Clinical trial NCT02655510
Conditions: Alcoholic Hepatitis
Sponsor: Mayo Clinic
Start date: 2016-02-01; Completion date: 2018-06-30
Enrollment: 18 participants; Allocation: ; Intervention model: SEQUENTIAL

Brief summary:
Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. The pathogenesis is not completely understood. Patients who are severely affected present with subacute onset of fever, hepatomegaly, leukocytosis, marked impairment of liver function (e.g., jaundice, coagulopathy), and manifestations of portal hypertension (e.g., ascites, hepatic encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any symptoms.

Alcoholic hepatitis usually persists and progresses to cirrhosis if heavy alcohol use continues. If alcohol use ceases, alcoholic hepatitis resolves slowly over weeks to months, sometimes without permanent sequelae but often with residual cirrhosis.

F-652 is a recombinant fusion protein containing human interleukin 22 (IL-22) and human Immunoglobulin G2 (IgG2)-Fc produced in CHO cells in serum-free culture. F-652 under development is intended to treat patients with graft vs host disease (GvHD) after bone marrow transplantation, and acute alcoholic hepatitis (AAH), a severe form of alcoholic liver disease (ALD). Both GvHD and AAH are diseases with unmet medical need. The current investigational new drug (IND) application is to conduct a phase Ia clinical study in GvHD patients to evaluate the safety and pharmacokinetic profile, and biomarkers of F-652 treatment by intravenous infusion (IV).

IL-22 is a member of the IL-10 family of cytokines which control bacterial infection, homeostasis, and tissue repair. IL-22 may be used to treat patients with ALD because of its antioxidant, anti-apoptotic, anti-steatotic, anti-microbial, and proliferative effect that have been demonstrated in various experimental systems.

Detailed description:
IL-22 is a member of the IL-10 family of cytokines which control bacterial infection, homeostasis, and tissue repair. IL-22 may be used to treat patients with ALD because of its antioxidant, anti-apoptotic, anti-steatotic, anti-microbial, and proliferative effect that have been demonstrated in various experimental systems.

The sponsor has developed F-652, a recombinant human IL-22 IgG2 Fc fusion protein produced in serum-free culture of Chinese Hamster Ovary (CHO) cells. F-652 is able to protect tissue from damage and enhance tissue repair during the inflammation process and infection by activation of STAT3 mediated by the interleukin-22 receptor subunit 1 (IL-22R1) expressed on epithelial cells such as hepatocytes.

Arms: arm 1: Participants will receive 10 μg/kg, 30 μg/kg or 45 μg/kg of F-652 on Day 1 and Day 7 via slow intravenous infusion. Three patients with MELD 11-20 will receive 10 μg/kg of F-652. Pharmacokinetic testing will be completed on these subjects. If evaluations demonstrate safety and efficacy signals, the next 3 patients will receive 30 μg/kg. If pharmacokinetic testing demonstrates safety and efficacy signals, the next 3 patients will receive 45 μg/kg. After demonstrating absence of side effects in this group, patients in MELD 21-28 will follow the same dose escalation regiment as the MELD 11-20 group.
Interventions: intervention 1: F-652
Intervention descriptions: intervention 1: Participants will receive 10 μg/kg, 30 μg/kg or 45 μg/kg of F-652 on Day 1 and Day 7 via slow intravenous infusion. Three patients will receive 10 μg/kg of F-652. Pharmacokinetic testing will be completed on these subjects. If evaluations demonstrate safety and efficacy signals, the next 3 patients will receive 30 μg/kg. If pharmacokinetic testing demonstrates safety and efficacy signals, the next 3 patients will receive 45 μg/kg.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
An Open-Label, Cohort Dose 
Escalation Study to Assess the 
Safety and Efficacy Signals of F-
652 in Patients with Alcoholic 
Hepatitis 
 
NCT02655510 
 
June 7, 2017 


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CLINICAL TRIAL PROTOCOL 
 
An Open-Label, Cohort Dose Escalation Study to Assess the Safety 
and Efficacy Signals of F-652 in Patients with Alcoholic Hepatitis 
 
 
 
 
Version 3.0 
 
IND Number:  IND 127276 
 
Date:  07Jun2017 
 
Principal Investigator:  Dr. Vijay Shah (Mayo Clinic) 
 
 
Co-Investigators:  Mayo Clinic:  Drs. Gregory Gores, Patrick S. Kamath, Douglas Simonetto, 
Naveen Gara, Hugo Vargas and Liu Yang; Indiana University:  Drs. Naga Chalasani, Suthat 
Liangpunsakul, Raj Vuppalanchi and David Crabb; Virginia Commonwealth University:  Drs. 
Puneet Puri and Arun Sanyal 
 
 
Disclosure 
 
 
This study is conducted by the TREAT (Translational Research and Evolving Alcoholic 
Hepatitis Treatment) Consortium which is funded by the National Institute of Alcohol Abuse and 
Alcoholism (NIAAA) to pursue translational investigations in alcoholic hepatitis.  The TREAT 
Consortium is made up of investigators from Indiana University School of Medicine 
(Indianapolis, IN), Mayo Clinic (Rochester, MN) and Virginia Commonwealth University 
(Richmond, VA).  Study drug will be provided by Generon (Shanghai) Corporation, Ltd. 
 
