Vitamin E Dosing Study (VEDS): A Dose Finding Study of Vitamin E for the Treatment of Adult NAFLD
Phase: PHASE2
Conditions: Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Vitamin E Dosing Study (VEDS): A dose finding clinical trial 
of vitamin E for the treatment of adult NAFLD 
 
Protocol Number: 10 
National Clinical Trial (NCT) Identified Number:  NCT04801849 
Principal Investigator: Arun Sanyal 
IND Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) 
 Funded by: NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH 
CRN) in partnership with Pharmavite 
Version Number:  2.1 
01 April 2022 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.3, 8.1.4, 
8.1.4.1, 8.2 
Allow the focused physical exam to be 
completed via telemedicine, lab tests to be 
collected at outside/local labs at select follow-
up visits, and questionnaires to be completed 
via correspondence (electronic or mail). 
Decrease patient contact when necessary 
due to local restrictions and patient safety 
related to pandemic/endemic diseases. 
1.1, 5.2 
Exclusion criteria regarding hepatitis C was 
clarified 
Updates needed to address potential 
participants that may have had HCV in the 
past. 
8.1.2, 8.1.5 
References to liver biopsy documentation 
were removed. Visits at which the Bev-Q 
questionnaire will be completed were 
corrected. 
Erroneously included in the text of the 
previous version. These were made to be 
consistent with the schedule of activities. 

 
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1.3, 8.1.4, 
10.2.1 
C-reactive protein (CRP) added to the data 
collection schedule and whole blood draw 
schedule. 
Erroneously omitted from data collection 
schedule. CRP is needed for a secondary 
objective. 
8.1.2, 8.1.3 
Clarified screening/randomization check 
procedures and visit window 
generation/display in the data system. 
New language is consistent with the 
mechanics of the data system developed 
for this trial. 

  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 1 
1.1 
Synopsis ............................................................................................................................................... 1 
1.2 
Schema ................................................................................................................................................. 5 
1.3 
Data Collection Schedule (DCS) ....................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................................ 7 
2.1 
Study Rationale ................................................................................................................................... 7 
2.1.1 
Definitions ......................................................................................................................... 7 
2.2 
Background .......................................................................................................................................... 7 
2.3 
Risk/Benefit Assessment.................................................................................................................. 11 
2.3.1 
Known Potential Risks .................................................................................................. 11 
2.3.2 
Known Potential Benefits .............................................................................................. 12 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 12 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 13 
4 
STUDY DESIGN .......................................................................................................................................... 15 
4.1 
Overall Design ................................................................................................................................... 15 
4.2 
Scientific Rationale for Study Design ............................................................................................. 15 
4.3 
Justification for Dose ......................................................................................................................... 15 
4.4 
End of Study Definition ..................................................................................................................... 16 
5 
STUDY POPULATION ................................................................................................................................ 16 
5.1 
Inclusion Criteria ................................................................................................................................ 16 
5.2 
Exclusion Criteria ............................................................................................................................... 16 
5.3 
Lifestyle Considerations ................................................................................................................... 17 
5.4 
Screen Failures .................................................................................................................................. 18 
5.5 
Strategies for Recruitment and Retention...................................................................................... 18 
5.5.1 
Recruitment .................................................................................................................... 18 
6 
STUDY INTERVENTION ............................................................................................................................ 18 
6.1 
Study Intervention(s) Administration ............................................................................................... 18 
6.1.1 
Study Intervention Description ..................................................................................... 18 
6.1.2 
Dosing and Administration ........................................................................................... 19 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 19 
6.2.1 
Acquisition and accountability ...................................................................................... 19 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 19 
6.2.3 
Product Storage and Stability ...................................................................................... 19 
6.2.4 
Preparation ..................................................................................................................... 19 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 20 
6.4 
Study Intervention Compliance ....................................................................................................... 20 
6.5 
Concomitant Therapy ....................................................................................................................... 21 
6.5.1 
Rescue Medicine ........................................................................................................... 21 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 21 
7.1 
Discontinuation of Study Intervention ............................................................................................. 21 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 22 
7.3 
Lost to Follow-Up ............................................................................................................................... 23 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 23 
8.1 
Efficacy Assessments ....................................................................................................................... 23 
8.1.1 
Visit Schedule Overview ............................................................................................... 23 

  
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8.1.2 
Screening and Baseline data Collection ..................................................................... 23 
8.1.3 
Randomization ............................................................................................................... 25 
8.1.4 
Follow-up Visits .............................................................................................................. 25 
8.1.5 
Standardized Questionnaires ....................................................................................... 27 
8.1.6 
Specimen Repositories ................................................................................................. 27 
8.2 
Safety and Other Assessments ....................................................................................................... 27 
8.3 
Adverse Events and Serious Adverse Events .............................................................................. 28 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 28 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 28 
8.3.3 
Classification of an Adverse Event .............................................................................. 28 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 29 
8.3.5 
Adverse Event Reporting .............................................................................................. 30 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 30 
8.3.7 
Reporting Events to Participants ................................................................................. 31 
8.3.8 
Events of Special Interest ............................................................................................. 31 
8.3.9 
Reporting of Pregnancy ................................................................................................ 31 
8.4 
Unanticipated Problems ................................................................................................................... 31 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................ 31 
8.4.2 
Unanticipated Problem Reporting ............................................................................... 32 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 33 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 33 
9.1 
Statistical Hypotheses ...................................................................................................................... 33 
9.2 
Sample Size Determination ............................................................................................................. 34 
9.3 
Populations for Analyses .................................................................................................................. 35 
9.4 
Statistical Analyses ........................................................................................................................... 35 
9.4.1 
General Approach .......................................................................................................... 35 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 35 
9.4.3 
Analysis of the Secondary Endpoint(s)....................................................................... 36 
9.4.4 
Safety Analyses ............................................................................................................. 36 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 36 
9.4.6 
Planned Interim Analyses ............................................................................................. 37 
9.4.7 
Sub-Group Analyses ..................................................................................................... 37 
9.4.8 
Tabulation of Individual participant Data .................................................................... 37 
9.4.9 
Exploratory Analyses..................................................................................................... 37 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 37 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 37 
10.1.1 
Informed Consent Process ........................................................................................... 37 
10.1.2 
Study Discontinuation and Closure ............................................................................. 39 
10.1.3 
Confidentiality and Privacy ........................................................................................... 39 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 40 
10.1.5 
Key roles and study governance ................................................................................. 40 
10.1.6 
Safety Oversight ............................................................................................................ 41 
10.1.7 
Clinical Monitoring ......................................................................................................... 41 
10.1.8 
Quality Assurance and Quality Control....................................................................... 42 
10.1.9 
Data Handling and Record Keeping ........................................................................... 43 
10.1.10 
Protocol Deviations ........................................................................................................ 43 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 43 
10.1.12 
Conflict of Interest Policy .............................................................................................. 44 

  
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10.2 
Additional Considerations ................................................................................................................ 45 
10.2.1 
Whole blood draw schedule (amounts in ml) ............................................................. 45 
10.3 
Abbreviations ..................................................................................................................................... 46 
10.4 
Protocol Amendment History ........................................................................................................... 48 
11 
REFERENCES ............................................................................................................................................. 49 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies and the NIDDK Terms of 
Award. The Principal Investigators will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the IND sponsor, funding agency and documented approval from the 
IRB, except where necessary to eliminate an immediate hazard(s) to the trial participants.  
 
All National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for 
the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the single Institutional Review Board (IRB) of record for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol, after DSMB and NIDDK approval, will require review and approval by the sIRB before the 
changes are implemented to the study.  In addition, all changes to the consent form will be sIRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from participants who 
provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Vitamin E Dosing Study (VEDS): A dose-finding clinical trial of vitamin E for the 
treatment of adult NAFLD 
Study Description: 
This is a 200 patient, multicenter, randomized, double masked, placebo-
controlled, parallel treatment groups dosing trial of vitamin E (d-alpha-
tocopherol) in adult nonalcoholic fatty liver disease (NAFLD). Adults age 18 years 
or older will be enrolled for 48 weeks and treated with 133.4 mg (200 IU), 266.8 
mg (400 IU), or 533.6 mg (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 based upon relative change in alanine aminotransferase (ALT) from 
baseline to 24 weeks.   
Objectives: 
 
Primary Objective:  To determine the minimum effective dose of vitamin E based 
upon relative change in alanine aminotransferase (ALT) from baseline to 24 
weeks. 
 
 
 
Secondary Objectives:  
To determine whether 24 weeks of treatment with vitamin E at 133.4 mg (200 
IU), 266.8 mg (400 IU), or 533.6 mg (800 IU) compared to treatment with placebo 
improves measures of nonalcoholic fatty liver disease (NAFLD) such as change in 
liver fat (controlled attenuation parameter: CAP) evaluated by ultrasound 
(FibroScan® Echosens) and other biomarkers. To explore post-treatment (24-48 
weeks) patterns of liver enzymes, CAP, and other biomarkers by vitamin E dose 
group compared to placebo group. 

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Study Population: 
The study population will be 200 adults age 18 years or older with NAFLD located 
in the United States.  
 
Phase: 
Phase 2 
Description of 
Sites/Facilities Enrolling 
Participants: 
Participants will be enrolled at 9 NASH CRN adult sites located throughout the 
United States. 
Description of Study 
Intervention: 
Participants will be given 133.4 mg (200 IU), 266.8 mg (400 IU), or 533.6 mg (800 
IU) of vitamin E or a matching placebo. All participants will be instructed to take 
assigned capsules with water by mouth once per day with breakfast. 
Study Duration: 
126 weeks 
• 
Recruitment phase: 72 weeks 
• 
Follow-up phase: 48 weeks 
• 
Expected enrollment rate: 1.2 participants per month per clinical center 
(22 participants each at 9 centers) 
Participant Duration: 
13 months total 
• 
Screening phase is 60 days 
• 
24-week treatment period; 24-week post-treatment follow-up 
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 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, 

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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: 
o Serum albumin less than 3.2 g/dL 
o International Normalized Ratio (INR) greater than 1.3 
o Direct bilirubin greater than 1.0 mg/dL 
o History of esophageal varices, ascites or hepatic encephalopathy 
• 
Evidence of other forms of chronic liver disease: 
o Hepatitis B as defined by presence of hepatitis B surface antigen 
(HBsAg) 
o 
Evidence of recent or current hepatitis C as marked by the 
presence of anti HCV antibody with detectable HCV RNA in serum 
within 1 year prior to enrollment. Participants with anti HCV 
antibody positivity who have undetectable HCV RNA at least 1 
year prior to enrollment (either due to spontaneous clearance or 
clearance with treatment) will be eligible to participate if HCV 
RNA at entry remains undetected. 
o Evidence of ongoing autoimmune liver disease as defined by 
compatible liver histology 
o Primary biliary cirrhosis as defined by the presence of at least 2 of 
these criteria 
 
Biochemical evidence of cholestasis based mainly on 
alkaline phosphatase elevation 
 
Presence of anti-mitochondrial antibody (AMA) 
 
Histologic evidence of nonsuppurative destructive 
cholangitis and destruction of interlobular bile ducts[1] 
o Primary sclerosing cholangitis 
o 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, autoimmune 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 

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• 
Males at high risk of prostate cancer, including: 
o PSA >ULN at baseline 
o History of prostate cancer 
o Age 45 or older with a first-degree relative (father or brother) 
diagnosed with prostate cancer at an early age (younger than age 
65). 
o 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 
 
Sample size / Power: 
 
• 
Total sample size = 200; 50 per group 
• 
Power = 90% 
• 
Type I error (2-sided) = 5% 
• 
Increase in sample size due to missing data = 10% 
• 
Mean (SD) difference (Vitamin E – Placebo) in relative change [(BL-FU)/BL] 
in ALT at 24 weeks = 20% (31%) 
• 
Mean relative change (%) in ALT at 24 weeks in placebo = 20% (based 
on data from PIVENS trial) 
• 
Mean relative change (%) in ALT at 24 weeks in Vitamin E = 40% 
(based on data from PIVENS trial) 
• 
Method of analysis = Williams’ test for minimum effective dose 
 
 

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1.2 
SCHEMA 
 
Screening (s): 
Prior to  
Randomization 
 
Visit 1 (rz) 
Day 0 
 
 
 
 
 
 
Visit 2 (f04) 
Week 4  
 
 
Visit 3 (f08) 
Week 8  
 
 
Visit 4 (f12) 
Week 12  
 
 
 
Visit 5 (f24) 
Week 24 
 
 
Visit 6 (f28) 
Week 28 
 
 
Visit 7 (f36) 
Week 36 
 
 
Visit 8 (f48) 
Week 48 
 
Total N = 200:  Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; obtain history, perform baseline assessments. Document eligibility. 
Review dosing instructions, physical exam, adverse effects, and hepatic panel (See Data 
Collection Schedule) 
Follow-up assessments of study objectives and adverse effects, physical exam, and 
hepatic panel (See Data Collection Schedule) 
Follow-up assessments of study objectives and adverse effects, physical exam, and 
hepatic panel (See Data Collection Schedule) 
Final Assessments (See Data 
Collection Schedule) 
Arm 1=133.4 mg
Vitamin E 
(N=50) 
Follow-up assessments of study objectives and adverse effects, physical exam, metabolic 
and hepatic panel, banking of serum and plasma(See Data Collection Schedule) 
Randomize and dispense Vitamin E or placebo 
Arm 2=266.8 mg 
Vitamin E 
(N=50) 
Arm 3=533.6 mg 
Vitamin E 
(N=50) 
Arm 4= Placebo 
(N=50) 
Primary endpoint measure data 
collection. End of intervention. 
Follow-up assessments of study objectives and adverse effects, physical exam, and 
hepatic panel (See Data Collection Schedule) 

