Alcoholic Hepatitis Network Observational Study
Conditions: Alcoholic Hepatitis
Sponsor: Indiana University

 
 
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AlcHepNet Consortium 
Clinical Study Protocol  
 
Protocol Title 
 
 
 
 
 
 
ALCOHOLIC HEPATITIS NETWORK OBSERVATIONAL STUDY  
 
Protocol Number 
AlcHepNet 01 
Version 3: March 9, 2021  
 
Primary Sponsor 
National Institute of Alcohol Abuse and Alcoholism 
 
 
Participating Sites 
Indiana University, IN (PI: Kavish Patidar) 
University of Louisville affiliated hospitals in Kentucky (PI: Craig McClain), 
Beth Israel Deaconess Medical Center (PI: Gyongyi Szabo), 
Mayo Clinic in Rochester, Minnesota (PI: Vijay Shah), 
Cleveland Clinic Foundation, Ohio (PI: Srinivasan Dasarathy), 
University of Pittsburgh Medical Center in Pennsylvania (PI: Ramon Bataller), 
University of Texas at Southwestern in Dallas, Texas (PI: Mack Mitchell), 
Virginia Commonwealth University in Richmond, Virginia (PI: Arun Sanyal) 
 
 
 
 
 
 
 
 
 
 
GCP Statement: This study will be performed in compliance with GCP, 
including the archiving of essential documents. 
 

 
 
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SPONSOR’S approval of the protocol 
 
Reviewed and Approved by: 
 
 
 
 
_____________________________                        ______________________ 
Samer Gawrieh, MD 
 
 
 
       Date 
 
Primary Investigator (Indiana University) 
 
 
 
 
 
Investigator’s Affirmation 
 
I have received and read the current version of the AlcHepNet-01 protocol. I understand 
that no data are to be made public or published without prior knowledge and written 
approval by the AlcHepNet Steering Committee. By my signature below, I hereby attest 
that I have read, understood and agreed to abide by all the conditions, instructions and 
restrictions contained in protocol AlcHepNet- 01 and in accordance with Good Clinical 
Practice (CPMP/ICH/135/95), 21CFR Part 312 and all applicable regulatory 
requirements. I acknowledge that the Steering Committee of the AlcHepNet Consortium 
has the right to discontinue this observational trial at any time. 
 
 
 
 
______________________________ 
Investigator’s Name (Printed) 
 
 
______________________________ 
 
     _______________________ 
Investigator’s Signature 
 
 
     Date 
 
 
 
 
 
 
 

 
 
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Table of Contents 
 
 
 
Page 
Number 
Ethical Conducts of the Study and Regulatory Requirements 
7 
Executive Summary 
8 
Key Inclusion/Exclusion Criteria 
10 
Research Strategy 
13 
Study Procedures 
16 
Management and Storage of Biosamples 
22 
Participant Compensation 
22 
Participant Recruitment 
22 
Development and Management of Data Collection 
 
22 
Statistical Analysis 
23 
Reporting Adverse Events 
 
24 
Length of Study 
 
24 
 
 
 
Tables 
 
Table 1:   
Abbreviations 
Table 2:  
Study procedures during the baseline and follow up visit 
 
 

 
 
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Table 1: Abbreviations 
 
 
AASLD 
American Association for the Study of Liver Disease 
AAH 
Acute alcoholic Hepatitis 
AE(s) 
Adverse event(s) 
AGA 
American Gastroenterological Association alcoholic hepatitis  
  
AH 
Alcoholic Hepatitis 
AKI 
Acute kidney injury 
ALT 
Alanine aminotransferase 
ALP 
Alkaline Phosphate 
AST 
Aspartate aminotransferase 
AUDIT 
Alcohol use disorder identification test 
BL 
Baseline 
BMP 
Basic metabolic panel 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of federal regulations 
CLDQ 
Chronic liver disease questionnaire 
CRA 
Clinical research associate 
CRF 
Case report form 
DCC 
Data coordinating center 
DCC-IU 
Data coordinating center-Indiana University 
dL 
Deciliter(s) 
DSMB 
Data and safety monitoring board 
ER 
Emergency room 
FDA 
Food and Drug Administration 

 
 