Some of the information contained herein is the property of Generon (Shanghai) Corporation, 
Ltd. and may not be reproduced, published, or disclosed to others without written authorization 
of Generon (Shanghai) Corporation, Ltd. 
 
 
 
 


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General Information 
 
 
 
Study Drug Provided by: 
 
Generon (Shanghai) Corporation Ltd.  
 
 
 
 
Suite 111, Building 9  
787 Kangqiao Road  
Shanghai, China 
 
 
 
 
86-21- 5132-0626 (Telephone) 
 
 
 
 
86-21- 5132-0623 (Fax) 
 
 
 
 
yanxq@generonbiomed.com 
 
Chief Medical Officer 
 
and Principal Investigator: 
Dr. Vijay Shah 
 
 
 
 
Mayo Clinic 
 
 
 
 
200 1st St SW 
 
 
 
 
Rochester, MN 55905 
 
Co-Investigators:  
 
Drs. Patrick S. Kamath, Douglas Simonetto and Gregory Gores 
 
 
 
 
Mayo Clinic 
 
 
 
 
200 1st St SW 
 
 
 
 
Rochester, MN 55905 
 
Dr. Hugo Vargas 
 
 
 
 
Mayo Clinic- Arizona 
5777 East Mayo Boulevard 
Phoenix, AZ 85054 
 
Dr. Liu Yang 
 
 
 
 
Mayo Clinic- Florida 
 
 
 
 
4500 San Pablo Rd S  
Jacksonville, FL 32224 
 
 
 
 
 
Dr. Naveen Gara 
Mayo Clinic Health System- Mankato 
1025 Marsh St. 
Mankato, MN 56001 
 
Drs. Naga Chalasani, Suthat Liangpunsakul, Raj Vuppalanchi and David Crabb 
 
 
 
 
Indiana University 
 
 
 
 
550 University Boulevard 
Indianapolis, IN 46202 
 
 
 
 
 
Drs. Arun Sanyal and Puneet Puri 
 
 
 
 
Virginia Commonwealth University 
 
 
 
 
401 North 11th Street 
Richmond, VA 23298 
 
 
Clinical Operations: 
 
Kevin Dreyer 
Generon (Shanghai) Corporation 
kfdgeneron@gmail.com 
(732) 261-0986 (c) 
(732) 291-9828 (o) 


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Table of Contents 
1 
INTRODUCTION .............................................................................................................................................. 6 
1.1 
BACKGROUND .................................................................................................................................................. 6 
1.2 
INVESTIGATIONAL AGENT................................................................................................................................ 7 
1.3 
PRECLINICAL DATA ......................................................................................................................................... 8 
1.4 
CLINICAL DATA TO DATE ................................................................................................................................ 9 
1.5 
RISKS/BENEFITS ............................................................................................................................................. 11 
1.6 
DOSE RATIONALE: ......................................................................................................................................... 12 
1.7 
TRIAL CONDUCT ............................................................................................................................................ 13 
1.8 
POPULATION .................................................................................................................................................. 13 
1.9 
POWER CALCULATION ................................................................................................................................... 14 
2 
STUDY OBJECTIVES .................................................................................................................................... 15 
2.1 
TRIAL DESIGN: ............................................................................................................................................... 15 
2.2 
STUDY DESIGN/TYPE ..................................................................................................................................... 20 
2.3 
PRIMARY STUDY ENDPOINTS/SECONDARY ENDPOINTS ................................................................................. 22 
2.4 
TRIAL TREATMENT ........................................................................................................................................ 22 
2.5 
REMUNERATION ............................................................................................................................................. 22 
2.6 
DURATION...................................................................................................................................................... 22 
2.7 
DISCONTINUATION ......................................................................................................................................... 23 
2.8 
PRODUCT ACCOUNTABILITY .......................................................................................................................... 23 
2.9 
DATA IDENTIFICATION ................................................................................................................................... 23 
3 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL................................................................ 23 
3.1 
INCLUSION CRITERIA ..................................................................................................................................... 23 
3.2 
EXCLUSION CRITERIA .................................................................................................................................... 23 
3.4 
SUBJECT WITHDRAWAL ................................................................................................................................. 24 
3.5 
DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN SUBJECTS ............................................................... 25 
4 
STUDY DRUG ................................................................................................................................................. 25 
4.1 
DESCRIPTION ................................................................................................................................................. 25 
4.2 
PACKAGING, LABELING AND STORAGE .......................................................................................................... 26 
4.3 
TREATMENT REGIMEN ................................................................................................................................... 26 
4.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................................. 27 
4.5 
IMMUNOGENICITY TESTING ........................................................................................................................... 28 
5 
ASSESSMENT OF EFFICACY SIGNALS .................................................................................................... 28 
5.1 
EFFICACY PARAMETERS ................................................................................................................................. 28 
5.2 
METHOD AND TIMING .................................................................................................................................... 28 
6 
ASSESSMENT OF SAFETY .......................................................................................................................... 29 
6.1 
SAFETY VARIABLES ....................................................................................................................................... 29 
6.2 
METHOD AND TIMING .................................................................................................................................... 30 
6.3 
ADVERSE EVENT REPORTING ......................................................................................................................... 30 
6.4 
RECORDING OF ADVERSE EVENTS ................................................................................................................. 33 
6.5 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................... 33 
6.6 
SPONSOR-INVESTIGATOR REPORTING: NOTIFYING THE MAYO IRB ............................................................... 34 
6.7 
SPONSOR-INVESTIGATOR REPORTING: NOTIFYING THE FDA ........................................................................ 34 
6.8 
STOPPING RULES ............................................................................................................................................ 37 
6.9 
INDIVIDUAL STOPPING RULES ........................................................................................................................ 37 
7 
STATISTICAL PLAN ...................................................................................................................................... 38 
7.1 
STATISTICAL METHODS ................................................................................................................................. 38 
7.2 
TERMINATION CRITERIA ................................................................................................................................ 38 
7.3 
DEVIATION REPORTING ................................................................................................................................. 38 