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1.3 
DATA COLLECTION SCHEDULE (DCS) 
 
Screening 
Visits 
Follow-up visits 
Weeks from Randomization 
Assessment/Procedure 
S 
RZ 
F04 
F08 
F12 
F24 
F28 
F36 
F48 
Consent and reaffirmation 
X 
X 
. 
. 
. 
. 
. 
. 
. 
Baseline medical history 
X 
. 
. 
. 
. 
. 
. 
. 
. 
Follow-up medical history (with AUDIT-C) 
. 
. 
X 
X 
X 
X 
X 
X 
X 
Alcohol Use Disorders Identification Test 
(AUDIT) 
X 
. 
. 
. 
. 
. 
. 
. 
. 
Lifetime Drinking History (Skinner) 
X 
. 
. 
. 
. 
. 
. 
. 
. 
Review for adverse effects 
. 
. 
X 
X 
X 
X 
X 
X 
X 
Review for concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensing 
. 
X 
. 
. 
. 
. 
. 
. 
. 
Review of study drug adherence 
. 
. 
X 
X 
X 
X 
. 
. 
. 
Detailed* (D) or Focused† (F) physical 
exam 
D 
. 
F 
F 
D 
D 
F 
F 
D 
NASH CRN Liver Symptom Questionnaire 
X 
. 
X 
X 
X 
X 
X 
X 
X 
Cardiovascular risk factor assessment 
X 
. 
. 
. 
. 
X 
. 
. 
X 
Beverage Intake Questionnaire (BEVQ-15) 
X 
 
 
 
 
X 
 
 
X 
FibroScan®: liver stiffness and steatosis 
(CAP) 
X 
. 
. 
. 
. 
X 
. 
. 
X 
Complete blood count (CBC) ǂ 
X 
. 
. 
. 
. 
X 
. 
. 
X 
Basic metabolic panel (BMP) § 
X 
. 
. 
. 
. 
X 
. 
. 
X 
Fasting lipid profile¶ 
X 
. 
. 
. 
X 
X 
. 
. 
X 
Hepatic panel** and GGT 
X 
. 
X 
X 
X 
X 
X 
X 
X 
Fasting glucose and insulin 
X 
. 
X 
X 
X 
X 
X 
X 
X 
Prothrombin time (PT), activated Partial 
Thromboplastin Time (aPTT), and INR 
X 
. 
. 
. 
. 
X 
. 
. 
X 
HbA1c 
X 
. 
. 
. 
. 
X 
. 
. 
X 
C-reactive protein (CRP) 
X 
. 
. 
. 
X 
X 
. 
. 
X 
Pregnancy test 
X 
. 
. 
. 
. 
X 
. 
. 
. 
Prostate Specific Antigen (PSA) Test†† 
X 
. 
. 
. 
. 
. 
. 
. 
X 
Bankingǂǂ: Fasting serum, plasma 
X 
. 
. 
. 
X 
X 
. 
. 
X 
Etiologic tests§§ 
X 
. 
. 
. 
. 
. 
. 
. 
. 
Closeout form 
. 
. 
. 
. 
. 
. 
. 
. 
X 
* Detailed physical exam: anthropometric assessments (body weight [kg], body height [cm], waist circumference [cm], and hip 
circumference [cm]); vital signs (temperature, heart rate, respiratory rate, blood pressure), organ systems (skin, chest, lungs, heart, 
abdomen, nervous); liver signs and changes in bleeding (e.g. bleeding gums). 
†Focused physical exam: anthropometric assessments (body weight [kg], body height [cm], waist circumference [cm], and hip 
circumference [cm]); vital signs (temperature, heart rate, respiratory rate, blood pressure); liver signs and changes in bleeding (e.g. 
bleeding gums). The focused physical exam may be completed remotely via telemedicine video call per institutional guidelines. 
ǂComplete blood count: hemoglobin, hematocrit, mean corpuscular volume (MCV), white blood cell count (WBC), red blood cell count 
(RBC), platelet count 
§Basic metabolic panel: glucose, calcium, sodium, potassium, CO2 (carbon dioxide, bicarbonate), chloride, blood urea nitrogen (BUN), 
creatinine. eGFR will be calculated using the CKD-EPI formula. 
¶Fasting Lipid profile: total cholesterol, triglyceride, LDL, HDL. 
**Hepatic panel: alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, albumin, 
total protein  
††Prostate Specific Antigen (PSA) Test: males (sex assigned at birth) only 
ǂǂBanking: Fasting plasma and serum will be collected for planned analysis of measures of vitamin E (alpha-tocopherol, gamma-
tocopherol, and carotenoids) and future ancillary analyses. 
§§Etiologic tests as needed: Hepatitis B surface antigen, hepatitis C antibody, alpha-1-antitrypsin level, ceruloplasmin. Autoantibodies: 
(ANA, AMA ASMA), serum iron, ferritin, total iron binding capacity (TIBC), and Thyroid Stimulating Hormone (TSH) 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
NAFLD has become the most common form of chronic liver disease in the developed world. It commonly 
occurs in the setting of obesity, insulin resistance, and a sedentary lifestyle, and it is often considered to be the 
liver manifestation of the metabolic syndrome. The primary form of treatment is lifestyle modification with 
changes focused on dietary and exercise habits. Unfortunately, achieving and maintaining these changes is 
difficult or unattainable for most individuals. Pharmacologic treatments have been sought but none has 
proved sufficiently efficacious. This may be related to the fact that the histopathological changes seen on liver 
biopsy currently described as NAFLD may be the result of multiple pathogenetic mechanisms acting in concert 
to varying degrees. Based on the prevalence and risk of progression of NAFLD to NASH, cirrhosis, and cancer, 
the burden of significant disease is large, and drug therapy to prevent or treat NAFLD is needed. 
 
2.1.1 DEFINITIONS 
 
Nonalcoholic fatty liver disease (NAFLD) is defined by the presence of greater than "normal" amounts of fat in 
the liver. The pathologists' definition is based on observed steatotic droplets (primarily triglyceride) in more 
than 5% of hepatocytes. In the largest population study of adults using MR spectroscopy, the threshold value 
for abnormal liver fat fraction was similar to these other assessments.[2] 
 
Nonalcoholic steatohepatitis (NASH) is the name applied to a constellation of biopsy abnormalities occurring 
in the presence of NAFLD that typically include hepatocyte ballooning with or without Mallory-Denk bodies, a 
mixed polymorphonuclear leukocyte and mononuclear inflammatory cell infiltrate in the lobules, chronic 
inflammation in the portal tracts, and sometimes zone 3-predominant perisinusoidal fibrosis.[3] 
 
A name for NAFLD that is not NASH has not been universally established. Terms such as nonalcoholic fatty 
liver (NAFL), simple steatosis, benign steatosis, bland steatosis, and isolated steatosis have been used, but each 
has limitations that preclude general acceptance.[4] 
 
2.2 
BACKGROUND  
Oxidative stress and free radicals in NAFLD  
Oxidative stress, resulting from an imbalance between pro-oxidant and antioxidant mechanisms in favor of 
pro-oxidation, has been recognized as a key mechanism in the progression of steatosis to steatohepatitis[5, 6]. 
Several studies have shown an association between NAFLD and biomarkers of oxidative stress or lipid 
oxidation[7-10]. Oxidative stress is mediated largely by reactive oxygen species (ROS). Molecular oxygen 
readily accepts electrons from exogenous substances and during intracellular metabolic processes to form 
various free radicals including hydroxyl radical, nitric oxide radical and superoxide anion. These free radicals 
react with proteins, free fatty acids (FFA), and DNA to mediate oxidative injury[11].  
The production of ROS occurs mainly in mitochondria, endoplasmic reticulum (ER), and peroxisomes, and to a 
lesser extent through various enzymatic processes including xanthine oxidase and cytochrome P450[9, 12]. 
Models of NAFLD have been shown to have altered mitochondrial morphology, impaired mitochondrial 
bioenergetics, increased mitochondrial lipid peroxides and increased mRNA levels of peroxisome proliferator 
activated receptor-α (PPAR-α), involved in regulating the expression of mitochondrial and peroxisomal β-
oxidation enzymes [9, 13][14, 15].  

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Oxidative stress and organelle dysfunction in NAFLD 
Mitochondrial dysfunction 
In mitochondria, the catabolic process of β-oxidation which breaks down FFA occurs through three main 
steps[6]. During the first step, long-chain FFA enter into the mitochondria. In the second step, the long-chain 
FFA are oxidized into medium and short chain fatty acids, a process that involves conversion of oxidized 
nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD) into their de-oxidized version, 
NADH and FADH2. In the third step, NADH and FADH2 are re-oxidized into NAD and FAD through the transfer 
of electrons along the mitochondrial respiratory complex (MRC) enzymatic chain. Most of these electrons 
combine with oxygen and protons to form water, however a few electrons react with oxygen to form ROS. 
Impairment of the MRC complex results in disruption of β-oxygenation and increased production of ROS, 
including superoxide, hydrogen peroxide, and hydroxyl radicals [9, 16-20] that increase steatosis and resultant 
inflammation. 
Mitochondrial dysfunction facilitates NASH pathogenesis at several levels, including impaired lipid metabolism, 
increased ROS and cytokine production, triggering cell death and promoting inflammation[6, 9]. Accumulation 
of lipid in the mitochondria leads to influx of water and calcium, causing release of cytochrome C and cell 
death[21]. Lysosomal permeabilization, associated with caspase activation and ROS generation via cytochrome 
P450 2E1 (CYP2E1) [22], can also mediate mitochondrial injury. Mitochondrial injury can subsequently lead to 
apoptosis via mechanisms involving Sab, SH3 Domain Binding Protein 5 (SH3BP5), a substrate of Janus kinase 
(JNK) located in the mitochondrial outer membrane [23]. Continuous mitochondrial injury further results in 
hepatocyte injury and progression to NASH. 
 
Other organelles  
Although the mitochondria are the main source of hepatocyte ROS, other organelles have also been shown to 
participate in this process [6]. Peroxisomes are able to rapidly oxidize long-chain FFA through β-oxidation, 
resulting in hydrogen peroxide that is converted into the highly reactive hydroxyl (OH) radical [21]. The 
generation of ROS in a lipid-rich environment induces lipid peroxidation of polyunsaturated fatty acids (PUFAs), 
leading to the formation of 4- hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) that have longer half-
lives than ROS and amplify the effects of ROS via diffusion into the extracellular space to affect distant cells.  
The increase in lipid peroxidation and protein oxidation impair the hepatocyte mitochondrial respiratory chain, 
increasing ROS production with resultant detrimental effects on fat metabolism in the liver.  Moreover, chronic 
ER stress may contribute to oxidative stress by promoting toxic accumulation of ROS which triggers other 
signaling pathways within the cell; ROS generated through inflammation of mitochondria and other organelles 
may also accelerate ER dysfunction [24, 25].  In addition, lipo-oxygenation of long chain fatty acids via 
microsomal cytochromes, CYP2E1 and cytochrome P450 4A (CYP4A), leads to release of ROS. 
Role of inflammation and oxidative stress in NAFLD  
The generation of intracellular ROS via mitochondria, ER, peroxisomes, or enzymatic pathways all contribute to 
disease progression in NAFLD.  In addition to excessive production of ROS within organelles, oxidative stress 
also occurs as a result of reduced antioxidant defense. NASH is associated with decreased levels of various 
antioxidant pathways and enzymes, including hepatic glutathione (GSH), glutathione transferase activity, SOD, 
glutathione peroxidase (GPx), and catalase[9, 26].  The process of oxidative injury is augmented by obesity and 
insulin resistance (IR), which lead to increased production of ROS in the liver, increased lipid peroxidation, and 
decreased plasma antioxidant capacity[27, 28].  
Mitochondrial dysfunction facilitates the production of ROS and contributes to NAFLD progression through 
induction of hepatic inflammatory cytokines. It has been proposed that obesity, IR, and adipokine/cytokine 

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pathways mediate liver fat accumulation and NASH development[6, 29]. This results in additional lipid 
peroxidation of mitochondrial membranes, augmenting mitochondrial dysfunction and ROS generation [30]. 
The resultant damage to nuclear and mitochondrial DNA results in necro-inflammation especially in the 
hepatocyte nucleus and cytoplasm and in sinusoidal cells [31, 32]. Hepatic necro-inflammation is evidenced by 
increased levels of 8- hydroxy-2′ deoxyguanosine (8-OHdG), a modified DNA base product generated by ROS 
[31]. Hepatic inflammation and fibrosis progression are key features in the pathogenesis of NASH.  
 
Vitamin E mechanisms in NASH  
Given the crucial role of oxidative stress and free radical injury in the pathogenesis of NASH, it is not surprising 
that free radical-scavenging agents have shown ameliorating effects on disease progression[33, 34]. Vitamin E 
is an antioxidant that has been studied in several animal models as well as in clinic trials of NAFLD. There are 8 
naturally occurring forms of vitamin E, including 4 tocopherol homologs (α-, β-, γ-, δ-) with a phytyl side chain, 
and 4 tocotrienols (α-, β-, γ-, δ-) that have 3 double bonds on the side chain[35-38]. The term vitamin E 
describes the antioxidant activity of any combination of tocopherol and tocotrienols. However, α-tocopherol is 
the only form recognized to meet human vitamin E requirements.[39] 
The hepatic α-tocopherol transfer protein (α-TTP) functions to select alpha-tocopherol for secretion from the 
liver in very low density lipoproteins; the non-alpha-tocopherol forms are not selected and are actively 
metabolized and excreted in urine.[35] Persons with a genetic defect in the α-TTP develop vitamin E deficiency 
early in life.[40] 
Vitamin E is efficient in scavenging peroxyl radicals in vivo and preventing lipid peroxidation [41, 42].  It also 
inhibits the production of isoprostanes which are biomarkers of lipid peroxidation [43, 44]. Vitamin E is rapidly 
consumed and converted back to its reduced form by the cytoplasmic antioxidant cycling network including 
vitamin C and glutathione [45]. The antioxidant role of vitamin E is important in maintaining membrane 
stability. 
 