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GCP 
Good clinical practice 
HIV 
Human immunodeficiency virus 
HIV RNA 
Human immunodeficiency virus ribonucleic acid 
ICF 
Informed consent form 
ICU 
Intensive care unit 
IgM 
Immunoglobulin M 
IRB 
Institutional review board 
IU/L 
international units per liter 
IV 
Intravenous 
MAP 
Mean arterial pressure 
MELD 
Model for end stage liver disease 
mg 
Milligram(s) 
mL 
Milliliter(s) 
mm Hg 
Millimeter of mercury 
mmol/l 
Millimoles per liter 
NAFLD 
Nonalcoholic fatty liver disease 
NASH 
Nonalcoholic steatohepatitis 
NDB 
Nutritional database 
NIAAA 
National Institute of Alcohol Abuse and Alcoholism 
NIH 
National Institute of Health 
PBC 
Primary biliary cirrhosis 
SAE 
Serious adverse event 
U/L 
Units per liter 
ULN 
Upper limit(s) of normal 
US 
United States (of America) 
Vs 
Versus 
WBC 
White blood cell 

 
 
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WIRB 
Western Institutional Review board 
 
 

 
 
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1. 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
REQUIREMENTS 
 
1.1 
Institutional Review Board (IRB) 
The study protocol and any amendments will be reviewed by Western Institutional 
Review Board (WIRB). WIRB will review the informed consent form, their updates (if 
any), and any written materials given to the subjects. A list of all IRB and contact 
information will be included in the study report. 
1.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki, in compliance with the approved protocol, GCP 
and applicable regulatory requirements. 
1.3 
Subject Information and Consent 
The investigator will obtain a freely given written consent from each subject or 
authorized representative after an appropriate explanation of the aims, methods, 
anticipated benefits, potential hazards, and any other aspects of the study that are 
relevant to the subject's decision to participate. The consent form must be signed and 
dated by the subject before he/she is exposed to any protocol-specific procedure. 
The investigator will explain that the subjects are completely free to refuse to enter the 
study or to withdraw from it at any time, without any consequences for their further 
care and without the need to justify. 
The patient will receive a copy of the patient information and the signed informed 
consent. 
The patient will be informed if information becomes available that may be relevant to 
his/her willingness to continue participation in the study. 
Each subject will be informed that a monitor or a health authority inspector, in 
accordance with applicable regulatory requirements, may review the portions of their 
source records and source data related to the study. Data protection and 
confidentiality will be handled in compliance with local laws. 

 
 
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2. 
EXECUTIVE SUMMARY 
 
Title 
ALCOHOLIC HEPATITIS NETWORK OBSERVATIONAL STUDY 
 
Study Type 
Prospective, observational study 
 
Investigational Sites 
Indiana University in Indianapolis, IN, University of Louisville affiliated hospitals in 
Louisville, KY, Beth Israel Deaconess Medical Center (BIDMC) in Boston, MA, Mayo 
Clinic in Rochester, MN, Cleveland Clinic Foundation, in Cleveland, OH, University of 
Pittsburgh Medical Center in Pittsburgh, PA, University of Texas at Southwestern in 
Dallas, TX, and Virginia Commonwealth University in Richmond, VA. 
 
Planned Number of Patients 
Approximately 1260 (720 subjects with alcoholic hepatitis (AH), 360 heavy drinkers 
without significant liver disease, and 180 healthy controls) will be enrolled. 
 
2.1 Objectives 
 
Primary Objective: To collect and store clinical data to facilitate investigations of the 
epidemiology, diagnosis, pathophysiology, natural history, and treatment of alcoholic 
hepatitis. 
 
Secondary Objective: To develop a bio-specimen bank comprised of plasma, serum, 
PBMC, saliva, DNA, urine, stool, liver biopsy and other biological specimens obtained 
from patients with alcoholic hepatitis, heavy drinkers without clinical liver disease, and 
healthy subjects to support translational research in the pathophysiology of alcoholic 
hepatitis. 
 
2.2 Methodology 
 
Screening phase: Subjects will be assessed for the eligibility criteria and a written 
informed consent will be obtained from the eligible subjects. 
Study phase: Subjects will undergo history taking, physical examination, 
questionnaire 
administration, 
and 
laboratory 
tests. 
Biosamples 
including 
serum/plasma, peripheral mononuclear cells (PBMC) (at select sites), genomic DNA, 
stool samples (when available), urine, saliva (until an adequate number of samples 
are collected from all sites), and liver tissue (when available) will be obtained. 
Follow up phase: Alcoholic hepatitis subjects will be followed for 24 weeks in study 
and then every 24 weeks for a maximum of 5 years, Heavy drinking controls for 24 
weeks, and healthy controls subjects for 1 day (at initial meeting for baseline). 
 