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8 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ..................................................................... 39 
9 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................................. 39 
9.1 
MONTHLY CHECK FOR COMPLETENESS AND EDITS ......................................................................................... 39 
9.3 
FORM AUDITS ................................................................................................................................................ 39 
9.4 
PERFORMANCE MONITORING ......................................................................................................................... 40 
9.5 
SITE VISITS .................................................................................................................................................... 40 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ......................................................................... 40 
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 40 
10.2 
DATA AND SAFETY MONITORING BOARD (DSMB) FOR THE TREAT CONSORTIUM ................................. 41 
10.3 
AUDITING AND INSPECTING ....................................................................................................................... 41 
11 
ETHICAL CONSIDERATIONS ..................................................................................................................... 41 
12 
DATA HANDLING AND RECORD KEEPING ............................................................................................ 42 
12.1 
CONFIDENTIALITY ..................................................................................................................................... 42 
12.2 
SOURCE DOCUMENTS ................................................................................................................................ 42 
12.3 
CASE REPORT FORMS ................................................................................................................................ 43 
12.4 
DATA MANAGEMENT AND PROCESSING .................................................................................................... 43 
12.5 
DATA SECURITY AND CONFIDENTIALITY .................................................................................................. 44 
12.6 
DATA QUALITY ASSURANCE ..................................................................................................................... 44 
12.7 
DATA CLARIFICATION PROCESS ................................................................................................................ 44 
12.8 
RECORDS RETENTION ................................................................................................................................ 44 
13 
FINANCE AND INSURANCE ....................................................................................................................... 45 
15 
LIST OF PLANNED LABORATORY ANALYTES ....................................................................................... 46 
16 
REFERENCES ................................................................................................................................................ 47 


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List of Abbreviations 
 
 
Ab 
Antibody 
AH 
Alcoholic hepatitis 
ALB 
Albumin 
ALD 
Alcoholic liver disease 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BMI 
Body Mass Index 
cGMP 
Current good manufacturing practice 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
ConA 
Concanavalin A 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CV 
Coefficient of variation 
DP 
Drug product 
DS 
Drug substance 
ECG 
Electrocardiogram 
FAS 
Fatty acid synthase  
FDA 
Food and Drug Administration of United States 
FIB 
Fibrinogen  
GI 
Gastrointestinal  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GvHD 
Graft vs host disease 
HBV 
Hepatitis B virus  
HCC 
Hepatocellular carcinoma 
HCT 
Hematocrit 
HCV 
Hepatitis C virus  
HFD 
High fat diet 
HGB 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
IgG 
Immunoglobulin G 
IL-22 
Interleukin 22 
IND 
Investigational New Drug 
IP 
Intraperitoneal 
IRB 
Institutional review board  
IV 
Intravenous  
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MELD 
Model for End Stage Liver Disease 
MHV 
Mouse hepatitis virus 


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NIAAA 
National Institute on Alcohol Abuse and Alcoholism 
PK 
Pharmacokinetics 
PLT 
Platelets 
PTSD 
Post-Traumatic Stress Disorder 
RBC 
Red blood cells 
SAA 
Serum amyloid A 
SAMe 
S-adenosylmethionine 
SC 
Subcutaneous  
SD 
Standard deviation 
STAT 
Signal transducer and activator of transcription 
TBil 
Total bilirubin 
USP 
The United States Pharmacopeia 
WBC 
White blood cell 
 
 
 
 


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Investigator’s Affirmation 
 
I have received and read the current version of the Investigator’s Brochure (IB) for F-652 and 
this protocol (TREAT-008).  Having fully considered all the information available, I agree that it 
is ethically justifiable to give F-652 to selected subjects/patients according to this protocol. 
 
I understand that all information concerning F-652 supplied to me by the TREAT Consortium 
and from Generon Corporation Ltd. and not previously published is confidential.  This includes 
the IB, Clinical Trial Protocol, Case Report Forms (CRF) and any other preclinical and clinical 
data. 
 
I understand that no data are to be made public or published without prior knowledge and written 
approval by the TREAT 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 TREAT-008 and in accordance 
with Good Clinical Practice and all applicable regulatory requirements. 
 
I acknowledge that the Steering Committee of the TREAT Consortium has the right to 
discontinue this trial at any time. 
 