Vitamin E in animal models of NAFLD 
Vitamin E has been studied in several experimental models of NAFLD. Vitamin E supplementation reduced the 
levels of liver enzymes, hepatic steatosis and necro-inflammation in a methionine-choline-deficient (MCD) 
diet-induced animal model of NASH[46]. Superoxide dismutase activity was enhanced in these animals, and 
levels of MDA and genes related to inflammation, apoptosis, and fibrosis were reduced. In another MCD diet-
induced model of NASH, hepatic glutathione stores were restored, while oxidative stress markers, hepatic 
stellate cell activation, and histologic fibrosis were reduced in mice on vitamin E[47].  
In a diet-induced obesity model in rats, vitamin E ameliorated oxidative stress[48]. In obese (ob/ob) mice, α- as 
well as γ-tocopherol protected against lipopolysaccharide-induced liver injury, decreasing hepatic MDA and 
tumor necrosis factor (TNF)-α levels[49]. In leptin-receptor deficient rats, vitamin E protected against bile acid-
induced hepatocyte injury, improving portal inflammation, lobular inflammation and hepatocellular 
necrosis[50]. These animal studies laid the groundwork for clinical trials in NAFLD. 
 
Clinical trials of vitamin E in NAFLD 
Plasma levels of α-tocopherol are decreased in NASH patients compared to healthy controls, providing a 
rationale for vitamin E supplementation[51]. Among the many agents that have been tested for NASH, vitamin 
E has had the most substantial effect on disease activity[52]. The impact of vitamin E on clinically meaningful 
outcomes and progression to cirrhosis are yet to be demonstrated. However, current recommendations for 
therapeutics focus on decreasing disease activity. Vitamin E is recommended by both European and North 

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American practice guidelines for the treatment of NASH [53, 54]. Although some studies have raised concerns 
about the long-term safety of Vitamin E[55, 56] other studies have challenged these concerns[57, 58]. Earlier 
studies assessing the efficacy of Vitamin E in NAFLD as monotherapy and combination therapy gave conflicting 
results likely due to small sample sizes, differences in primary end points, and differences in vitamin E 
formulations.  
Two separate multicenter randomized-control trials conducted by the NASH Clinical Research Network (CRN) 
showed that vitamin E was effective in improving steatohepatitis. In Pioglitazone versus Vitamin E versus 
Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, 247 non-
diabetic and non-cirrhotic adults with NASH received vitamin E (800 IU/day), pioglitazone (30 mg/day), or 
placebo for a period of 96 weeks[41]. The primary outcome measured was improvement in histological 
features, based on standardized scores for steatosis, inflammation, and hepatocellular ballooning. A p-value 
less than 0.025 between the treatment group (vitamin E or pioglitazone) versus the placebo group was 
considered significant. Vitamin E therapy demonstrated significant histologic improvement in NASH (43% vs 
19%, P= 0.001) while pioglitazone did not reach statistical significance (34% vs 19%, P= 0.04). Significant 
reduction in hepatic steatosis, lobular inflammation, and hepatocellular ballooning was observed, however, no 
significant improvement in fibrosis was seen in both treatment groups compared to placebo. It is noteworthy 
that in a prior small pilot study, combination therapy with vitamin E and pioglitazone was shown to be superior 
to vitamin E alone in reducing the histological features of NASH and improving pericellular fibrosis [59].  
In the Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC) trial, 173 children received vitamin E 
(400 IU twice daily), metformin (500 mg twice daily), or placebo for a 96-week period[60]. Resolution of NASH, 
attributed mainly to improved hepatocellular ballooning, was significantly greater for vitamin E treatment 
group compared to placebo (p=0.006); however, neither vitamin E nor metformin was superior to placebo in 
attaining the primary outcome of reduction in alanine aminotransferase (ALT) level by 50% or more compared 
to baseline, or a level of 40 U/L or less from 48 to 96 weeks.   
Two meta-analyses reported significant improvement in liver histology in NASH patients treated with vitamin 
E[61, 62]. A meta-analysis of five studies showed significant improvement in liver enzymes as well as the 
individual histological features of NASH, steatosis, lobular inflammation, and hepatocellular ballooning. Among 
adult patients, there was also an improvement in fibrosis[61]. Another meta-analysis performed by a different 
group showed improvement in all the histological parameters of NASH, including fibrosis[62]. 
 
Vitamin E in other forms of chronic liver disease 
Oxidative injury and decreased levels of vitamin E have been implicated in various etiologies of chronic liver 
diseases other than NAFLD, including alcoholic liver disease and viral hepatitis. However, the role of vitamin E 
in these conditions remains to be defined. In a randomized, placebo-controlled study of alcoholic hepatitis, 
vitamin E did not confer any benefit on liver function or survival during the 1-year study period[63]. In chronic 
hepatitis C patients, high-dose vitamin E significantly reduced oxidative stress with no effect on liver enzymes 
or the degree of hepatocellular inflammation or fibrosis[64]. In a small pilot study of 32 patients with chronic 
hepatitis B, treatment with vitamin E was associated with improved ALT levels and complete response (normal 
ALT and negative hepatitis B virus DNA) in 47% of the patients treated[65]. These findings are yet to be 
replicated in larger studies. At present, vitamin E supplementation can be proposed only for patients with 
NASH, with the role of vitamin E supplementation in other etiologies of chronic liver disease remaining 
controversial.   
 
Safety of vitamin E 

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Some studies have raised concerns about the long-term safety of vitamin E [55, 56], while other studies have 
challenged these concerns[57, 58]. A meta-analysis published in 2005 suggested that high-dose vitamin E 
increased all-cause mortality in a dose-dependent manner, and cautioned against the use of any high-dose 
vitamin supplementation until appropriately designed trials were available [55]. However, this meta-analysis 
has been criticized because it excluded several studies with low mortality. Moreover, concomitant use of 
vitamin A and other drugs, as well as factors such as smoking, were not taken into consideration during the 
analyses. Subsequently, a meta-analysis of those trials, together with more studies investigating vitamin E 
suggested that the observed differences were due to a disproportionately higher number of male patients in 
the trials, compared to other trials, thus casting doubt on the causal relationship of vitamin E supplementation 
and increased mortality[66]. 
A large meta-analysis of 57 studies involving 246,371 subjects studied for 1 to 10 years did not demonstrate an 
association between vitamin E supplementation and all-cause mortality[57].  More recently, another large 
meta-analysis involving 123,001 participants confirmed the lack of association between vitamin E on both all-
cause mortality (Risk Ratio=1.00, 95% CI=0.97-1.03) and cardiovascular mortality (Risk Ratio=0.95, 95% 
CI=0.88-1.03)[67]. A RCT in 2011, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) trial, showed 
modestly increased incidence of prostate cancer in healthy men on vitamin E over a 7-year period, translating 
to an absolute increase of 1.6 per 1,000 person-years of vitamin E 400 IU/day [56]. However, based on 
subsequent analysis, it appears that this risk may be modified by baseline selenium concentration[68] or 
genetic variants involved in the metabolism of vitamins[69].  
Based on the efficacy of vitamin E in improving the histological features of NASH, it is recommended as first 
line off-label therapy for NASH. Current practice guidance from the American Association for the Study of Liver 
Disease (AASLD) recommends consideration of vitamin E in treating non-diabetic, non-cirrhotic NASH patients 
with biopsy-proven NASH[53, 54, 70]. It is suggested that risks and benefits should be discussed with the 
patient prior to initiating therapy. Guidance from a joint task force including the European Association for the 
Study of the Liver (EASL)/ European Association for the Study of Diabetes (EASD)/ European Association for the 
Study of Obesity (EASO) suggests the use of vitamin E for NASH, with a plan to stop treatment if there is no 
significant improvement in liver enzymes after 6 months of therapy[54].   
 
Conclusion 
 
Vitamin E is beneficial in improving the biochemical and histological features of NAFLD, a major cause of 
chronic liver disease which increases the risk of cirrhosis and liver cancer. Although the mechanisms by which 
vitamin E improves NAFLD, and more specifically NASH, are unclear, vitamin E is known to restore antioxidant 
activity in NASH patients. The beneficial effects of vitamin E on NAFLD and NASH have been demonstrated 
both in animal studies as well as in human clinical trials. This trial aims to determine the optimal dose of 
vitamin E. Larger studies and longer follow-up RCTs are crucial in defining long-term beneficial effects of 
vitamin E as well as potential side effects. Nonetheless, current findings substantiate an important role of 
vitamin E in ameliorating chronic liver disease including NASH. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Risks of vitamin E: Vitamin E at 533.6 mg (800 IU) daily dose (the maximum dose for this study) has no 
significant toxicity in adults [71, 72].  Side effects of long-term use of vitamin E in excess of 400 to 800 IU/day 
may include: diarrhea, nausea, flatulence, stomach cramps, weakness, dizziness, headache, fatigue, and 
blurred vision [73]. Long-term use of supplemental vitamin E has also been associated with an increased risk of 
bleeding, specifically gingival bleeding [74]. While some studies have shown no effect of vitamin E on 

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biomarkers of bleeding (eg. prothrombin time)[75, 76], vitamin E use has been associated with increased 
bleeding tendencies in vitamin K deficient patients, which is very rare in adults without specific underlying 
conditions (e.g. cystic fibrosis, biliary obstruction) [73]. In one study, vitamin E supplementation was associated 
with prostate cancer in men [56]. Additionally, one meta-analysis suggested that doses of vitamin E >400 
IU/day were associated with an increase in all-cause mortality[55]. However, this analysis has been criticized, 
as explained in section 2.2, and at least one subsequent meta-analysis has failed to demonstrate a relationship 
between vitamin E supplementation and all-cause mortality [57]. 
 
Blood drawing: Blood draw may cause mild discomfort, such as swelling, temporary sensation of pain, burning, 
or a bruise that may develop and last for a few days. Less common risks include a blood clot at the site of 
puncture, swelling of the vein and surrounding tissues, and possible bleeding from the puncture site. Very 
rarely, fainting, blood clots, or an infection at the site can occur. During the entire study period (up to 56 
weeks), subjects will have approximately 20 tablespoons of blood drawn (300 mL). 
 
Study visits: This study requires approximately 9 visits to the study center (screening visit, randomization visit, 
and 7 post randomization visits) which may cause some inconvenience to some individuals.  
 
Safety issues related to participant privacy: For this study, data are being recorded about each participant’s 
medical condition via medical records and case report forms. All data will be kept confidential. Case report 
forms on which a participant’s data or results from specified procedures have been recorded and will be stored 
in locked drawers of file cabinets. Study data are keyed to the NASH CRN web-based study database with 
encrypted (https:) transmission of data and via a secure network using an encrypted, password-protected 
computer accessible only by the study coordinator, the site Principal Investigator (PI), and study-certified 
personnel. It is the investigator’s responsibility to conduct the protocol under the current version of the 
Declaration of Helsinki, Good Clinical Practice, and the rules of local IRBs. Each investigator must ensure that 
the participant’s anonymity is maintained in their data submissions to the DCC. Participants will be identified 
by an arbitrary unique identification code and not by their name, social security number, address, or hospital 
medical record number. Under no circumstances will any identifiable data be transmitted and stored in the 
NASH CRN database or be sent in email, scans, or paper-based transmissions to the DCC. Investigators will 
locally maintain a separate confidential enrollment log, which links identification codes with the participants’ 
names and addresses (i.e., available only to local clinic staff). All study material will be maintained in strict 
confidence. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Individual participants in the trial will receive several potential benefits. First, vitamin E has been shown in 
several studies to improve markers of inflammation and fibrosis in NASH. For example, the PIVENS trial 
demonstrated that 43% of patients treated for two years met the histological endpoint compared to 19% in 
the placebo group (P<0.01) [77]. Improvement in fibrosis was not observed. Similar to the pioglitazone-treated 
patients, the ALT improved over a period of 3-6 months. Second, all participants will receive lifestyle 
counseling at baseline, which is standard of care for NAFLD. Lifestyle counseling will be standardized and based 
upon the established protocols of the NASH CRN. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Rationale for necessity of exposing participants to risk and minimization of risks: Risks to patients in this 
study include that vitamin E (d-alpha-tocopherol) may cause increased bleeding, diarrhea, nausea, flatulence, 
stomach cramps, weakness, dizziness, headache, fatigue, or blurred vision with prolonged use. Risks are 
minimized by exclusion of patients with higher than normal risk of bleeding and by close monitoring. Risks are 

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also minimized in this trial by using ALT as a surrogate marker of histologic response, thus avoiding the need 
for repeat liver biopsies in this phase 2 study. 
 