 

 
 
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2.3 Duration of the study 
Up to 5 years 
 
2.4 Biosample Repository 
 
Plasma/serum 
Peripheral blood mononuclear cells (PBMC) (collected at select sites)  
Genomic DNA 
Urine (when available) 
Saliva (until an adequate number of samples are collected from all sites) 
Liver tissue (when available)  
Stool (when available) 
 
 
 

 
 
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3. 
KEY INCLUSION/EXCLUSION CRITERIA 
 
CASES: Heavy drinkers with alcoholic hepatitis 
Inclusion criteria 
1. A clinical diagnosis of alcoholic hepatitis as defined by the NIAAA pan-consortia 
for AH:  
a) Onset of jaundice (defined as serum total bilirubin >3 mg/dL) within the prior 8 
weeks to screening visit  
b) Regular consumption of alcohol with an intake of > 40 gm daily or >280gm 
weekly on average for women and > 60 gm daily or >420gm weekly on average 
for men for 6 months or more, with less than 8 weeks of abstinence before 
onset of jaundice  
c) AST > 50 IU/l  
d) AST:ALT > 1.5 and both values < 400 IU/l  
e) and/or histological evidence of AH* 
2. Serum total bilirubin >3 mg/dL 
3. Subject or guardian ability to understand and willingness to provide written consent 
4. Age greater or equal to 21 years 
5. Re-enrolment of an alcoholic hepatitis donor is permissible up to 4 times if the 
donor presents with a new episode of alcoholic hepatitis 24 weeks or longer after 
the most recent enrolment in the study 
 
Exclusion criteria 
1. Liver disease significantly caused by hemochromatosis, autoimmune liver disease, 
Wilson disease, and acute viral hepatitis (NOTE: The presence of chronic hepatitis 
C, hepatitis B, HIV, or stage 1 (one lesion <2 cm) HCC is not exclusion to 
participation) 
2. Pregnant or breast feeding 
3. Received liver transplant 
4. Based on the judgment of the investigator, subject is not capable of understanding 
or complying with the study requirements 
 
CONTROLS: Heavy drinkers without significant liver disease 
 Inclusion criteria 
1. History of chronic alcohol consumption sufficient to cause liver damage. Generally, 
this is considered to be >40 g/day or >280g/week on average for women and >60 
g/day or >420 g/week on average for men, for 6 months or more, with less than 8 
weeks of abstinence. Judgement about chronic alcohol consumption will be made 
by the site investigator. 
2. Subject or guardian ability to understand and willingness to provide written consent 
3. Age greater or equal to 21 years 
 
Exclusion criteria 
1. Past evidence of alcoholic liver disease, defined as a bilirubin > 2.0 mg/dL, an AST 
> 1.5 ULN, and any hospital admission for liver disease, or the presence of 

 
 
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esophageal varices or ascites (at any time in the past) 
2. Liver disease significantly caused by hemochromatosis, autoimmune liver disease, 
Wilson disease, NAFLD, and acute viral hepatitis (NOTE: The presence of chronic 
hepatitis C, hepatitis B, or HIV is not exclusion to participation.) 
*Individuals with a diagnosis of Gilbert’s can have total bilirubin up to 3.0 mg/dL and 
still be eligible for participation. 
 
3. Alcohol intake at less than 40 g/day or 280g/week on average for women and 60 
g/day or 420 g/week on average for men for longer than the past 28 days 
4. If liver stiffness has been assessed within the prior 90 days, then stiffness 
suggesting fibrosis of F1 or greater is excluded. For Fibroscan, this is a fibrosis 
score >7.0 kPa. 
5. Received liver transplant 
6. Pregnant or breast feeding 
7. Any of the following laboratory abnormalities within 90 days prior to signing the 
consent. 
a) Total bilirubin: >ULN* 
b) INR: > 1.4 
 
Healthy Controls 
 
Inclusion criteria 
1. AUDIT-C scores of <4 for men and <3 for women (signifying no alcohol misuse) 
2. Abstinent (consumption of less than one standard drink/week) during the 6 months 
prior to enrolment 
3. Ability to understand and willingness to provide written consent. 
4. Age greater or equal to 21 years 
Exclusion criteria 
1. Clinical history or laboratory evidence of liver disease including alcoholic liver 
disease, NAFLD, hemochromatosis, alcoholic hepatitis, autoimmune liver disease, 
Wilson disease, hepatitis C, or hepatitis B. 
2. Presence of diabetes (requiring treatment with oral agents or insulin). 
3. Significant heart disease (prior history of heart disease, other than hypertension) 
4. Chronic lung disease (requiring chronic treatment) 
5. Immune related conditions (such as Crohn’s disease, rheumatoid arthritis, 
ulcerative colitis, systemic lupus erythematosus, severe psoriasis, etc.) 
6. Known infection with HIV 
7. Presumed infection, or use of antibiotics or other medications (e.g., corticosteroids) 
that would affect immune function, within the past 14 days 
8. BMI>35 
9. Current or known history of cancer (except in situ carcinoma of the cervix or 
adequately treated basal or squamous cell carcinoma of the skin) within 5 years 
prior to enrollment 
10. Received liver transplant 