 
 
 
 
_____________________________________ 
Investigator’s Name (Printed) 
 
 
 
 
_____________________________________ 
 
 
_______________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
 


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Study Summary 
Title 
An Open-Label, Cohort Dose Escalation Study to Assess the Safety and Efficacy 
Signals of F-652 in Patients with Alcoholic Hepatitis 
Protocol Number 
TREAT- 008 
Phase 
Clinical Study Phase 1b-2a 
Methodology 
Cohort dose escalation study 
Overall Study 
Duration 
Approximately three years 
Subject 
Participation 
Duration 
Estimated duration of participation is up to 56 days. 
Single or Multi-
Site  
A multi-center clinical trial by the TREAT consortium. 
Objectives 
a. 
Assess the safety and tolerability of F-652 in patients with alcoholic hepatitis 
as determined by absence of unexpected serious adverse events up to Day 42 
or Day 56 following administration of first dose of study drug. 
b. 
Determine the pharmacokinetics (PK) and pharmacodynamics (PD) of F-652 
in patients with alcoholic hepatitis. 
c. 
Assess the efficacy signals of F-652 in patients with alcoholic hepatitis 
(compared to historical patient data) as determined by : 
A. Clinical: improvement in clinical status 
B.  Biochemical: Improvement in liver biochemistry, MELD and Lille scores 
at days 7, 28, 42 and 56. 
C. Biomarkers of Il 22 activity (CRP, SAA, triglycerides), 
Number of 
Subjects 
Up to 18 participants at approximately six sites. 


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Diagnosis and 
Main Inclusion 
Criteria 
Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated 
with long-term heavy intake of ethanol. The pathogenesis is not completely 
understood7.  Patients who are severely affected present with subacute onset of fever, 
hepatomegaly, leukocytosis, marked impairment of liver function (e.g., jaundice, 
coagulopathy), and manifestations of portal hypertension (e.g., ascites, hepatic 
encephalopathy, variceal hemorrhage). However, milder forms of alcoholic hepatitis 
often do not cause any symptoms. 
 
To participate in this study, patients must meet all of the following criteria: 
 
1. Able to provide written informed consent (either from patient or patient’s 
legally acceptable representative) 
2. Male or female patients 21 years of age or older 
3. Patients with alcoholic hepatitis defined as:  
a. History of heavy alcohol abuse use: >40 g/day in females and 
>60 g/day in males for a minimum period of 6 months AND 
b. Consumed alcohol within 6 weeks of entry into the study AND 
c.  Serum bilirubin > 3mg/dL AND AST >ALT, but less than 500 
U/L 
d. MELD score between 11-28 
e. Liver biopsy will be carried out to confirm diagnosis in all 
patients except those who meet criteria a-c and in whom 
other causes of liver disease have been excluded (viral, 
drug, autoimmune etc). 
4. Women of child-bearing potential must utilize appropriate birth control. 
 
*Patients on steroids and/or pentoxifylline will not be excluded from the study. 
Study Product, 
Dose, Route, 
Regimen 
F-652 with a dose escalation regimen using 10 μg/kg, 30 μg/kg and 45 μg/kg. 
Duration of 
Administration 
Participants will be given a dose of F-652 on Day 1 and Day 7 of the study.  
Following demonstration of safety with the Day 1 and Day 7 dose in the patient 
group with MELD score 21-28, a 3rd dose of the maximum tolerated dose will be 
administered on Day 14  
Reference 
therapy 
There is not a standard reference therapy or placebo against which the study product 
is being compared. 
Statistical 
Methodology 
Detailed methodology for summary and statistical analyses of the data collected in 
this trial will be documented in a Statistical Analysis Plan, which will be 
implemented by the Indiana University Data Coordinating Center. This document 
will expand upon and may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. In this cohort dose escalation study all statistical 
tests will be two-sided with no adjustment for multiplicity.  
 
Descriptive summaries of variables will be provided where appropriate. For 
continuous variables, the number of non-missing values (n) and the median, mean, 
standard deviation, minimum, and maximum will be summarized. For categorical 
variables, the number and percent of each variable will be summarized. All collected 
data will be presented in listings.  
 


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1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic 
research policies and procedures.  The described study will be conducted in compliance 
with the protocol, Good Clinical Practices standards and associated Federal regulations, 
and all applicable institutional research requirements.   
1.1 Background 
 
Alcohol-related liver disease is a major cause of morbidity and mortality in the US, and is 
the third leading preventable cause of death in the US.  In general, the risk of alcoholic 
liver disease increases with the quantity and duration of alcohol intake.  Alcoholic liver 
disease encompasses a clinical/histologic spectrum of disease including fatty liver, 
alcoholic hepatitis, and cirrhosis.  While fatty liver is a benign and generally reversible 
condition with abstinence or moderation, further progression to alcoholic hepatitis is 
more ominous.  One in five heavy drinkers develops alcoholic hepatitis, and among these 
patients, one in four develops cirrhosis. 
 
Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated 
with long-term heavy intake of ethanol. The pathogenesis is not completely understood.  
Patients who are severely affected present with subacute onset of fever, hepatomegaly, 
leukocytosis, marked impairment of liver function (e.g., jaundice, coagulopathy), and 
manifestations of portal hypertension (e.g., ascites, hepatic encephalopathy, variceal 
hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any 
symptoms.  
 