Justification of the risks: All participants will receive standard of care treatment as part of the trial and will 
potentially benefit if they are in a treatment group (133.4 mg, 266.8 mg, or 533.6 mg of vitamin E) by 
improvement in ALT. The value of identifying a minimal effective dose for vitamin E in NAFLD is high because 
vitamin E has been shown to be effective in NAFLD at high doses (533.6 mg per day), but if a lower dose can be 
used effectively, potential long term adverse effects may be avoided. By conducting the trial and furthering the 
understanding of vitamin E for adult NAFLD, all of the participants in the study stand to benefit in the future if 
the minimum effective dose of vitamin E is identified. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
The primary objective is to 
determine the minimum effective 
dose of vitamin E (133.4 mg, 266.8 
mg, or 533.6 mg) at which 
measures of NAFLD are improved 
 
 
Relative change in ALT at week 24 
from baseline [i.e., (ALT at baseline – 
ALT at week 24)/ ALT at baseline] 
ALT is the most 
accepted short term 
(<12 months) surrogate 
marker for histologic 
improvement in 
NAFLD. 
Secondary 
 
 
The secondary objectives have 
been selected to provide further 
information on the minimum 
effective dose of vitamin E needed 
to improve measures of NAFLD 
progression, and to provide 
information on the post-treatment 
effects of vitamin E on the liver. 
 
Proportion of patients achieving 
normalization* of ALT at 24 weeks  
 
Mean change in ALT from baseline to 
24 weeks 
 
Mean change in AST and GGT from 
baseline to 24 weeks 
 
Mean change in hepatic fat 
determined by FibroScan® CAP score 
from baseline to 24 weeks 
 
Mean change in liver stiffness as 
assessed by FibroScan® from baseline 
to 24 weeks 
 
Time course and end of treatment 
improvement in ALT, AST, GGT, and 
alkaline phosphatase 
 
Time course and end of treatment 
improvement in C-reactive protein 
(serum marker of inflammation) 
 
These endpoints were 
selected because they 
measure important co-
morbidities of NAFLD 
and are useful for 
determining if vitamin 
E improves other 
features commonly 
associated with NAFLD. 
Safety and quality of 
life outcomes are also 
included. 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Time course and end of treatment 
improvement in change in total 
cholesterol, LDL cholesterol, HDL 
cholesterol, and serum triglycerides 
 
Changes in fasting glucose levels 
from baseline to 24 weeks 
 
Change in anthropometric 
measurements (weight, BMI, waist to 
hip ratio, waist circumference) from 
baseline to 24 weeks  
 
Change in symptom assessment 
scores from baseline to 24 weeks  
 
Change in frequency of CTCAE 
defined adverse events from baseline 
to 24 weeks  
 
Mean change in ALT from 24 to 48 
weeks (post-treatment). 
 
Mean change in AST and GGT from 
24 to 48 weeks (post-treatment). 
 
Mean change in hepatic fat 
determined by FibroScan® CAP score 
from 24 to 48 weeks (post-
treatment). 
 
Mean change in liver stiffness as 
assessed by FibroScan® from 24 to 48 
weeks (post-treatment). 
 
 
Tertiary/Exploratory  
 
 
Tertiary/exploratory objectives 
have been selected to serve as a 
basis for explaining or supporting 
findings of primary analyses and for 
suggesting further hypotheses for 
later research. 
Change in measures of vitamin E 
(including alpha-tocopherol, gamma-
tocopherol, and carotenoids) from 
baseline to 12 weeks and 24 weeks 
 
The pharmacokinetics 
of vitamin E are not 
well known in NAFLD 
 
*Normalization of ALT 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 ULN are defined at each clinical center per institutional 
guidelines. 

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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
• 
The hypothesis of the trial is that 24 weeks of treatment with vitamin E (at 133.4 mg (200 IU), 266.8 
mg (400 IU), or 533.6 mg (800 IU) daily) in adults with NAFLD will find the minimum effective dose to 
improve ALT compared to placebo.  
• 
Phase 2 trial 
• 
A 200 patient, multicenter, randomized, double-masked, placebo-controlled, parallel treatment groups 
trial with relative change (%) in serum ALT from baseline to 24 weeks as the primary endpoint. 
• 
Methods to decrease bias will include placebo control, double masking, and randomization. 
• 
Four study arms 
• 
Nine centers 
• 
Study intervention is vitamin E at 133.4 mg (200 IU), 266.8 mg (400 IU), or 533.6 mg (800 IU) daily or 
matching placebo. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This study design is a multicenter, randomized, double-masked, placebo-controlled, parallel treatment groups, 
phase 2 trial. 
 
Rationale for a Placebo Group: In order to assess the efficacy of an agent in NAFLD, a placebo-arm is needed 
to determine its relative efficacy in improving NAFLD histology beyond that achieved with a placebo.[78] 
Currently, there are no FDA approved therapies for NAFLD. The PIVENS trial for NASH did not find either 
vitamin E or pioglitazone to be uniformly effective. The study demonstrated that 43% of vitamin E treated 
patients and 34% of pioglitazone treated patients met a pre-determined histological endpoint compared to 
19% of placebo treated patients (P = 0.001 and P = 0.04 for each drug respectively).[77] Previous non-
randomized and pilot studies have shown the efficacy of several agents such as ursodiol and betaine in the 
treatment of NASH, but follow-up randomized, placebo-controlled studies failed to show improvement in liver 
histology in patients with NASH beyond that observed in placebo groups.[79, 80] In order to have the highest 
quality of evidence to test our hypothesis, this phase 2 pilot study utilizes a randomized, double-masked, 
placebo-controlled study design. As there is no proven pharmacologic therapy for NAFLD/NASH, using a 
placebo for comparative purposes is justified. The trial is double masked to prevent bias by investigators and 
participants; participants will be randomly assigned to either the 133.4 mg (200 IU), 266.8 mg (400 IU), or 
533.6 mg (800 IU) vitamin E dose or matching placebo (neither the study staff nor the participants will know if 
they have active or placebo capsules). 
 
Rationale for treatment duration of 24 weeks: An ideal duration of a treatment should only expose 
participants to a study drug long enough to show meaningful improvement in ALT if it is going to occur. This 
enables any positive findings to be reported as soon as possible. The duration of treatment in the PIVENS and 
TONIC trials demonstrated significant changes relative to placebo in serum ALT at 24 weeks. 
 
4.3 
JUSTIFICATION FOR DOSE 
The purpose of this study is to find the minimum effective dose of vitamin E as a therapy from NAFLD. For this 
reason, three separate doses of vitamin E will be tested alongside a placebo group. The maximum daily dose 
being tested in this trial (533.6 mg (800 IU)) has been show to successfully lower ALT levels in previous studies. 

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The additional doses of 133.4 mg (200 IU) and 266.8 mg (400 IU) are to be included in this study to explore the 
ability of vitamin E to improve ALT at lower doses than previously studied. 
 
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the study 
including the last visit or the last scheduled procedure shown in the Data Collection Schedule (DCS), Section 
1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the DCS in the trial 
globally. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
Patients must satisfy all of the following criteria to be eligible for randomization: 
• 
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 
 
 
5.2 
EXCLUSION CRITERIA 
Patients who satisfy any of the following exclusion criteria will be ineligible for randomization: 
• 
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 

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 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) 
 Evidence of recent or current hepatitis C as marked by the presence of anti HCV antibody with 
detectable HCV RNA in serum within 1 year prior to enrollment. Participants with anti HCV 
antibody positivity who have undetectable HCV RNA at least 1 year prior to enrollment (either due 
to spontaneous clearance or clearance with treatment) will be eligible to participate if HCV RNA at 
entry remains undetected 
 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: 
o PSA >ULN at baseline 
o History of prostate cancer 
o Age 45 or older with a first-degree relative (father or brother) diagnosed with prostate cancer 
at an early age (younger than age 65). 
o 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 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
In addition to the study medication, participants will receive a standardized set of recommendations about 
life-style modification (dietary modification, weight loss, exercise), use of prescription or non-prescription 
medicines or herbal remedies or dietary supplements, consumption of alcohol, and management of various co-
morbid illnesses. These recommendations have been prepared by the NASH CRN Standard of Care Committee 

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and are approved by the NASH CRN Steering Committee to be applied across all study sites. This will help 
ensure that the participants in both groups receive the same standard of care treatment for NAFLD/NASH. 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a low ALT, low 
CAP, or other acute issue may be rescreened once. Participants may also be rescreened once in the case of 
unexpected delay between registration and randomization (more than 60 days). Rescreened participants 
should be assigned the same participant number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
5.5.1 RECRUITMENT 
 
Approximately 200 adult participants in 4 groups of equal size (50 per group) will be recruited at the 9 
participating centers of the NASH CRN (averaging 22 patients per center) over a 72-week (18 month) period. 
 
Eligible patients will be identified and recruited at the participating clinical centers subject to the inclusion and 
exclusion criteria. Clinics will be expected to recruit sufficient overall numbers of minorities and females so 
that results can be generalized to these populations. Each clinic will develop a recruitment plan. These plans 
will vary from clinic to clinic depending on the available pools of patients and local recruitment resources and 
referral patterns. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Natural vitamin E, d-α-tocopherol (RRR-alpha-tocopherol), will be the active ingredient used in the study drug 
for the VEDS trial. The total chemical composition of the raw Vit E DA tocopherol blend to be used in the 
manufactured capsules will be: d-alpha tocopherol (66.80%), mixed tocopherols (0.40%), soybean oil (32.80%). 
Active ingredient (d-α-tocopherol) 
Structural formula: 
 

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Chemical formula: C29H50O2 
Vitamin E will be supplied to participants in identical softgel capsules. Each capsule will contain 133.4 mg or 
266.8 mg of vitamin E, d-alpha tocopherol, and inactive ingredients (eg. soybean oil). The 133.4 mg and 266.8 
mg capsules will contain 200 IU and 400 IU of the d-alpha tocopherol, respectively. The matching placebo will 
contain high oleic safflower oil. All capsules will be identical in size and color with an oval shape containing a 
straw to amber colored, viscous liquid. 
The softgel shell will be made in situ using 43.0% gelatin (bovine), 38.4% water, 18.0% glycerin (vegetable-
based), and 0.6% natural colorant. 
6.1.2 DOSING AND ADMINISTRATION 
 
Participants will be treated with 133.4 mg (200 IU), 266.8 mg (400 IU), or 533.6mg (800 IU) of vitamin E or 
matching placebo for 24 weeks. These doses will be delivered to patients as follows: 
- 
133.4 mg (200 IU): one capsule of 133.4 mg (200 IU) vitamin E AND one matching placebo capsule. 
- 
266.8 mg (400 IU): two capsules of 133.4 mg (200 IU) vitamin E. 
- 
533.6 mg (800 IU): two capsules of 266.8 mg (400 IU). 
- 
Placebo: two matching placebo capsules. 
 
Participants will be instructed to take the two capsules contained in one blister packaging compartment with 
water by mouth each morning with breakfast. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
An investigator may not administer an investigational new drug to human subjects until the IND goes into 
effect (30 days after IND receipt by FDA) or sooner if notified. An investigational drug under IND may only be 
used by an investigator in compliance with 21 CFR Part 50 and 21 CFR Part 56. All drug and placebo will be 
distributed to the individual sites by the Drug Distribution Center (DDC) at the direction of the Data 
Coordinating Center (DCC) and received by the research pharmacist at each site. Expired or unused drug at the 
end of the study will be disposed of by each site. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
For this study, each of the 133.4 mg (200 IU) and 266.8 mg (400 IU) vitamin E and placebo capsules will be 
specially formulated to be identical in size and coloring. Capsules will be provided by Pharmavite. 
Study drug will be supplied to participants in blister packaging labeled as “Vitamin E or placebo for 
investigational use only”. Each compartment or ‘blister’ in the blister packaging will contain the intended two 
capsule dose (ie, 200 IU + matching placebo).  
 
6.2.3 PRODUCT STORAGE AND STABILITY 
Capsules should be stored at 59 °F to 75 °F in tightly closed containers and relative humidity not to exceed 
50%. 
6.2.4 PREPARATION 

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No preparation is required because capsules will be provided to sites in patient ready packaging. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Randomization: The randomization scheme will assign patients into four groups to receive vitamin E at 133.4 
mg (200 IU), 266.8 mg (400 IU), or 533.6 mg (800 IU) or placebo daily. The randomization design will be 
stratified by clinical center with assignments in permuted blocks of random length within each clinic. This 
scheme will ensure that the four groups will be balanced by calendar time of randomization (to minimize 
secular effects) and by clinic (to minimize clinic-specific effects of differences in patient populations and 
management). 
 
The randomization plan will be prepared and administered centrally by the Data Coordinating Center (DCC) but 
will not require real time interaction with a DCC staff member. Requests for randomizations will be made by 
the clinics using a web-based application. An assignment will be issued only if the database shows that the 
patient is eligible, has signed the consent statement, and has had all required baseline data keyed into the 
database. 
 
Treatment assignments are double masked throughout the study until all data collection for the VEDS trial has 
been completed (i.e., after completion of the post-trial follow-up for all participants). Every effort will be made 
to maintain the masking throughout the study except in emergencies. The code of specific pharmacological 
treatment will not be broken without the knowledge of the clinical center’s principal investigator and the study 
leadership. 
 
Unmasking of study medication may occur under the following conditions: 
 
• 
Severe allergic reaction (Stevens-Johnson Syndrome): Study medication is stopped indefinitely. The 
patient, primary care provider (PCP), and the investigator may be unmasked. 
• 
Pregnancy during the study: Study medication will be stopped indefinitely, and the coded medication 
may be unmasked. The patient, PCP, and investigator will be notified of the associated risks of 
teratogenicity. 
• 
Development of hepatotoxicity: The drug induced liver injury (DILI) criteria described in section 7.1 
will be used to define hepatotoxicity for this study. Study medication will be discontinued; however, 
there will be no unmasking until study conclusion. 
• 
Development of serious bleeding: Serious bleeding will be defined as bleeding associated with a 
serious adverse event (SAE) (see section 8.3.2). The patient, primary care provider (PCP), and the 
investigator may be unmasked. 
 