 
 
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11. Pregnant or breast feeding 
12. Any of the following laboratory abnormalities within 90 days prior to signing the 
consent. 
a. Hemoglobin: <10 g/dL 
b. Conjugated bilirubin: > ULN 
c. INR: > 1.4 
d. AST:  >40 IU/mL 
e. ALT:  >40 IU/mL 
13. Based on the judgment of the investigator, subject is not capable of complying with 
the study requirements 
 
 

 
 
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4. RESEARCH STRATEGY 
 
4.1 Background and Significance 
 
Alcoholic liver disease (ALD) is a complex disorder and its pathogenesis is a multi-
step and multi-factorial process that progresses through a series of histopathological 
changes [1]. More than 90% of drinkers develop alcoholic steatosis which is reversible 
upon abstinence. 
However, if alcohol abuse continues, the disease may progress to alcoholic hepatitis 
(AH), advanced fibrosis, and cirrhosis in up to 10-15% of heavy drinkers [2;3]. It is 
completely unknown why some heavy drinkers develop AH and what determines the 
severity of the condition. These questions can only be answered by studying sufficient 
numbers of patients with AH as well as heavy drinkers at risk for AH, and developing 
clinical studies testing basic pathophysiological mechanisms. 
 
While alcoholic steatosis is a reversible condition, AH is associated with significant 
morbidity and mortality [4;5]. In mild cases, patients may recover with conservative 
medical management and alcohol abstinence. Those with more severe cases of AH; 
however, have a high mortality rate [6;7]. Using the National Inpatient Sample data, 
we reported that AH accounted for 0.7% of all inpatient admissions in the United 
States. The average length of stay (LOS) was 7 days and nearly 7% died during 
hospitalization. Of importance, hospitalized AH patients result in significant healthcare 
cost and utilization [8]. The average total charges during hospitalization for AH were 
$37,769; which was higher than that from acute myocardial infarction (~$16,200), 
acute cerebrovascular disease (~$11,100), and acute pancreatitis ($9,870). Costs per 
hospitalization and cost adjusted for LOS were higher in those who died during the 
hospital stay, presumably from more severe forms of AH ($84,642 and $11,754/day, 
respectively) [8]. These data were obtained during a period of time when current best 
therapy (corticosteroids or pentoxifylline) was in broad use [9]; thus, they confirm the 
disease burden of AH in the US and attest that better understanding of pathogenesis 
and treatment of AH are urgently needed to improve patients’ outcome. 
 
The collection of clinical information and biosamples in subjects with AH are very 
crucial to pursue research and advance the science in the field of alcoholic liver 
disease. The current protocol provides a system to uniformly obtain demographics, 
clinical information, and biological samples from AH subjects and well-matched 
controls with heavy alcohol use without clinical presentation of AH and heathy controls 
for future investigations. In addition, they will serve as the potential subjects to be 
enrolled in the future clinical trials of the AlcHepNet consortium. 
 
 

 
 
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4.2  Study Objectives 
 
Primary Objectives: To collect and store clinical data to facilitate investigations of the 
epidemiology, diagnosis, pathophysiology, natural history, and treatment of alcoholic 
hepatitis. 
 
Secondary Objectives: To develop a bio-specimen bank comprised of plasma, 
serum, PBMC, saliva, stool, urine, liver biopsy, DNA, and other biological specimens 
obtained from patients with alcoholic hepatitis, heavy drinkers without clinical liver 
disease, and healthy subjects to support translational research in the pathophysiology 
of alcoholic hepatitis. 
 
4.3 
Research and study procedures 
 
4.3.1 Target enrollment: 
 
90 patients with AH, 45 Heavy drinkers without significant liver disease and 22-23 
healthy controls will be enrolled at each site. They will be followed for 24 weeks 
following their enrollment. The cohort will be characterized demographically, 
anthropometrically, clinically, through laboratory tests, and histologically wherever 
applicable. 
 