The characteristic clinical manifestation of AH is new onset jaundice, often accompanied 
by malaise, tender hepatomegaly, and hepatic decompensation (ascites, encephalopathy 
and variceal bleeding). Patients are diagnosed to have alcoholic hepatitis in the presence 
of:  
a. History of heavy alcohol abuse use: >40 g/day in females and >60 g/day in 
males for a minimum period of 6 months 
b. Consumed alcohol within 6 weeks of entry into the study 
c. Serum bilirubin > 3mg/dL AND AST >ALT, but less than 500 U/L 
 
Serum bilirubin is > 3 mg/dL (and, in most patients, is >5 mg/dL). AST is elevated (>40 
IU/mL), and AST>ALT ratio is typically more than 1.5. When the AST exceeds 500 
IU/mL other liver diseases such as drug induced liver injury (DILI) and ischemic 
hepatitis need to be excluded.  Imaging may be required to exclude biliary obstruction. 
Viral hepatitis, autoimmune liver disease, and Wilson disease also need to be excluded.  
If these conditions (biliary obstruction and viral, drug, or autoimmune disease) are 
excluded in a patient with alcohol abuse and liver test abnormalities outlined earlier,  
fewer than 10% of patients will have a diagnosis other than alcoholic hepatitis. 


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A liver biopsy is required for confirmation of ASH for all patients with clinically-
diagnosed AH who have one or more of the following possible confounding factors: 
1. Possible ischemic hepatitis (e.g., severe upper gastrointestinal bleed, hypotension, 
or cocaine use within the prior 7 days) 
2. Possible drug-induced liver injury/jaundice 
3. Recent sepsis (i.e., infection requiring antibiotics within the prior 7 days) 
4. Uncertain alcohol assessment (e.g., patient denies recent/excessive alcohol use) 
5. Atypical laboratory tests (e.g., AST < 40 IU/mL or >500 IU/mL, AST/ALT ratio 
<1.5.  
 
Alcoholic hepatitis usually persists and progresses to cirrhosis if heavy alcohol use 
continues. If alcohol use ceases, alcoholic hepatitis resolves slowly over weeks to 
months, sometimes without permanent sequelae but often with residual cirrhosis.  
 
Corticosteroids have been utilized as a standard of care in various treatment guidelines 
for patients with severe alcoholic hepatitis, as manifested by hepatic encephalopathy or a 
Maddrey Discriminant Function > 32.  However, their applicability in clinical practice is 
limited in “special populations” of patients who have contraindications to corticosteroids 
and/or fall into subcategories of patients who were not included in the corticosteroid 
treatment trials that formed the basis of these treatment guidelines.  These special 
populations are substantial and include patients with renal failure, infection, GI bleed, 
pancreatitis, and viral hepatitis.  Pentoxifylline has also been used because of its safety, 
but several well-conducted studies have not supported the efficacy of pentoxifylline for 
the treatment of severe AH. A recent study has questioned the efficacy of both 
prednisone and pentoxifylline inn the treatment of alcoholic hepatitis. Mortality at 6 
months was similar in patients on either prednisone, pentoxifylline, or both as compared 
with placebo. Therefore, there is a need for investigational therapies. 
 
Translational investigations are needed on new mechanisms and suitable pharmacological 
agents relevant to alcoholic hepatitis (AH). This study is one of five studies of a 
consortium that includes Indiana University, Virginia Commonwealth University, and 
Mayo Clinic (Translational Research and Evolving Alcoholic Hepatitis Treatment; 
TREAT Consortium).  This study is being funded by a grant from the National Institute 
on Alcohol Abuse and Alcoholism (NIAAA), one of the institutes that comprise the 
National Institutes of Health (NIH).   
 
Generon (Shanghai) Corporation, Ltd. is the sponsor of the Investigational New Drug 
application (IND 121673) for F-652 in graft versus host disease (GvHD).  Generon is 
providing the investigational medicinal product, F-652, for this study. 
1.2 Investigational Agent 
 
F-652 is a recombinant fusion protein consisting of human interleukin 22 (IL-22) and 
human IgG2 Fc fragments. F-652 is glycosylated with an apparent molecular weight of 
approximately 101.97 kDa and is produced in CHO cells with serum-free medium. F-652 
has an immunoglobulin-like structure with an IL-22 dimer at the N-terminal. Therefore, 


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F-652 is expected to have the same mechanism of action as the native or recombinant IL-
22 described in literatures, but with extended and/or improved pharmacokinetics and 
pharmacodynamics properties due to the addition of human Fc fragments at the C-
terminal.  
1.3 Preclinical Data 
 
F-652 under development is intended to treat patients with graft vs host disease (GvHD) 
after bone marrow transplantation, and acute alcoholic hepatitis (AAH), a severe form of 
alcoholic liver disease (ALD).  Both GvHD and AAH are diseases with unmet medical 
need.  The current investigational new drug application is to conduct a phase 1b-2a 
clinical study in alcoholic hepatitis patients to evaluate the safety and pharmacokinetic 
profile, and measures biomarkers associated with treatment with F-652 which is 
administered by intravenous infusion (IV).  
 
IL-22 is a member of the IL-10 family of cytokines which control bacterial infection, 
homeostasis, and tissue repair. IL-22 may be used to treat patients with ALD because of 
its antioxidant, anti-apoptotic, anti-steatotic, anti-microbial, and proliferative effect that 
have been demonstrated in various experimental systems (Gao 89-93; Gao and Bataller 
1572-85). 
 
