206) 536-3030; Email: kkaur@liverinstitutenw.org

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: University of California, San Diego; The Cleveland Clinic; Duke University; University of Southern California; University of California, San Francisco; Virginia Commonwealth University; Indiana University; St. Louis University; Liver Institute Northwest
• Investigators: Principal Investigator: Arun Sanyal, MD, Virginia Commonwealth University

Publications and helpful links

Helpful Links

• Nonalcoholic Steatohepatitis Clinical Research Network Centers
• The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2022
• Primary Completion (Estimated): February 15, 2025
• Study Completion (Estimated): August 30, 2025

Study Registration Dates

• First Submitted: March 12, 2021
• First Submitted That Met QC Criteria: March 12, 2021
• First Posted (Actual): March 17, 2021

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 9, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Vitamin E; Nonalcoholic Fatty Liver Disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin E; Tocopherols; alpha-Tocopherol
• Other Study ID Numbers: 10 VEDS; U24DK061730 (U.S. NIH Grant/Contract); U01DK061732 (U.S. NIH Grant/Contract); U01DK061713 (U.S. NIH Grant/Contract); U01DK061737 (U.S. NIH Grant/Contract); U01DK061728 (U.S. NIH Grant/Contract); U01DK061718 (U.S. NIH Grant/Contract); U01DK061734 (U.S. NIH Grant/Contract); U01DK061738 (U.S. NIH Grant/Contract); U01DK061731 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: This study will comply with the NIH Data Sharing Policy and Results information from this trial will be submitted to ClinicalTrials.gov and a public use database deposited with the NIDDK Central Repository.
• IPD Sharing Time Frame: Data from this study may be requested from the NIDDK Central Repository (https://www.niddkrepository.org/search/study/) two years after the completion of the primary outcome.
• IPD Sharing Access Criteria: Apply through the NIDDK Central Repository:
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No