4.3.2 Definitions: 
 
Subjects with AH: We plan to enroll 720 patient with AH. The diagnosis of AH will be 
established on published criteria [6;10] and  this  is  based  on  history  of  heavy  
alcohol  consumption  (defined  as >40 g/day or >280g/week on average for women 
and >60 g/day or >420 g/week on average for men for 6 months or more, with less 
than 8 weeks of abstinence before onset of jaundice), clinical evaluation and 
appropriate laboratory testing (as defined as total bilirubin > 3 mg/dL and AST > 40 
U/L). When the diagnosis of AH remains in question, a liver biopsy (if clinically feasible 
and subject has no contra-indications) will be required. A sizable proportion of 
individuals with AH have co-existing viral hepatitis or HIV, and there is an unmet need 
in terms of understanding the nature of their liver disease and to develop suitable 
therapies. Therefore, we plan to enroll patients with AH in special population infected 
with chronic HBV, chronic HCV, or HIV. 
 
Heavily Drinking Controls: We plan to enroll 360 heavy drinking controls without 
significant evidence of liver disease at the time of recruitment. For this application, 
heavy alcohol drinking will be defined as >40 g/day or >280g/week on average for 
women and >60 g/day or >420 g/week on average for men  for 6 months or more, with 
less than 8 weeks of abstinence before onset of jaundice. Heavy drinkers, who have 
just become abstinent within prior 2 weeks, including those we convince to seek 
alcohol abuse/addiction treatment as part of the recruiting process, are eligible for 
enrollment. The study team (investigators-coordinators) will emphasize to both 

 
 
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alcoholic hepatitis subjects and heavy drinking subjects the importance of abstinence 
from alcohol and encourage them to seek an alcohol abuse/addiction treatment. We 
envision that some of these subjects will maintain sobriety and can serve to 
demonstrate the results of withdrawal from alcohol; some will relapse to drinking, and 
resemble non-treatment seeking heavy drinkers over 24 weeks. Control subjects must 
meet the following criteria: (INR < 1.4 and total bilirubin levels must ≤ULN (If bilirubin 
is increased due to a suspected Gilbert’s Syndrome, patient may be still be enrolled; 
(2) no prior history of known alcoholic liver disease; and (3) absence of 
hepatosplenomegaly (from physical examination or radiographic imaging) or stigmata 
of liver disease. 
 
Healthy Controls: Approximately 180 healthy donors will be recruited to serve as a 
comparison group.  
 
4.3.3 Recruitment of Subjects with AH: 
 
Subjects with AH will be site specific. 
 
4.3.3 Recruitment of controls: 
 
Heavy drinking controls and Healthy Controls will be site specific. 
 
4.3.4 Matching strategies 
 
We will perform approximate frequency matching for recruiting control subjects using 
age, gender and race.  The purpose of frequency matching is to ensure similar enough 
distributions between case and control groups to allow for appropriate statistical 
adjustment in the analyses. For every 30 heavy drinking controls the Data 
Coordinating Center (DCC) will evaluate the distribution of age (categories: 20-40, 41-
60, 61-80, >80), gender, race (whites, blacks, others) overall and at each site. We will 
then compare that to the distributions of already recruited cases to determine if the 
distributions in age, gender, and race are similar. If the controls differ markedly, the 
DCC will instruct the coordinators to concentrate on recruiting the underrepresented 
groups in the control cohorts. The distribution of matching variables in the case and 
control groups will be re-examined periodically (approximately every 30 heavy drinking 
controls) and the control subjects will be recruited based on the updated distributions 
of demographic variables, as needed. 
 
4.3.5 Variables and Data to be collected: 
 
We will collect the following clinical details from subjects with AH and their controls 
(as appropriate). The detailed data collection and the questionnaires that we will use 
are outlined in the case report form (CRF). 
a) Demographics and anthropometric measures: These variables characterize the 
study cohort. 
b) Medical History: Detailed past medical history including prior history of AH. Specific 

 
 
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attention will be paid to collecting family history of alcohol abuse and alcoholic liver 
disease and history of bariatric surgery. 
c) Medicinal history: A medication review of prescription and over the counter 
medications will be completed 
d) Detailed alcohol consumption history: We will use AUDIT, AUDIT-C and Time Line 
Follow-Back Questionnaires (TLFB) for quantifying alcohol consumption [11;12]. 
e) Quality of life: We will use the Chronic Liver Disease Questionnaire (CLDQ) for 
quantifying quality of life. 
f) Signs and symptoms associated with liver disease and routine laboratories. These 
include the presence of ascites, jaundice, varices, and hepatic encephalopathy. 
Additionally, the subject’s HBV, HCV and HIV status will be recorded, if available. 
g) Discriminant factor (DF), Model for End Stage Liver disease (MELD) score, and 
Child- Pugh score will be calculated [7].  
 
5. STUDY PROCEDURES 
 
The study consists of two parts, a baseline phase and a follow-up phase. 
 