Alcoholic hepatitis (AH) is a severe form of ALD and includes a spectrum that ranges 
from mild injury to severe, life threatening injury.  The prevalence of AH has not been 
accurately determined; it is believed to occur in 10% to 35% of heavy drinkers. On 
histology, AH is characterized by infiltration of the liver by inflammatory cells and 
hepatocellular injury. AH is usually associated with progressive fibrosis in the presence 
of continued alcohol abuse.  No new drugs for ALD have been successfully developed 
since the introduction of corticosteroids as a treatment in the early 1970s. Therefore, 
development of novel therapeutics to treat ALD, especially for AH remains a tremendous 
challenge. Based on the current accumulated knowledge of IL-22 biology, the sponsor 
believes that IL-22 could be used for the treatment of ALD.  
 
Several publications have described the protective role of IL-22 in hepatitis in various 
animal models.  In the ConA and carbon tetrachloride (CCl4)-induced liver injury mouse 
model, injection of rmIL22 ameliorated the elevated serum levels of ALT and AST.  
Delivery of IL-22-expressing plasmid in the liver significantly reduced the elevated 
serum levels of ALT, AST and apoptotic damage in these models.   In an alcoholic 
hepatitis mouse model, mice fed with ethanol exhibited elevated serum levels of ALT, 
AST and TG.  Administration of IL-22 adenovirus ameliorated the elevation of serum 
AST, ALT as well as the TG level in the liver.  In the HFD-induced liver steatosis mouse 
model, administration of rmIL-22 not only reduced liver steatosis, but also down-
regulated SREBP1-c and HMGCR, key enzymes for the synthesis of triglyceride and 
cholesterol, and the mRNA level of FAS, a critical modulator for de novo lipogenesis.  
The efficacy of IL-22 in mitigating liver injury induced by alcohol, CCl4 and high fat diet 
was clearly demonstrated.  
 


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In developing recombinant IL-22 for human therapeutic use, it is anticipated that the 
restriction of IL-22 receptors (IL-22 R1) to epithelial cells, such as hepatocytes, would 
also limit the potential side effects. Corticosteroids, which are widely used to treat AH, 
have well-documented side effects that include increased risk of infection. Therefore, 
Corticosteroids and IL-22 could be a good combination treatment for AH because IL-22 
might overcome the corticosteroid-mediated promotion of infection. For this study, 
concomitant steroid use is therefore not an exclusion criterion.  IL-22could potentially 
also be used as monotherapy for AH due to its unique biology acting specifically on 
epithelial cell types.   
 
The sponsor has developed F-652, a recombinant human IL-22 IgG2 Fc fusion protein 
produced in serum-free culture of Chinese Hamster Ovary (CHO) cells.  F-652 is able to 
protect tissue from damage and enhance tissue repair during the inflammation process 
and infection by activation of STAT3 mediated by the IL-22R1 expressed on epithelial 
cells such as hepatocytes.  
 
The efficacy of F-652 was demonstrated in the acute liver injury models including ConA 
and MHV-A59-induced murine hepatitis.  In monkey models of alcohol-induced liver 
steatosis with and without CCl4 treatment, F-652 was able to reduce hepatic steatosis and 
serum levels of ALT and AST.  F-652 demonstrated a favorable safety profile in acute 
and long-term (3-month) toxicity studies in rats and monkeys with a large safety window.  
 
Administration of pharmacological doses of F-652 could benefit patients with alcoholic 
hepatitis, and is unlikely to induce immunological complications since the specific IL-22 
R1 is not expressed on immune or hematopoietic cells.  
1.4 Clinical Data to Date 
 
A Phase I randomized double-blind, placebo-controlled, single dose escalating study of 
F-652 was conducted in healthy male volunteers for the evaluation of the safety, 
tolerability and pharmacokinetics (PK) of this drug. A total of 40 subjects were enrolled 
in the study. F-652 was administered subcutaneously (2 μg/kg) or placebo, and 
intravenously (IV; 2, 10, 30, 45 μg/kg) or placebo. Safety evaluations were conducted 
during the study including adverse events (AEs), physical examination, clinical safety 
laboratory (hematology, biochemistry, coagulation panel, immunological test, urinalysis), 
vital signs and 12-lead electrocardiogram (ECG). PK endpoints were derived from the 
serum concentration-time profile of F-652: total exposure (area under the curve), 
maximum serum concentration, time at maximum concentration, last measurable serum 
concentration, time at last measurable concentration, clearance, volume of distribution, 
elimination half-life, accumulation ratio and dose proportionality.  
 
A total of 41 treatment-emergent adverse events (TEAEs) were reported in 23 subjects 
(58%). All TEAEs reported were mild or moderate in severity. There were no severe or 
life threatening AEs, or any SAEs reported. Twenty-six TEAEs were considered related 
to F-652. Fewer TEAEs were reported following F-652 dosing via IV compared to 
subcutaneous at the 2 μg/kg dose level. TEAEs reported following 2.0 μg/kg IV dosing 


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were all mild in severity, while three moderate events were reported following 2.0 μg/kg 
subcutaneous dosing. This indicated that the study subjects better tolerated IV dosing. 
The number of TEAEs reported did increase with IV dose, increasing above what was 
observed for placebo at the 30 and 45 μg/kg dose groups. Further, the number of 
moderate TEAEs reported increased with dose, and compared to IV placebo. The most 
frequently reported related TEAEs were dry skin (12 events reported by 12 subjects 
occurring locally after subcutaneous administration and more widely after IV dosing) and 
eye pruritus (3 events reported by 3 subjects following IV dosing). These showed 
improvement with the use of moisturizer cream and saline containing ocular drops, 
respectively.  
 