The Data and Safety Monitoring Board will review all instances of unmasking that occur. 
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Two important goals of this protocol are to optimize adherence to the pharmacological regimen and to 
maximize the retention of participants in the study. Assessment of adherence to the assigned study drug will 
provide clinic staff a means to identify participants having problems with adherence. Adherence will be 
assessed during the trial by conducting a brief, structured interview, in which the study coordinator will assist 
the patients in identifying problems in taking the study drug and in estimating adherence to the prescribed 
medicine since their previous visit. These assessments will guide the consideration of strategies to improve 
adherence. Resources may be provided by clinics to remove barriers to participation such as child care, 

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transportation, and parking expenses. These resources can be provided as cash, transportation vouchers, or 
parking passes. An honorarium may be paid to participants in recognition of their time and effort when 
scheduled visits and procedures are completed successfully. Certificates of appreciation may be given at 
randomization and at conclusion of the VEDS trial as an incentive. Counts of capsules in the patient’s returned 
blister packaging will be used as a measure of adherence at the end of the treatment period. 
 
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications, and supplements. 
 
 
6.5.1 RESCUE MEDICINE 
N/A 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
If the participant is in the treatment phase of the trial, and he/she develops a treatment related CTCAE v5.0-
defined adverse event grade 3 or above, the medication will be stopped and the participant assessed by the 
site study investigator who is a licensed physician/hepatologist. If the adverse event was severe, prolonged, or 
in the view of the investigator the participant is intolerant of the medication, the study drug will be stopped 
and the participant will no longer receive the study medication, but will continue to be followed in the study 
according to the protocol, in keeping with the “intention-to-treat” paradigm. 
 
Participants will be monitored for drug induced liver injury and will use the scale below to grade the adverse 
effects*: 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT 
BSL elevated: 3x BSL 
or >400 U/L 
 
BSL elevated: >3-5x 
BSL  
 
BSL elevated: >5 -20x 
BSL 
BSL elevated: >20x BSL 
AST 
BSL nl:3 x ULN 
BSL elevated: 3x BSL  
 
BSL nl:>3-5 x ULN 
BSL elevated: >3-5x 
BSL  
 
BSL nl:>5-20 x ULN 
BSL elevated: >5-20x 
BSL  
 
BSL nl:>20 x ULN 
BSL elevated: >20x BSL  
Total 
Bilirubin  
1.5 x ULN  
>1.5-3.0 x ULN 
>3.0-10.0 x ULN 
>10.0 x ULN 
Any participant found to meet the above criteria for grade 2 or higher drug induced liver injury will have the 
study medication stopped pending further study investigator evaluation. 
In addition, participants will have the study medication stopped if ANY of the following occur[81]:  
If normal baseline AST: 

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• 
AST value >5 x ULN in two repeat tests (within 14 days); OR 
• 
AST value is >8 x ULN; OR 
• 
AST value >5 x ULN AND total bilirubin >2x ULNǂ OR presence of symptoms suggesting liver injury 
(severe fatigue, nausea, vomiting or right upper quadrant pain), 
If elevated baseline AST or ALT: 
• 
ALT or AST value >3 x BSL or 300 U/L in two repeat tests (within 14 days); OR 
• 
ALT or AST value >5 x BSL or >500 U/L (whichever occurs first); OR 
• 
ALT or AST value >3 x BSL or >300 U/L (whichever occurs first) AND total bilirubin >2x ULNǂ OR 
presence of symptoms suggesting liver injury (severe fatigue, nausea, vomiting, or right upper 
quadrant pain) 
 
Follow-up visits will continue, but the study medication will not be restarted. The participant will be included in 
intention-to-treat analyses.  
 
Additionally, if a participant is found to have signs of increased bleeding (i.e. petechiae) on physician 
assessment or a participant reports any signs of increased bleeding (i.e. bleeding gums), the study medication 
will be discontinued until the participant can be further examined by a study physician. The study medication 
may be restarted after further examination if the bleeding was not associated with a serious adverse event 
(CTCAE grade 3 or higher) and if the study physician deems a re-challenge appropriate. 
* Values for ULN are defined at each clinical center per laboratory guidelines. 
ǂ For participants with suspected Gilbert’s Syndrome at baseline: doubling of direct bilirubin  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance (as determined by primary investigator) 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation 
• 
Participant unable to receive study drug for > 4 weeks. 
Discontinuation from the study medication (vitamin E or matching placebo) does not mean discontinuation 
from the study and remaining study procedures should be completed as indicated by the study protocol. The 
reason for participant discontinuation or withdrawal from the study will be recorded on the Case Report Form 
(CRF). Participants who sign the informed consent form and are registered but do not receive the study 
intervention may be replaced.  Participants who sign the informed consent form, and are randomized and 
receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the study 
will not be replaced. 

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7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is unable 
to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant, reschedule the missed visit within 4 weeks, counsel the 
participant on the importance of maintaining the assigned visit schedule, and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified 
letter to the participant’s last known mailing address or local equivalent methods). These contact 
attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable after two visit windows have passed, he or she will 
be considered to have withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 VISIT SCHEDULE OVERVIEW 
• 
Screening for eligibility for randomization (60 days) 
• 
Randomization to treatment (1 visit) 
• 
Treatment phase (4 visits over 24 weeks) 
• 
Post-treatment phase (3 visits over 24 weeks) 
8.1.2 SCREENING AND BASELINE DATA COLLECTION 
Patients who appear to be eligible after chart review will be invited to undergo screening. Recording of 
screening data on NASH CRN forms may not start until the patient has signed the consent statement. 
Screening and baseline data collection procedures detailed below will include questionnaires, baseline medical 
history, cardiovascular risk factor assessment, physical examination, measurement of fasting serum glucose 
and insulin, lipid and metabolic tests, etiologic tests, FibroScan® VCTE exam, and blood collection for serum 
and plasma banking. Prior therapy for NAFLD will be reviewed as outlined in the inclusion and exclusion 
criteria. Patient charts will be reviewed for historical information.  
All participants who sign the consent documents will be registered in the trial database. Each participant who 
starts screening will be accounted for at the end of screening, as either a screening success (enrolling in the 
trial) or a screening failure. A screening failure is defined as a participant who signed the consent form, but is 
found to be ineligible prior to randomization. Screening failures include patients who meet medical eligibility 
criteria but who refuse randomization in the trial. Reasons for screening failure will be recorded in the trial 
database. Screening data collection will be conducted over two clinic visits usually completed on separate 
calendar days. The goal of the first screening visit is to obtain consent and record data regarding the trial’s 
inclusion and exclusion criteria; the goal of the second screening visit is to complete collection of baseline data 
on patients who appear eligible. This separation of procedures between two visits is provided as a practical 

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guideline. Screening procedures and data collection can be organized as appropriate at each clinical center. 
The procedures completed during screening are described below.  
Screening visits  
Determination of eligibility will be based mostly on chart review of standard of care tests and procedures that 
were completed before the first screening visit. The participant will sign the consent at the first screening visit 
(or before) to obtain any tests and procedures needed to finalize eligibility after chart review. Participants will 
undergo a medical history and detailed physical examination including anthropometric assessments (body 
weight [kg], body height [m], body mass index [BMI], waist circumference [cm], and hip circumference [cm]) to 
identify other illnesses and contraindications for participation, including signs of bleeding (gum, petechiae), 
hepatosplenomegaly, peripheral manifestations of liver disease, and ascites. Laboratory test results that need 
to be recorded from chart review or obtained as part of the screening visits include: tests for hepatitis B 
(HBsAg) and hepatitis C, anti-nuclear antibody (ANA), anti-mitochondrial antibody (AMA), anti-smooth muscle 
antibody (ASMA), ceruloplasmin, A1AT concentration, iron overload (iron, TIBC, and ferritin) and thyroid 
stimulating hormone (TSH). The ALT measurement must be completed within 30 days of randomization. The 
additional lab tests for screening must be completed within 60 days of randomization: fasting serum glucose, 
insulin, HgbA1C, complete blood count (CBC) with white blood cell differential, hepatic panel (total and direct 
bilirubin, AST, alkaline phosphatase, albumin, total protein, GGT), coagulation tests (aPTT, PT, INR), metabolic 
panel (sodium, potassium, chloride, carbon dioxide, calcium, BUN, creatinine, uric acid), eGFR (using the CKD-
EPI equation), C-reactive protein, and lipid panel (total cholesterol, triglyceride, LDL, HDL), PSA (males only). 
Use of medications that could potentially interact with vitamin E (e.g. anticoagulants, those altering fat 
absorption) will be queried and documented.  
Females of childbearing potential must have a negative pregnancy test and will be assessed for willingness to 
use ≥ 1 form(s) of effective birth control for the duration of the study. Frequency and amount of alcohol intake 
will be obtained using the Skinner Questionnaire and the Alcohol Use Disorders Identification Test (AUDIT). 
Patients will complete the BEV-Q questionnaire to document habitual beverage intake (grams, energy) and a 
liver symptoms questionnaire developed by the NASH CRN to identify symptoms associated with liver disease, 
severity of symptoms, and impact on lifestyle. A blood sample will be drawn to obtain serum/plasma for 
banking for future analysis of markers of exploratory endpoints including measures of vitamin E.  
Baseline FibroScan® 
A FibroScan® procedure will be performed within 60 days of randomization for baseline data collection 
purposes. Before the procedure, the patient will verify that he/she has fasted for 3 hours prior to the exam. 
The FibroScan® exam will be performed by a FibroScan®-certified technician. Duration of the exam will be no 
longer than 30 minutes. 
The NASH CRN clinic data system will include coding to check patient eligibility based on keyed data forms.  
The randomization visit will only become available in the data system when all forms are keyed, and any issues 
will be flagged as red until resolved or verified, so clinic staff can use the data system to visually identify the 
items that still need to be completed, keyed, or verified after data from the screening visit are keyed. The 
randomization visit should not take place until the data system indicates that the patient is eligible except for 
the items that can be completed only at the randomization visit. 

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8.1.3 RANDOMIZATION 
The randomization visit is the visit at which randomization takes place and the patient is issued the study 
medication randomly assigned to the patient. Randomization is the act of generating the random study 
medication assignment and is the procedure which defines a patient’s enrollment into the trial. Randomization 
can only occur after eligibility has been fully checked and all data collected at the screening visits have been 
keyed to the trial database. Since these processes take time, randomization cannot be done at a screening 
visit, and since study medication needs to be issued to the patient, the randomization visit must be completed 
in person with the patient. Therefore, a visit separate from the screening visit is necessary. Since this will be a 
visit on a different calendar day and the study medication will be prescribed at this visit, good clinical practice 
requires that a few basic checks of the patient’s well-being be completed at the randomization visit. 
The procedures completed at the randomization visit are: verification that the patient is feeling well; 
affirmation of consent; review of concomitant drugs and vital signs (systolic and diastolic blood pressure, heart 
rate, respiratory rate, body temperature). All patients will be given information on a healthy life style and diet 
appropriate for their weight and other factors. 
Generation of the random treatment assignment will occur at this visit. The randomization process includes 
the same electronic check on eligibility that the staff may run prior to the randomization visit. The medication 
assignment will not be generated unless the check finds that the patient is eligible, and the clinic staff indicates 
that they want to randomize the patient. The random treatment assignment will consist of medication ’kit’ 
numbers; these numbers will be unique and will be specific to the particular patient it was generated for. They 
will correspond to numbered cartons (‘kit’) of medications which have been sent to the clinical center’s 
research pharmacy (or clinical coordinator if not using a pharmacy) by the Drug Distribution Center. The 
research pharmacy (or clinical coordinator) will issue the specific numbered kit to the patient. Each patient’s 
random treatment assignment will be generated for that specific patient and will not be transferable to 
another patient. Once the assignment has been generated, the patient should be issued the assigned study 
drug and instructed about starting the drug and monitoring for adverse effects. The date of randomization is 
the 0 time for reckoning all follow-up visits (i.e., all follow-up visits are scheduled at specific times measured 
from the date of randomization). The data system will display a personalized appointment schedule for the 
patient; this schedule will indicate the ideal date for each follow-up visit, as well as the time window around 
the ideal date during which the follow-up visit may be done. This will ensure that the data collected at the 
follow-up visit may be used in the trial. 
8.1.4 FOLLOW-UP VISITS 
Patients will return to the clinical center (see section 8.1.4.1 for optional remote visit allowances) for 
treatment phase follow-up visits at 4, 8, 12, and 24 weeks after randomization. Post-treatment phase visits will 
occur at week 28, week 36, and week 48 after randomization. Each visit will have an interval of time 
surrounding the ideal date for the visit during which the visit may be done and the data included in the trial 
database. The ideal date for a visit is the exact anniversary date from randomization. Visit windows will be 
constructed to be contiguous, so that at any point in time, some visit window is open, subject to a check on the 
minimum separation of at least two weeks is required between consecutive visits. The specific procedures to 
be completed at each of the follow-up visits are:  