5.1Baseline Phase 
 
All subjects: 
Patients will sign the consent and data will be collected on demographics, ethnicity, 
clinical characteristics, alcohol history, anthropometric measures, biosamples 
(Plasma/serum, peripheral blood mononuclear cells [at select sites], genomic DNA, 
urine [when available], stool [when available], saliva and liver tissue [where available] 
will be collected and stored). 
 
5.2 Follow up visits 
 
Alcoholic hepatitis cases: will be seen at (week 4), (week 12), (week 24). During these 
follow-up visits, data on clinical characteristics, alcohol use, and biosamples will be 
obtained. If a patient misses a follow-up visit, the patient will be called and the data 
will be collected from their medical records (if available). Cases will then be followed 
until the end of study after their final visit (week 24) by checking their medical record. 
Vitality status will also be checked via National Death Index to ensure survival status 
could be collected for subjects who could not be followed through medical record 
review. 
 
Heavy drinking controls without significant liver disease: The second part consists of 
a follow-up visit during week 24, data on clinical characteristics, alcohol use, and 
biosamples will be obtained. 
 
Healthy Controls: There will be no follow-up visits

 
 
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Table 2. Study procedures during the baseline and follow up visit. 
 
 
Procedures 
Baseline1 
Week 4 
(D15 - 
D56) 
Week 12 
(D57 - D 
126) 
Week 24 
(D127 - D 252) 
Every 24 weeks 
for a maximum 
of 5 years 
Source of data 
Patient visit 
& medical 
records 
Patient visit, 
medical 
records 
±phone call 
Patient visit, 
medical 
records 
±phone call 
Patient visit, 
medical 
records 
±phone call 
Medic
al 
Recor
ds  
Group 
AH, Drinking 
Controls, 
and Healthy 
Controls 
AH 
AH 
AH and 
Drinki
ng 
Contro
ls 
AH 
Informed Consent 
X 
Demographics 
X 
Anthropometric 
measurements 
X 
  X 
  X 
  X 
Vital Signs 
X 
X 
X 
X 
Medical history 
X 
Alcohol use History  
X 
X 
X 
X 
Questionnaires3 
X 
 X 
 X 
 X 
Con-Med Review 
X 
X 
X 
X 
Events of Special 
Interest5 
X 
X 
X 
General PE 
X 
PE (liver-related) 
X 
X 
X 
Blood tests and other procedures 
Hepatic Function 
X 
X 
X 
X 
Basic metabolic panel 
X 
X 
X 
X 
Hematology/CBC 
X 
X 
X 
X 
Coagulation/INR 
X 
X 
X 
X 
Infection screen2 
X 
Imaging/X-ray2 
X 
Endoscopy2 
X 
Fibroscan or other4 
X 
X 
Pregnancy Test, Urine 
X 
X 
X 
X 
Research Specimen Collection+ 
Plasma 
X 
X 
X 
X 
Serum 
X 
X 
X 
X 
Stool (when available) 
 X 
  X 
  X 
 X 
Saliva6 
 X 
 X 
Urine (when available)  
X 
X 
X 
X 
Liver Biopsy (when 
available)  
 X 
  X 
  X 
  X 
PBMC (optional by site) 
 X 
  X 
  X 
  X 
DNA (if patient consents) 
X 
Survival, from medical 
records, phone call or 
death indices 
X 
1For patients with AH, data obtained prior to start of treatment for AH. If patient did not receive 
specific treatment for AH, then data obtained as early as possible after admission to hospital. 
2Data will be recorded only if it has been obtained as standard of care. 
3 Questionnaires include timeline follow back (TLFB), AUDIT- C, AUDIT, and Chronic Liver Disease 
Questionnaire. TLFB will be the only questionnaire done at follow-up visits  
 4Assessment of liver fibrosis includes Fibroscan, ARFI, MRE and others, and will be recorded if they were 
performed as SOC. 

 
 
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5 Events of special interest include complications of liver disease, such as variceal bleeding, new/worsening  
hepatic encephalopathy, acute kidney injury, new/worsening ascites, and infections. 
6 Saliva will only be collected until an adequate number of samples are collected from all sites. 
           + Specimen collection at baseline can be collected and processed 24-48 hours after enrollment 
 
 
 

 
 
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5.2.1 Baseline Evaluations: 
 
Prospectively enrolled patients will undergo baseline evaluations. The below 
procedures/evaluations will be performed during the baseline phase: 
 