 
When AEs were assessed according to dosing, subcutaneous route at a dose of 2 μg/kg 
had a delayed injection site reaction (2 mild, 4 moderate) consistent of dry skin, erythema 
and rash whereas IV route at a dose of 30 μg/kg was associated with dry skin (1 
moderate, 2 mild), skin allergic reaction (1 moderate), eye pruritus (1 moderate), and at a 
dose of 45 μg/kg with dry skin (2 mild, 5 moderate), erythema (1 moderate), eye pruritus 
(1 mild, 3 moderate). Review of laboratory test results, vital signs, or ECG parameters 
revealed no trends or changes over time following dosing with F-652 at any dose level as 
either subcutaneous or IV dosing.  
 
To characterize the PK profile, single IV infusion of F-652 or placebo was administered 
to four cohorts of 32 healthy male volunteers at doses of 2, 10, 30 and 45 μg/kg. Both 
Cmax and exposure (area under the maximum plasma concentration-time curve [AUC]0-
24h) of F-652 increased proportionally with increasing doses in the dose range of 2 μg/kg 
to 45 μg/kg. Tmax observed was 0.7 hr for 2 μg/kg and 0.2 hr for 10, 30, and 45 μg/kg. 
The t1/2 values ranged from 39.4–206 hours and also increased with increasing dose 
levels. No F-652 was detected in the samples collected from control subjects.  
 
Summary of Related 
TEAEs for IV 
Infusion Adverse 
Event 
IV (N=40) S (%) E 
 
Dry skin 
 
10 (25.0%)  
Eye pruritus 
3 (7.5%) 
Rash erythematous 
2 (5.0%)  
Chills 
1 (2.5%)  
Infusion related 
reaction 
1 (2.5%)  
Headache 
1 (2.5%)  
Somnolence 
1 (2.5%)  
Dermatitis allergic 
1 (2.5%)  
 
 
 


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1.5 Risks/Benefits 
 
1. Beneficial Findings: 
 
Animal studies have demonstrated that treatment with F-652 reduces ALT/AST 
levels in serum and TG in liver. Treatment with IL-22 adenovirus also reduces 
serum ALT and liver/serum TG levels.  Activation of pSTAT3 was seen at 1 hr and 
was undetectable at 3 hrs.  IL-22 induced ALT/AST/TG decreases, however, are 
not seen in STAT3 (hep-/-) mice.  IL-22R1 expression was up-regulated in 
hepatocytes of alcoholic patients and ethanol-fed mice. 
 
2. Potential Risks:  
 
a. Overdose risk 
There has been limited human experience with F-652, either at potential clinical 
doses or with overdose. Treatment of overdose with F-652 should consist of 
general supportive measures. If the symptom or sign is judged as a severe disease 
or disorder, treatment will be administered as per standard of care. 
There is no known specific antidote for overdose with F-652. 
 
b. Warnings, precautions 
There are dose-dependent increases in C reactive protein (CRP) and fibrinogen 
(FIB) following IV dosing with higher doses of F-652 (30 and 45 µg/kg), 
commencing at 12-24 hours post-dose.  FIB reaches a peak at 96-120 hours post-
dose; CRP may reach a peak at 48-72 hours post-dose, returning to normal 2 weeks 
later. 
 
c. Hypersensitivity  
The risk of hypersensitivity reactions to F-652 is unknown. If a significant 
hypersensitivity reaction occurs, no further doses of F-652 will be administered to 
that patient and appropriate treatment initiated. 
 
d. Laboratory abnormalities 
Increased serum CRP and FIB levels may be observed; these increases will be 
documented. 
 
e. Local reactions at the injection site 
Local injection site reactions such as erythema, dry skin and nummular eczema 
have occurred after the investigational product was administrated by subcutaneous 
injection.  These changes were seen following intravenous administration at the 
highest dose (45 ug/kg).  Local reactions generally occurred 10 to 17 days after 
administration of F-652, are usually were mild to moderate. Some subjects required 
treatment with Elocon (mometasone furoate) 0.1% cream, a moderate to strong 
topical corticosteroid for their skin reactions.  
 
 
 


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f.  Drug interaction 
The potential for drug-drug interactions with F-652 is not known.  
 
g. Pregnancy  
Adequate contraceptive methods should be used during treatment with F-652. 
 
h. Geriatric use 
There has been no geriatric experience to date.  
 
Since no clinical data is available for F-652; any related SAE will be considered as 
unexpected. 
1.6 Dose Rationale:  
 
                         Phase I: Patients with AH and MELD score 11-20 
 
Cohort 
N 
F-652 
 
1 (MELD 11-20) 
3 
10 ug/kg 
2 (MELD 11-20) 
3 
30 ug/kg 
3 (MELD 11-20) 
3 
45 ug/kg 
 
Patients will initially be enrolled on dose level 1. At any dose level, three (3) patients 
will be treated. If no dose-limiting toxicity (DLT) is observed, the next cohort of three 
(3) patients will be treated at the next higher dose level. If 1 of the 3 patients 
demonstrates DLT in a given dose level, an additional 3 patients will be treated at that 
dose level. If only 1 of the 6 patients demonstrates DLT, the next cohort of three 
patients is entered at the next dose level. If 2 or more of the 6 demonstrate DLT at that 
dose level, we will deescalate to one dose level lower. At subsequent dose levels, the 
maximum tolerated dose (MTD) is defined as the dose level where no more than 1 of 6 
patients experiences DLT.   
  