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• 
Week 4 visit: Follow-up medical history including review of medications, adverse effects, and interim 
drinking history; review of study drug adherence; blood draw for fasting glucose and insulin, hepatic 
panel (total and direct bilirubin, AST, ALT, alkaline phosphatase, albumin, total protein); questionnaire 
for symptoms of NAFLD; focused physical examination including height, weight, waist and hip 
measurements, vital signs, oropharynx, and skin examination for petechiae or other signs of increased 
bleeding. 
• 
Week 8 visit: Follow-up medical history including review of medications, adverse effects, and interim 
drinking history; review of study drug adherence; blood draw for fasting glucose and insulin, hepatic 
panel (total and direct bilirubin, AST, ALT, alkaline phosphatase, albumin, total protein); questionnaire 
for symptoms of NAFLD; focused physical examination including height, weight, waist and hip 
measurements, vital signs,  oropharynx, and skin examination for petechiae or other signs of increased 
bleeding. 
• 
Week 12 visit: Follow-up medical history including review of medications, adverse effects, and interim 
drinking history; review of study drug adherence; blood draw for fasting glucose and insulin, fasting 
lipid profile, hepatic panel (total and direct bilirubin, AST, ALT, alkaline phosphatase, albumin, total 
protein), and C-reactive protein; blood draw for plasma and serum  banking at a central repository; 
questionnaire for symptoms of NAFLD; detailed physical examination including height, weight, waist 
and hip measurements, vital signs, oropharynx, and skin examination for petechiae or other signs of 
increased bleeding. 
• 
Week 24 visit: Follow-up medical history including review of medications, adverse effects, and interim 
drinking history; detailed physical examination, including height, weight, waist and hip measurements, 
vital signs (temperature, heart rate, respiratory rate, blood pressure), organ systems and liver signs; 
FibroScan®; blood draw for CBC, comprehensive metabolic panel (sodium, potassium, chloride, carbon 
dioxide, calcium, BUN, creatinine, eGFR), hepatic panel (total and direct bilirubin, AST, ALT, alkaline 
phosphatase, albumin, total protein), GGT, PT, aPTT, INR, C-reactive protein, fasting glucose, insulin, 
HbA1c, and lipid profile; blood draw for plasma and serum  banking at a central repository; pregnancy 
test for women of childbearing potential, questionnaire for symptoms of NAFLD; BEVQ; standardized 
nutrition and exercise prescription and counseling. Review study drug adherence with patient. Collect 
all study drug blister packaging, including empty packaging. END OF TREATMENT PHASE 
• 
Week 28 visit: Follow-up medical history including review of medications, adverse effects, and interim 
drinking history; blood draw for fasting glucose and insulin, hepatic panel (total and direct bilirubin, 
AST, ALT, alkaline phosphatase, albumin, total protein); questionnaire for symptoms of NAFLD; focused 
physical examination including height, weight, waist and hip measurements, vital signs, oropharynx, 
and skin examination for petechiae or other signs of increased bleeding. 
• 
Week 36 visit: Follow-up medical history including review of medications, adverse effects, and interim 
drinking history; blood draw for fasting glucose and insulin, hepatic panel (total and direct bilirubin, 
AST, ALT, alkaline phosphatase, albumin, total protein); questionnaire for symptoms of NAFLD; focused 
physical examination including height, weight, waist and hip measurements, vital signs, oropharynx, 
and skin examination for petechiae or other signs of increased bleeding. 
• 
Week 48 visit: Follow-up medical history including review of medications, adverse effects, and interim 
drinking history; detailed physical examination, including height, weight, waist and hip measurements, 
vital signs (temperature, heart rate, respiratory rate, blood pressure), organ systems and liver signs; 
FibroScan®; blood draw for CBC, comprehensive metabolic panel (sodium, potassium, chloride, carbon 

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dioxide, calcium, BUN, creatinine, eGFR), hepatic panel (total and direct bilirubin, AST, ALT, alkaline 
phosphatase, albumin, total protein), GGT, PT, aPTT, INR, C-reactive protein, fasting glucose, insulin, 
HbA1c, lipid profile, and PSA (males only); blood draw for plasma and serum banking at a central 
repository; BEVQ questionnaire for symptoms of NAFLD; Closeout form 
8.1.4.1 REMOTE VISITS 
Investigators and staff may elect to perform the week 4, 8, 28 and/or 36 visit(s) either in part or completely 
remotely, via telemedicine. Remote visits will adhere to the Data Collection Schedule (section 1.3) with the 
following modifications allowable for visit procedure completion: 
- 
Focused physical exam may be completed via the local institutional telemedicine portal. Video calls 
should be utilized. 
- 
Laboratory test results may be obtained through an outside lab, as needed. 
- 
Questionnaires may be completed via correspondence. 
8.1.5 STANDARDIZED QUESTIONNAIRES 
Alcohol Use Disorders Identification Test (AUDIT) is a 10-item questionnaire with a simple scoring scale that 
will be administered during screening. A 3-item interim drinking history (AUDIT-C) measuring consumption 
since the last visit will be obtained during follow-up visits as part of the follow-up medical history. The purpose 
of these questionnaires is to ascertain that there is no significant alcohol consumption prior to randomization 
or during the study period. 
Skinner Lifetime Drinking History:  is an interview based questionnaire that will be administered during 
screening. The purpose of this tool is to obtain quantitative indices of the patient’s alcohol consumption 
patterns from the onset of regular drinking. 
 
Bev-Q: The Beverage questionnaire will be administered during screening and at the 24 week and 48 week 
follow-up visits. The purpose of this questionnaire is to determine the patient’s regular beverage intake, 
including nonalcoholic beverages. 
 
8.1.6 SPECIMEN REPOSITORIES 
 
Specimens will be collected and stored in the NIDDK central repositories for use as approved by the Steering 
Committee of the NASH CRN. Specimens include serum and plasma. The blood collected during screening, and 
at the 12, 24, and 48 week follow-up visits will be separated into plasma and serum, and divided into 0.5 mL 
aliquots. Aliquots will be kept in a storage facility at -70 degrees C until they are shipped to the NIDDK Central 
Repository on dry ice. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Assessments for Safety  

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• 
Physical examination (e.g., height, weight, waist and hip measurements, vital signs (temperature, 
heart rate, respiratory rate, blood pressure), liver symptoms, gingival/orocutaneous bleeding; 
petechiae. 
• 
Laboratory results – All labs including creatinine (and calculated GFR) potassium levels and 
bicarbonate will be monitored at sites and in the central database and all abnormal values will be 
managed by the site investigator. 
• 
Bleeding risk – Participants will be evaluated for bleeding risk throughout the study using physician 
examination, laboratory results of prothrombin time, activated Partial Thromboplastin Time (aPTT), 
and INR, and patient self-report. 
• 
Concurrent use of anticoagulant – Participants will be questioned about use of any anticoagulants, 
including aspirin, throughout the study. 
 
Biological specimen collection and laboratory evaluations – There will be consistent methods throughout 
the study to ensure comparison. ALT will be measured at each site and the same lab at each site will be 
used for the measurement at baseline, 24 week and 48 week visits. Other local labs may be used, if 
necessary, when completing an allowable remote visit (see section 8.1.4.1), and will be noted in the data 
system. Follow up of Ongoing Adverse Events  
Provisions for follow up of adverse events include phone calls by the coordinators to assess symptoms, in 
person follow up exams when needed to assess vital signs and physical findings and referral to local 
ongoing care by the patient’s primary care physician or hospital when needed. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and 
may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will be 
used to describe severity.  

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Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, the 
term “severe” does not necessarily equate to “serious”. 
  
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may 
have contributed to the event (e.g., the participant’s clinical condition, other concomitant events). 
Although an AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the study intervention) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician. 
  
8.3.3.3 EXPECTEDNESS  
 
Site PIs and investigators will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 

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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study 
personnel during study visits and interviews of a study participant presenting for medical care, or upon review 
by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as baseline 
and not reported as an AE. However, if the study participant’s condition deteriorates at any time during the 
study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at 
each level of severity to be performed. AEs characterized as intermittent require documentation of onset and 
duration of each episode. 
 
Site coordinators will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At each 
study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be 
followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
Adverse events will be recorded on study data forms whether or not they are thought to be associated with 
the study or with the study drug. Adverse events may be discovered during regularly scheduled visits or 
through unscheduled patient contacts between visits.   
 
Summary data on adverse events will be monitored by the DSMB quarterly and at its semiannual meetings or 
more frequently, as needed. These summaries will include analyses comparing rates of adverse events by 
treatment group, by clinic, or in other subgroups requested by the DSMB. Where applicable, signs and 
symptoms associated with the adverse event will be graded as to severity by the clinical site staff as mild, 
moderate, or severe using Version 5.0 of the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events (CTCAE).[82] 
 
After each DSMB meeting, the NIDDK will issue a written summary of the review of the study data, including 
adverse events, for transmission to the sIRB. Analyses or listings of adverse events will not be provided to the 
sIRB; however, adverse events involving unanticipated problems involving risks to patients, or breaches of 
protocol which might entail risk to patients must be reported to the sIRB and, as required, to the local IRB as 
soon as possible after they are discovered. Each participating center is responsible for ensuring that all sIRB 
and local IRB requirements for reporting adverse events are met. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 

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Serious adverse events (SAE) must be reported upon discovery at the clinical center. This will involve 
completing a data form describing the severity and details of the event, which must be submitted to the Data 
Coordinating Center within one business day for review by the Safety Officer. 
 
 
If the SAE is unexpected AND there is a reasonable possibility that the study drug caused the SAE, then the 
clinical center must complete a data form for an IND Safety Report and submit it along with a narrative and a 
copy of the IRB report to the DCC.  The DCC will submit a preliminary report to the NIDDK Program Official, 
Project Scientist and the NIDDK Regulatory Affairs Specialist for review within three business days of receiving 
the SAE data form. The study drug manufacturer will also be notified within 7 days of the serious adverse 
event, if applicable.  If NIDDK determines that the SAE requires an expedited IND Safety Report, the NIDDK 
Program Official or the NIDDK Regulatory Affairs Specialist will notify the FDA no more than 15 calendar days 
from the initial receipt of the SAE by the DCC (no later than 7 calendar days if the SAE is fatal or life 
threatening). The clinical center investigator may also be responsible for completing an FDA MedWatch 3500 
form and additional information for a follow-up SAE report as information becomes available. If the FDA 
determines that a change to the Investigator’s Brochure (IB), IND, or protocol is needed, the Data Coordinating 
Center will send a copy of the IND Safety Report to all clinical centers, with instructions to forward the report 
to their IRB.  
 
The DCC will maintain a list of all SAEs for reporting and review at Steering Committee meetings and DSMB 
meetings. The DSMB will review each SAE report. If requested by any member of the DSMB, a teleconference 
will be scheduled to discuss the SAE and recommend any actions to the NIDDK sponsor. The clinical center 
must submit to the NIDDK and to the Data Coordinating Center a follow-up memo within one month of the 
SAE (and periodic updates if needed) to report the details of the disposition of the SAE. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
 
Participants will be monitored for pregnancy and will be required to take precautions to prevent pregnancy.  
However, if a participant is found to be pregnant, the study medication will be stopped immediately and the 
coded medication may be unmasked. The participant, primary care physician, and investigator will be notified 
of the associated risks of teratogenicity. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
patients or others to include, in general, any incident, experience, or outcome that meets all of the following 
criteria: 
 

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• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved 
research protocol and informed consent document; and (b) the characteristics of the patient 
population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places patients or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
Other events meeting prompt reporting criteria as detailed by the Johns Hopkins Medicine, Institutional 
Review Board (JHM IRB) “Organizational Policy on Prompt Reporting of Reportable Events” are: 
• 
Potential serious or continuing non-compliance. Non-compliance is defined as “the failure to follow 
the research protocol, federal, state, or local laws or regulations governing human subjects research, 
institutional policies, or the requirements or determinations of the IRB”. Incidents of non-compliance 
are reportable when they are instances of either: 
o Serious Non-compliance that either “(a) significantly harms or poses an increased risk of 
significant harm to subjects or others, or (b) significantly compromises the rights and welfare 
of research subjects.” 
o Continuing Non-compliance, where “a pattern of non-compliance significantly compromises 
the scientific integrity of the study or the rights and welfare of the subjects or the integrity of 
the Organization’s human research protection program” 
• 
Potential Breaches of Confidentiality, which are defined as “any unauthorized disclosure of subject’s 
personally identifiable information”. 
• 
Incarceration. If a patient becomes incarcerated during their participation in the study, and the local 
clinical team intends to continue any data collection while the subject is incarcerated, it is immediately 
reportable. 
Unresolved Subject Complaints. “Complaints of subjects when the complaint indicates unexpected risks or 
cannot be resolved by the research team. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing single Institutional Review Board 
(sIRB), the local relying IRB), and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP 
report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study sponsor 
within 10 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 10 days of the 
investigator becoming aware of the problem.  

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All UPs should be reported to appropriate institutional officials (as required by an institution’s written 
reporting procedures), the supporting agency head (or designee), and the Office for Human Research 
Protections (OHRP) within 10 days of the IRB’s receipt of the report of the problem from the 
investigator. 
• 
Reports should be sent to: IRPT.OS@hhs.gov 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
AEs will be reported to participants if they are unexpected, related or possibly related, and suggest greater risk 
of harm to participants. 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s): That one of the doses of vitamin E at 133.4 mg (200 IU), 266.8 mg (400 
IU), or 533.6 mg (800 IU) daily is the minimum effective dose for improving relative change in alanine 
aminotransferase (ALT) from baseline to 24 weeks. 
 