• Obtain Consent 
• Verify Inclusion/Exclusion Criteria 
• Obtain Background Information 
- 
Patient Profile (age, gender, race, ethnicity, etc.) 
- 
Complications of Liver Disease 
- 
Physical Examination 
- 
Medication Review 
- 
Family history of alcohol use/ complications 
- 
Liver Biopsy History 
- 
History of alcoholism counselling/treatment 
• Anthropometric Measurements 
• Vitals 
• Timeline Follow back 
• AUDIT/AUDIT-C 
• Chronic Liver Disease Questionnaire 
• Collect all samples below as outline in Table 2 
• Collection of 60 mls of blood for research (Plasma/Serum and peripheral blood 
mononuclear cells [at select sites]) 
• Collection of 15 mls of blood for standard biochemistry tests (CBC, Platelet count, 
INR and CMP) if not already completed as standard of care. 
• Collection of saliva 
• Collection of a urine sample (when available) 
• Collection of stool sample (when available) 
• Collection of liver tissue (when available) 
• Perform a Laboratory Examination All Subjects: 
An examination of the medical record for laboratory results of the following tests will 
be conducted. If the laboratory tests have been completed as standard of care within 
the timeframe specified, those results will be used. If laboratory results are not 
available, these tests will be completed as part of the baseline phase. 
 
Within 30 days of visit: 
- 
Complete Blood Count (CBC)  
- 
Hepatic Function 
- 
International Normalized ratio (INR)  
- 
Basic metabolic panel (BMP) 
 
Optional tests: (data collected only if completed as standard of care within the 
timeframe specified): 
• Infection screen 
• Imaging/X-ray 

 
 
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• Endoscopy 
• Fibroscan  
 
5.2.2 Follow-up visits evaluations: 
 
Alcoholic hepatitis subjects and heavy drinkers without clinical liver disease controls 
will also be seen for a follow-up visit at week 4, 12, and 24 from the date of their 
“baseline visit”. At the follow-up visit the below procedures/evaluations will be 
performed. 
• Physical Examination 
• Medication Review 
• History of alcoholism counselling/treatment 
• Review of complications of liver disease 
• Laboratory examination 
• Anthropometric Measurements 
• Vitals 
• Timeline Follow back 
• Collect all samples below as outlined in Table 2 
• Collection of 60 mls of blood for research(Plasma/Serum and peripheral blood 
mononuclear cells [at select sites]) 
• Collection of 15 mls of blood for standard biochemistry tests (CBC, Platelet count, 
INR and CMP) if not already completed as standard of care. 
• Collection of saliva 
• Collection of a urine sample (when available) 
• Collection of stool sample (when available) 
• Collection of liver tissue (when available) 
• Perform a Laboratory Examination All Subjects: 
An examination of the medical record for laboratory results of the following tests will 
be conducted. If the laboratory tests have been completed as standard of care within 
30 days of the visit, those results will be used. If laboratory results are not available, 
these tests will be completed as part of the follow up visit. 
 
- 
Complete Blood Count (CBC) 
- 
Hepatic function 
- 
International Normalized ratio (INR) 
- 
Basic metabolic panel (BMP) 
 
Optional tests: (data collected only if completed as standard of care within the 
timeframe specified): 
• Infection screen 
• Imaging/X-ray 
• Endoscopy 
• Fibroscan  
 
 

 
 
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 5.2.3 Exemptions to the Eligibility Criteria: 
 
Exemptions may be allowed on a case by case basis for individuals narrowly missing 
the eligibility criteria. Exemptions may be sought either for cases or controls. Requests 
for exemptions should be initiated by the clinical center PI using an Exemptions Form 
which explains the rationale for seeking the exemption. Each request for the 
exemption will be reviewed by two investigators not associated with the site requesting 
the exemption. An exemption will be granted only if both reviewers agree to allow the 
exemption. 
 
 

 
 
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1. MANAGEMENT AND STORAGE OF BIOSAMPLES: 
 
Plasma/serum, peripheral blood mononuclear cells, genomic DNA, saliva, urine (when 
available), stool samples (when available), and liver tissue (where available) will be 
collected at individual sites and shipped on a quarterly basis to be stored at the AH 
Tissue Bank at the University of Massachusetts until they are needed for translational 
studies, or the study is complete. 
 
2. PARTICIPANT COMPENSATION  
 
Participant compensation is site specific. 
 
3. PARTICIPANT RECRUITMENT  
 
Avenues of recruitment will be site specific for example: website, flyers, social media, 
craigslist, studykik, newspaper, and newsletters. 
 
4. DEVELOPMENT AND MANAGEMENT OF DATA COLLECTION 
 
The data coordinating unit will be operated under the auspices of the Indiana CTSI 
Dr. Barry Katz from the Department of Biostatistics, with an MS level biostatistician 
and an experienced data manager will run the data coordinating unit. The data 
coordinating unit will work with the steering committee and other study personnel, and 
will be responsible for establishing and/or conducting the following: 
 
• Configure and set up the prospective, multicenter, observational study of 
patients with well characterized AH and suitable controls, within the 
CTMS/EDC as well as each of the smaller studies to be carried out by the 
consortium; 
• Design specific case report forms and set up patient calendar and schedule; 
• Review and test the system for the large prospective observational study and 
each of the smaller studies configured within the CTMS/EDC; 
• Define and develop Standard Operating Procedures (SOPs) such as a process 
for paper- based or electronic data capture including instructions for data entry 
for participating sites, quality control procedures, data dictionary standards, 
reporting AEs/SAEs, etc.; 
• Develop and implement study-specific quality assurance procedures to ensure 
data integrity; 
• Write a data monitoring plan for the observational study and the randomized 
studies; 

 
 
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• Establish a process to facilitate/conduct audits for participating sites; audits will 
be done electronically and/or in person at the site, as needed; 
• Provide appropriate training and/or educational material to project team 
members on specific aspects of each clinical study including data management 
and statistics; 
• Prepare an implementation (“go live”) plan for each study and facilitate this plan; 
• In collaboration with the site study coordinators, provide assistance in the 
oversight of screening, enrollment, randomization, and data collection; this 
includes monitoring patient recruitment, compliance with visit schedules and 
retention. 
• Coordinate periodic protocol review visits to sites on as needed basis; 
• Monitor of study sites to ensure accurate execution of protocols; 
• Prepare and distribute data reports to summarize performance of participating 
sites; 
• Prepare data monitoring, performance and safety reports for interim monitoring 
by the steering committee, DSMB, or governmental agency; 
• Submit DSMB reports of adverse events to IRBs; 
• Perform final data audits and any necessary edits and prepare files for analysis; 
• Coordinate data analysis with study and/or site deadlines; 
• Perform appropriate statistical analyses and provide overall coordination for 
preparing the analysis and results needed for submitting abstracts and 
manuscripts 
• Implement plans for final disposition of study data 
• Monitor for adherence to agreed-upon patient close-out procedures 
 
10. STATISTICAL ANALYSIS 
 
Subjects’ demographics, anthropometric measurements, medical history, alcohol 
consumption, lab test results, MELD score, quality of life, and other variables will be 
summarized by groups (case vs. control groups) and by visits. Mean and 95% 
confidence intervals will be calculated for continuous variables for each group. 
Proportion and frequency will be used to describe the categorical variables by groups. 
Two-sample t-tests will be used to compare the continuous variables and Chi-square 
tests will be used to compare the categorical variables by groups at each visit. 
Appropriate nonparametric test will be used if there is normal assumption violation. All 
the tests will be performed using SAS 9.3(Cary, NC). 
 
More importantly, this aim serves as the backbone for conducting future clinical, 
mechanistic, biomarker discovery, therapeutic, and natural history studies. After a 

 
 
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structured process of requesting ancillary study proposals from consortium 
investigators, submitted proposals will be assessed for feasibility and scientific merit. 
For studies selected, a formal statistical plan will be developed that will include 
statistical models and methods to be used to address each specific aim of the study. 
Methods may be simple parametric or nonparametric methods for two-group 
comparisons such at t-tests or rank tests or may involve complex multivariable 
methods such as linear, logistic, or Poisson regression modeling. Each proposal must 
specify the primary and secondary outcomes. Sample size calculations associated 
with the primary analysis must be given, including clear specification of the outcome 
measure, error rates (Type I / II), minimal clinical important difference, and statistical 
power of at least 0.8. The expect amount and methods for dealing with missing data 
must be specified. Questions requiring longitudinal data analyses should apply 
statistical methods that account for, as applicable, time to events, repeated 
measurements, counts, or other discrete measurements. For time to event data, Cox 
proportional hazards regression model with appropriate covariates will be used. For 
hypotheses involving repeated measurements or discrete events, we will use either 
generalized linear models with generalized estimating equations or multilevel 
generalized linear mixed models with random coefficients. 
 
11. 
REPORTING OF ADVERSE EVENTS 
 
Reporting of adverse events, unanticipated problems involving risks to participants 
or others, and noncompliance will be reported to the Data Monitoring and Safety 
Board (DSMB), Western Institutional Review Board (IRB) and institutional IRBs 
when applicable per its Standard Operating Procedures. 
 
12. 
LENGTH OF STUDY 
 
We anticipate that we can accomplish the target enrollment within the 5 years of 
funding cycle.