• 
Secondary Efficacy Endpoints(s): That one or more of vitamin E at 133.4 mg (200 IU), 266.8 mg (400 
IU), or 533.6 mg (800 IU) daily is better than placebo in improving: 
o Proportion of patients achieving normalization* of ALT at 24 weeks  
o Mean change in ALT from baseline to 24 weeks 
o Mean change in AST and GGT from baseline to 24 weeks 
o Mean change in hepatic fat determined by FibroScan® CAP score from baseline to 24 weeks 
o Mean change in liver stiffness as assessed by FibroScan® from baseline to 24 weeks 
o Time course and end of treatment improvement in ALT, AST, GGT, and alkaline phosphatase 
o Time course and end of treatment improvement in C-reactive protein (serum marker of 
inflammation) 
o Time course and end of treatment improvement in change in total cholesterol, LDL cholesterol, 
HDL cholesterol, and serum triglycerides 
o Changes in fasting glucose levels from baseline to 24 weeks 
o Change in anthropometric measurements (weight, BMI, waist to hip ratio, waist 
circumference) from baseline to 24 weeks  
o Change in symptom assessment scores from baseline to 24 weeks  
o Change in frequency of CTCAE defined adverse events from baseline to 24 weeks  
o Mean change in ALT from 24 to 48 weeks (post-treatment). 

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o Mean change in AST and GGT from 24 to 48 weeks (post-treatment). 
o Mean change in hepatic fat determined by FibroScan® CAP score from 24 to 48 weeks (post-
treatment). 
o Mean change in liver stiffness as assessed by FibroScan® from 24 to 48 weeks (post-
treatment). 
 
*Normalization of ALT 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 ULN are defined at each clinical center per institutional 
guidelines. 
 
9.2 
SAMPLE SIZE DETERMINATION 
The primary endpoint is the relative change in ALT at week 24 from baseline [i.e., (ALT at baseline – ALT at 
week 24)/ALT at baseline]. There are three vitamin E treatment groups: 133.4 mg/day, 266.8 mg/day, 533.6 
mg/day and one placebo group. The primary analysis is intention-to-treat analysis of minimum effective dose 
using Williams’ test of mean 24-week relative change in ALT. If the percentage of patients with missing follow-
up data on the primary endpoint is greater than 10%, multiple imputation using chained equations method 
with 50 imputations modeling will be used to impute missing values; otherwise complete-case analysis will be 
used. 
Among patients in PIVENS with baseline ALT ≥ 60 U/L, the mean 24-week relative change in ALT was 40% in the 
vitamin E (800 IU/day) group and 20% in the Placebo group. The Mean (SD) of the vitamin E – placebo 
difference in relative change (%) was -20% (31%).  Using this estimate as the clinically meaningful difference, 
the trial has 90% power to detect a significant minimum effective dose given a sample size of 200 patients (50 
per group with equal allocation) given a 2-sided Type I error of 5%, missing data rate of 10% and using 
Williams’ test for minimum effective dose (MED) (Williams 1971, Williams 1972) obtained from PASS 2019 
software (PASS 2019 Power Analysis and Sample Size Software (2019). NCSS, LLC. Kaysville, Utah, USA, 
ncss.com/software/pass). 
The testing for minimum effective dose starts by comparing the 24-week relative change in ALT in each of the 
3 dose groups with the placebo group using critical values obtained from Williams’ test for MED. (Critical 
values will be obtained using SAS PROBMC function.) Williams’ test assumes the same or increasing efficacy 
with increasing dose; therefore, if the mean change at a dose level is less in absolute value than the mean 
change in a lower adjacent dose category, the groups are combined for statistical comparison. The lowest dose 
that is significantly different from placebo is declared the MED. By definition, all doses greater than the MED 
are also significantly different from placebo. 
Sample size estimates for varying sizes of the treatment effect are given below given the same assumptions as 
above. 
24-week relative change in ALT 
Sample size 
Vitamin E 
Placebo 
Vitamin E – Plbo 
No. / group 
Total 
48% 
20% 
28% 
25 
100 
44% 
20% 
24% 
34 
136 
40% 
20% 
20% 
50 
200 
36% 
20% 
16% 
76 
304 

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32% 
20% 
12% 
135 
540 
28% 
20% 
8% 
303 
1212 
 
 
9.3 
POPULATIONS FOR ANALYSES 
 
The analysis dataset will include: 
 
• 
Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants) 
• 
Safety Analysis Dataset: defines the subset of participants for whom safety analyses will be conducted 
(e.g., participants who took at least one dose of study intervention) 
• 
Other Datasets that may be used for sensitivity analyses (e.g. subgroups by dose, sex, age, baseline 
labs, adherence) 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
The primary intention-to-treat analysis uses Williams’ ANOVA-based test to find, with high statistical power 
(90%), the minimum effective dose of vitamin E that improves the per-person primary endpoint, defined as the 
percentage relative change in ALT from baseline over 24 weeks of treatment with either vitamin E or matching 
placebo. The sample size justification allows for 10% missing data using a complete-case Williams’ test on the 
non-missing data; however, if the percentage of patients with missing data on the primary endpoint is greater 
than 10%, multiple imputation modeling at each step in the Williams’ test procedure will be used to include all 
randomized patients in the determination of the step-by-step p-values needed for the Williams’ test dose-
finding procedure. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
• 
Intention-to-Treat (ITT) Analysis Dataset  
The primary endpoint is 24-week relative change in serum ALT, defined as the ALT obtained at the 24-week 
visit minus ALT at the baseline visit divided by ALT at baseline [i.e., (ALT at baseline – ALT at week 24)/ALT 
at baseline]. The change in serum ALT is measured on a continuous scale and is a single endpoint. The 
Williams’ ANOVA-based test for minimum effective dose of vitamin E starts by comparing the primary 
endpoint between the lowest vitamin E dose of 133.4 mg (200IU) vs. placebo. If significantly better 
(p<0.05) using the 5th percentile from the Williams’ test, then 133.4 mg is declared the minimum effective 
dose and no other comparisons are made; If the previous step is not significantly better, then the 266.8 mg 
(400 IU) dose is compared vs placebo. If significantly better (p<0.05) using the 5th percentile from of the 
Williams’ test, then 266.8 mg (400IU) is declared the minimum effective dose and no other comparisons 
are made. If the previous step is not significantly better, the 533.6 (800IU) mg dose is compared vs 
placebo. If significantly better (p<0.05) using the 5th percentile from the Williams’ test, the 533.6 (800IU) 
mg is declared the minimum effective dose and no other comparisons are made.  If the previous step is not 
significantly better, then declare that no minimum effective dose for vitamin E was found. The primary 
analysis will present the (up to) 3 p-values from the Williams’ test steps above and, only if the William’s 

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test finds a minimum effective dose, the primary analysis will also include the estimated difference and 
95% confidence interval for 24-week percentage relative change vs. baseline, comparing the minimum 
effective 24-week dose group vs placebo. As sensitivity analyses, the 3 separate comparisons of each 
vitamin E dose group vs placebo with estimates and 95% confidence limits be presented. Sensitivity 
analyses will include use of robust regression to down-weight the effect on the Williams’ test minimum 
effective dose selection of influential outliers in the relative ALT change from baseline measures. Other 
sensitivity analyses may be used to balance potential effects on results of confounders not balanced out by 
randomization, as judged by the trial Data Safety and Monitoring Board.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
For each secondary endpoint: 
 
• 
Analyses of secondary endpoints are not dependent on findings of the primary endpoint or on the 
results of the Williams’ test performed on the primary endpoint.  
• 
Analyses will use complete case subjects of the Intention-to-Treat (ITT) Analysis Dataset (i.e., all 
randomized participants with complete data on each specific secondary endpoint).  
 
The analysis of the 16 secondary endpoints listed in Section 3, Objectives and Endpoints, endpoints will use 
ANCOVA for continuous endpoints, logistic regression for binary endpoints, and Poisson regression for counts. 
Complete case analyses will be used for each secondary endpoint, if missing data on that endpoint < 10% and 
multiple imputation will be used if missing data on the secondary endpoint is 10% or greater. The covariate in 
the continuous endpoint ANCOVA models will be the baseline value of the continuous endpoint.  Sensitivity 
analyses include use of non-parametric and influence-reducing regression for continuous endpoints (lowess 
plots and robust regression) and generalized linear models with scale factor estimation to account for under- 
or over-dispersion for binary endpoint data (dispersion-corrected logistic regression) and count endpoint data 
(dispersion-corrected negative binomial regression). Each secondary endpoint in the planned table of 16 
secondary endpoints will be compared across the 3 vitamin E doses vs Placebo using treatment effect 
estimates, 95% confidence limits, and p-values. The Benjamini-Hochberg Method will be use to adjust the 
presented p-values for the false discovery rate (FDR) from the 16x3=48 pairwise p-values. 
 
9.4.4 SAFETY ANALYSES 
 
Safety data will be presented by treatment group to the Data and Safety Monitoring Board during the course 
of the trial. Each adverse event will be displayed showing AE name per the CTCAE v5.0 when applicable, class, 
severity, patient ID, clinic, treatment group, time since randomization, resolution status and physician’s 
assessment of relatedness to treatment. Patient-specific summary tables including any adverse event (yes vs 
no), frequency of multiple adverse events (i.e., 0, 1, 2, 3+) and highest severity of adverse event (none, mild, 
moderate, severe, life-threatening) will be displayed by treatment group along with p-values from Fisher’s 
exact tests. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline data will be presented by treatment group and total. Data include stratification variables (clinic) 
demographics, liver enzymes, lipids, hematology, chemistries, metabolic factors, concomitant medications, 
comorbidities, and liver histology findings. P-values will be presented as descriptive statistics noting that any 
treatment group differences are due to chance. 
 

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9.4.6 PLANNED INTERIM ANALYSES  
 
There are no planned interim analyses. 
 
9.4.7 SUB-GROUP ANALYSES 
 
There are no formal planned sub-group analyses. Exploratory sub-group analyses will include treatment effects 
of primary and selected secondary endpoints by stratum variable (clinic), demographics (age, race, sex), 
severity of NAFLD, and study drug adherence. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
For monitoring of adverse effects, individual data may be presented to the Data and Safety Monitoring Board. 
In that case, study patients will be identified only by study ID. Names and other unique individual identifiers 
such as Social Security Number are not collected by the study and therefore will not be presented to the 
DSMB. Data on individual patients will not be presented in any manuscript or presentation.  
 
9.4.9 EXPLORATORY ANALYSES 
 
In parallel to the ANCOVA statistical methods used to compare continuous endpoints between the treatment 
groups for both the primary and secondary endpoints, we will compare results arising from ANOVA analysis 
(linear regression of 24-week change among treatment groups without adjusting for the baseline value of the 
continuous endpoint) will be used for exploratory analyses. Since ANCOVA and ANOVA are alternative models 
for “difference in difference” data as in the VEDS trial, we expect, given the randomized design, that the two 
methods will give similar results or the primary and secondary endpoints. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the patient 
and written documentation of informed consent is required prior to participation in the study. 
 
Master consent documents will be approved by the single Institutional Review Board of reliance (sIRB) for the 
study for screening to determine eligibility with an affirmation of consent for enrollment in the study. Relying 
sites may not delete material from the master consent. Relying sites will add a site-specific addendum 
containing locally required language to the master consent. The consent document will describe the purpose 
of the study, the procedures to be followed, and the risks and benefits of participation. Copies of the signed 
consent forms will be provided to the patient by paper or electronically, and this fact will be documented in 
the patient’s record. 
 
At relying sites in which Spanish-speaking patients will be recruited, certified translations of the consent 
document will be available in Spanish. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 

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Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and 
continues throughout the individual’s study participation. Consent forms will be Institutional Review Board 
(IRB)-approved and the participant will be asked to read and review the document. The investigator will 
explain the research study to the participant and answer any questions that may arise. A verbal explanation 
will be provided in terms suited to the participant’s comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants.  Participants will have the opportunity to carefully 
review the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing to 
participate. The participant will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants must be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the informed consent document will be 
given to the participants for their records. The informed consent process will be conducted and documented in 
the source document (including the date), and the form signed, before the participant undergoes any study-
specific procedures. The rights and welfare of the participants will be protected by emphasizing to them that 
the quality of their medical care will not be adversely affected if they decline to participate in this study. This 
process may be completed in-person or remotely. 
 
If the consent process is to be completed remotely WITHOUT an electronic signature, the following procedures 
must be followed: 
• 
A copy of the sIRB approved Informed Consent document must be provided to the participant prior to 
the teleconsent meeting either via email, fax or mail or must have been previously provided during an 
in person visit.   The person conducting the consent process may conduct the process via telephone or 
video conference. 
• 
After the consent designee and participant reviews the consent form, the participant is offered the 
opportunity to ask any questions and have those questions answered. 
• 
The participant will sign and date/time the informed consent document.  
• 
The consent designee must verify the participant physically signed the consent document either by 
viewing via video conference, obtaining a photo of the complete signed consent document, or 
obtaining verbal confirmation from the participant that he/she signed the consent form and agreed to 
participate electronically.  
• 
The signed document is then mailed, emailed or faxed to the consent designee. 
• 
If the signed consent is emailed or faxed or returned via photo, the participant will be asked to return 
the original signed document on their first in person visit. Once received, the sIRB-approved consent 
designee signs, dates/times the original informed consent document. Both the original and emailed or 
faxed copy should be retained in the patient record and a copy of the original signed by both parties 
should be provided to the patient. 
• 
If the informed consent form is mailed to the consent designee by the participant, the sIRB-approved 
consent designee will sign the copy which they possess after the participant has acknowledged 
signature on their copy.  Once the original is received by the consent designee the copies will be 
attached to make a single document. 
 
If electronic signatures are permitted per local institutional guidelines, an electronic documentation of the 
consent process is permissible.  

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10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause.  
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study participants, investigator, funding agency, the Investigational New 
Drug (IND) sponsor and regulatory authorities.  If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform study participants, the reviewing single Institutional Review 
Board (sIRB), local IRB, and sponsor and will provide the reason(s) for the termination or suspension.  Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
• 
Cessation of in-person clinical activities due to a pandemic or other catastrophe 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, sIRB and/or Food and Drug Administration (FDA). The DCC will ensure that sites follow 
local, state, and institutional requirements regarding cessation and restart of Human Subjects research during 
the COVID19 pandemic or other natural disaster and collect IRB approvals, as indicated. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s). This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No information concerning the 
study or the data will be released to any unauthorized third party without prior written approval of the 
sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the single Institutional 
Review Board (sIRB), regulatory agencies or company supplying study product may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a period 
as dictated by the reviewing sIRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at the NASH CRN Data Coordinating Center. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be identified by a 

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unique study identification number. The study data entry and study management systems used by clinical sites 
and by the NASH CRN Data Coordinating Center research staff will be secured and password protected. At the 
end of the study, all study databases will be de-identified and archived at the NASH CRN Data Coordinating 
Center and NIDDK Central Repository.  
 
To further protect the privacy of study participants, the research is covered under a Certificate of 
Confidentiality by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to research records 
to refuse to disclose identifying information on research participation in any civil, criminal, administrative, 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies by 
helping assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the NASH CRN Data Coordinating Center. After the 
study is completed, the de-identified, archived data will be transmitted to and stored at the NIDDK Central 
Repository, for use by other researchers including those outside of the study. Permission to transmit data to 
the NIDDK Central Repository will be included in the informed consent.  
 
With the participant’s approval and as approved by the single Institutional Review Boards (sIRB), de-identified 
biological samples will be stored at the NIDDK Central Biorepository with the same goal as the sharing of data 
with the NIDDK Central Repository. These samples could be used to research the causes of NASH, its 
complications and other conditions for which individuals with NASH are at increased risk, and to improve 
treatment. The NIDDK Central Repository will also be provided with a code-link that will allow linking the 
biological specimens with the phenotypic data from each participant, maintaining the blinding of the identity 
of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have biological 
specimens stored for future research. However, withdrawal of consent with regard to biosample storage may 
not be possible after the study is completed.  
 
When the study is completed, the NIDDK Central Repository will provide oversight for the access to and use of 
study data and/or samples. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Independent Medical Monitor 
Arun J. Sanyal, MD 
Victor Chen, MD  
Virginia Commonwealth 
University Medical Center  
Johns Hopkins University 
West Hospital, 14th Floor 
1200 East Broad Street 
Box 980341 
Richmond, VA 23298 
1830 E Monument St 
Baltimore, MD 21205 
(804) 827-0716 
(410) 550-1793 
Arun.sanyal@vcuhealth.org 
pchen37@jhmi.edu 

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NASH CRN Executive Committee (EC)- Consists of NASH CRN chairperson, SC representatives, principal 
investigator of the Data Coordinating Center, safety officer, NIDDK program official, and NIDDK project 
scientist. The NASH CRN EC discusses directions and strategic issues related to the scientific aims of the NASH 
CRN, organizes and sets agenda for Steering Committee meetings, and provides oversight of the study.  
 
NASH CRN Steering Committee (SC) – Consists of principal investigators of each of the clinical centers, the 
principal investigator of the Data Coordinating Center, the co-chairs of the Pathology Committee (who share 
one vote), the chair of the Radiology Committee, and the NIDDK project officer, each of whom has one vote in 
any decision requiring formal vote. Ex officio members include NIDDK scientific staff.  The NASH CRN SC is the 
major decision making body for NASH CRN, which provides oversight in planning and conduct of the study.  
The SC votes on all important decisions and approves the final protocol and any amendments or modifications 
of the protocol.  
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including gastroenterology, hepatology, cardiology and statistics. 
Members of the DSMB are independent from the study conduct and free of conflict of interest, or measures 
should be in place to minimize perceived conflict of interest.   
 
An Independent Medical Monitor and an independent Data and Safety Monitoring Board (DSMB), appointed 
by the NIDDK, will review the protocol for the VEDS trial and monitor the safety data as the trial progresses to 
ensure patient safety and to review efficacy. The DSMB is a multidisciplinary group with a written charge 
provided by the NIDDK. The DSMB reports to the NIDDK, which will communicate DSMB recommendations to 
the investigators, as appropriate. The DSMB will hold a meeting to approve the protocol. The DSMB will review 
performance and safety data. The DSMB may request more frequent meetings if necessary to fulfill its charge. 
It may also request additional safety reports on a more frequent basis. For example, all serious adverse events 
are reported to the DSMB for their consideration and recommendations as they occur.  
 
Interim data on safety measures requested by the DSMB are reviewed at each of the scheduled semi-annual 
full meetings. Serious adverse events will be reviewed by the DSMB as they occur with the option of a 
teleconference discussion if any DSMB member so requests. 
 
The DSMB will review quarterly reports by masked treatment groups of incident hepatotoxicities, as well as 
counts of patients who required more frequent liver function testing due to rises in ALT levels of more than 2 
times baseline ALT or beyond 300 U/L. The DSMB will also examine the trends in ALT or AST levels for each 
patient who experiences a rise in ALT. 
 
The DSMB also reviews the overall progress of the trial in terms of recruitment and data quality and makes a 
formal recommendation to the NIDDK at the end of each scheduled meeting as to whether the trial should 
continue unmodified, continue with protocol modifications, or be stopped. 
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in 
compliance with the currently approved protocol/amendment(s), with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).  
 

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• 
Monitoring for this study will be performed by the NASH CRN DCC.  
• 
To ensure data quality, the DCC will incorporate into the data entry programs a series of edit checks, 
including range checks, logic checks (e.g., skip patterns), and consistency checks, both within a data 
form and across forms.  These integral checks are designed to detect deficiencies in the data before 
they are saved into the study database, so that the deficiencies may be easily and accurately corrected 
as they are being entered.  In addition, the DCC will perform frequent computerized edit checks on 
entered data.  The DCC will also perform ongoing comparisons of copies of source documents with the 
databases to ensure that data entered into the data system reflect those recorded on the source 
documents.  Such database validations will help to pinpoint problems that cannot be detected by 
computer editing and may be used to guide increased scrutiny when needed.  Any data queries 
identified will be flagged for action by the clinical site until resolved.  
• 
The data system will maintain a clear and complete audit trail of all changes to the study databases.  
All changes to data forms will be documented appropriately on the source document and entered into 
NASH CRN data system.  All forms entered and/or edited in the data system will be identified by the 
PIN of the operator, the network address (the “IP” address) of the computer being used, and the date 
and time of the operation.  Records will not be deleted but rather marked as having been superseded. 
• 
Performance monitoring: The web-based data system will allow for real-time reporting of most 
recruitment and data management activities.  However, additional performance reports will be 
generated and circulated monthly and typically reviewed at each Steering Committee (SC) meeting.  
These reports include several key indicators of study performance, including counts of patients 
screened and randomized, of completed visits and of missing key data, of missed visits, and statistics 
summarizing performance with respect to timeliness of data entry and response to data queries. 
• 
The SC and the DSMB will conduct a formal review of the study by webinar twice a year and will 
address quality assurance as part of their agenda.  These committees will have responsibility for 
recommending corrective actions based on the performance data.  It is anticipated that the primary 
responsibility for formulating and implementing these actions will reside in the SC.  Potential actions 
might include specific recommendations for training, redistribution of study resources, or possibly 
termination of support for a center. 
• 
Independent audits outside the DCC will not be conducted. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks 
that will be run on the database will be generated. Any missing data or data anomalies will be communicated 
to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the NASH CRN monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice 
(ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports 
for the purpose of monitoring and auditing by the NASH CRN, and inspection by local and regulatory 
authorities. 
 

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10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.   
 
Hard copies of the study visit worksheets will be printed by clinics for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report form 
(eCRF) derived from source documents should be consistent with the data recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions data) 
and clinical laboratory data will be entered into the 21 CFR Part 11-compliant electronic data capture system. 
The data system includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Under the HIPAA Privacy rule, investigators must maintain study records for 7 years after the study ends or 7 
years after the last disclosure of identifiable health information from study records, whichever is later. 
 
10.1.10 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Standard Operating Procedures (SOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a result 
of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 10 working days of the scheduled 
protocol-required activity.  All deviations must be addressed in study source documents and reported to 
NIDDK Program Official and the Data Coordinating Center. Protocol deviations must be sent to the reviewing 
single Institutional Review Board (sIRB) and the local Institutional Review Board (IRB) per their policies. The site 
investigator is responsible for knowing and adhering to the reviewing sIRB and local IRB requirements. Further 
details about the handling of protocol deviations will be included in the SOP. 
 
10.1.11 PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations and the policies of the NASH CRN: 

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National Institutes of Health (NIH) Public Access Policy ensures that the public has access to the published 
results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that 
arise from NIH funds to the digital archive PubMed Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical 
Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial 
will be registered at ClinicalTrials.gov, and the results of this trial will be submitted to ClinicalTrials.gov. In 
addition, every attempt will be made to publish results in peer-reviewed journals.  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 endpoint.  
 
 
10.1.12 CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, conduct, 
analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have 
a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to 
their participation in the design and conduct of this trial.  The NASH CRN leadership in conjunction with the 
NIDDK has established policies and procedures for all study group members to disclose all conflicts of interest 
and will establish a mechanism for the management of all reported dualities of interest. 
 
 

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10.2 ADDITIONAL CONSIDERATIONS 
10.2.1 WHOLE BLOOD DRAW SCHEDULE (AMOUNTS IN ML) 
 
 
 
Study visit 
 
Procedure 
S 
RZ 
F04 
F08 
F12 
F24 
F28 
F36 
F48 
Total 
Fasting glucose 
and insulin 
5 
- 
5 
5 
5 
5 
5 
5 
5 
40 
Fasting lipid 
5 
- 
- 
- 
5 
5 
- 
- 
5 
20 
Complete 
blood count 
5 
- 
- 
- 
- 
5 
- 
- 
5 
15 
Clinical 
chemistry 
5 
- 
- 
- 
- 
5 
- 
- 
5 
15 
Hepatic panel 
5 
- 
5 
5 
5 
5 
5 
5 
5 
40 
PT, aPTT, INR 
5 
- 
- 
- 
- 
5 
- 
- 
5 
15 
HbA1c 
5 
- 
- 
- 
- 
5 
- 
- 
5 
15 
C-Reactive 
Protein 
1 
- 
- 
- 
1 
1 
- 
- 
1 
4 
Plasma 
10 
- 
- 
- 
10 
10 
- 
- 
10 
40 
Serum 
20 
- 
- 
- 
20 
20 
- 
- 
20 
80 
Other 
screening* 
20 
- 
- 
- 
- 
- 
- 
- 
- 
20 
PSA (males 
only) 
1 
- 
- 
- 
- 
- 
- 
- 
1 
2 
Total 
86 
(87) 
0 
10 
10 
46 
66 
10 
10 
66 
(67) 
304 
(362) 
VEDS study visits are fasting visits and need to be scheduled for early morning. Fasting is defined as 
nothing by mouth except water in the 12 hours prior to blood draw. 
* Etiologic tests as needed 
 

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10.3 ABBREVIATIONS 
 
A1AT 
Alpha-1-antitrypsin 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AMA 
Antimitochondrial antibody 
ANA 
Antinuclear antibody 
ANCOVA 
Analysis of Covariance 
aPTT 
Activated partial thromboplastin time 
ASMA 
Anti-smooth muscle antibody 
AST 
Aspartate aminotransferase 
AUDIT 
Alcohol Use Disorders Identification Test 
BMI 
Body mass index (kg/m2) 
BUN 
Blood urea nitrogen 
CC 
Clinical center 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRN 
Clinical Research Network 
CRP 
C-reactive Protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DCS 
Data Collection Schedule 
DSMB 
Data and Safety Monitoring Board 
EC 
Executive Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyltransferase 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IMM 
Independent Medical Monitor 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
MCV 
Mean corpuscular volume 
NAFL 
Nonalcoholic fatty liver 
NAFLD 
Nonalcoholic fatty liver disease 
NAS 
Nonalcoholic fatty liver disease activity score 
NASH 
Nonalcoholic steatohepatitis 

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NCT 
National Clinical Trial 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PT 
Prothrombin time 
QC 
Quality Control 
SAE 
Serious Adverse Event 
sIRB 
Single Institutional Review Board 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
ULN 
Upper limit of normal 
UP 
Unanticipated Problem 
US 
United States 
WBC 
White blood cell count 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.1 
08 May 20 
Add pregnancy test at 24 weeks and 
delete z-score 
Changes requested by DSMB 
1.2 
07 Aug 20 
Change study drug information 
throughout 
New study drug supplier: 
Pharmavite 
1.3 
25 May 21 
Corrections made throughout for 
additional study drug information 
provided, adjusted dosing scheme, 
and language compliant with sIRB 
requirements. 
Updated information available 
2.0 
28 Jul 21 
Corrections and additions made 
throughout in response to FDA 
comments 
Requested by FDA 
2.1 
01 Apr 22 
Allowances for remote 
visits/procedures. 
Updated exclusion criteria regarding 
HCV. Remove baseline data 
collection listed that is inconsistent 
with the data collection schedule. 
Add CRP to data collection schedule. 
Updated language pertaining to the 
data system mechanics. 
Need for limitations to in-
person contact. Corrections 
throughout for inconsistencies 
or clarification. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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