Dose escalation will occur only when all patients in the given cohort have completed 
the 42 or 56 days follow up and PK/PD data are available.  The MTD will be based on 
DLT in the first cycle, and the ability to receive at least 70% of the target dose in cycle 
2.  
 
                           
 
 


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                             Phase II: Patients with AH and MELD score 21-28 
 
Cohort 
N 
F-652 
1 (MELD 21-28) 
3 
10 ug/kg 
2 (MELD 21-28) 
3 
30 ug/kg 
3 (MELD 21-28) 
3 
45 ug/kg 
 
In the second phase, once safety of the drug in patients with MELD scores 11-20 has 
been demonstrated, patients with AH as defined by criteria listed earlier and MELD 
scores 21-28 will be studied. Dose escalation in these patients will follow the identical 
format to the Phase 1 of the study as described earlier. That is, in patients with MELD 
scores 21-28, the initial dose will be 10mcg/kg in 3 patients followed by 30mcg/kg, and 
ultimately 45 mcg/kg.  Finally, we will test a 3rd dose of the maximum tolerated dose at 
Day 14 (10mcg/kg, 30 mcg/kg, or 45mcg/kg dose) – dose expansion cohort (see 
below). 
 
Dose Expansion cohort: 
 
We define response to the study drug as a decrease in the AST/ALT or serum 
triglycerides by 30% or more from baseline to Day 42 or Day 56. We will evaluate the 
patients’ response rate for each cohort in phase I. If at the MTD level, the response rate 
is seen in only 1 of the 3 patients, an additional group of 6 patients will be recruited and 
treated at the MTD dose level. If efficacy signals can yet not be demonstrated in 2 or 
more of the 6 patients, the drug will be deemed ineffective. If efficacy signals are 
demonstrated at the highest safe dose,  patients in the final cohort will be administered 
a third dose (10mcg/kg, 30 mcg/kg, or 45mcg/kg) of the MTD on Day 7 (+3 days) 
following the second dose to determine if efficacy can be increased with additional 
dosing. 
1.7 Trial Conduct 
 
This study will be conducted in compliance with the protocol approved by the 
Institutional Review Board, and according to Good Clinical Practice standards.  No 
deviation from the protocol will be implemented without the prior review and approval of 
the IRB except where it may be necessary to eliminate an immediate hazard to a research 
subject.  In such case, the deviation will be reported to the IRB as soon as possible. 
1.8 Population 
 
Patients with alcoholic hepatitis that will be recruited for this study should meet the 
following criteria:  
 


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a. History of heavy alcohol abuse use: >40 g/day in females and >60 g/day in males 
for a minimum period of 6 months 
b. Consumed alcohol within 6 weeks of entry into the study 
c. Serum bilirubin > 3mg/dL AND AST >ALT, but less than 500 U/L 
d. MELD score range between 11-28.  Patients with MELD scores 11-20 will be 
included in the first phase and patients with MELD scores 21-28 will be recruited 
for the second phase and escalation phase.  
 
Patients with alcoholic hepatitis will be enrolled at approximately six clinical sites in the US. 
Additional sites may be added later to help accrual. The target number of participants to 
complete the study is 18 (see below). 
 
STUDY NUMBERS: 
 
Phase I (MELD scores 11-20): 
3+3+3  = 9 
Phase II (MELD scores 21-28):        3+3+3  = 9 
TOTAL participants:                     18          
 
Expected duration of patient participation is as follows: 
 
Time expected for all patients to be enrolled: 
 
 Approximately 3 years 
 
Duration of individual patient participation: 
 
 Up to 56 days (3 days Screening, 7-17 days of treatment, Follow up for 42 
days following first dose) 
 In the Dose Expansion Cohort, subjects receive 3 doses at approximately 7 
day intervals. The duration of follow up will be for 56 days following first 
dose, or 42 days following third dose.  
 
1.9 Power Calculation 
 
As the primary outcome is observational, we have powered this study based upon the 
efficacy outcome, which is defined as a biochemical signal for success if AST/ALT is 
reduced by at least 30% on treatment.  With no treatment, approximately 15-20% of patients 
reach this outcome following study drug treatment.  We anticipate that a minimum of 50% 
will achieve this outcome.  Using a conservative 2-sided assessment of superiority (50% 
with outcome vs. 20%), we will require 22 subjects to reach 80% statistical power.  
 
For our efficacy outcome of AST/ALT, our primary analysis will assess a binary outcome of 
at least 30% reduction when on treatment.  We will evaluate this with a 95% confidence 
interval of the percentage of subjects who have at least 30% reduction in AST/ALT on 
treatment, using an exact binary confidence interval.  As a secondary analysis, we will use 


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robust linear regression with the change in AST/ALT at follow-up as compared to baseline 
as the outcome variable and baseline AST/ALT as the predictor.  We will pair this analysis 
with a Bland-Altman plot.  The goal of the secondary analysis is to assess the degree to 
which the reduction in AST/ALT attributable to treatment changes according to the subject's 
baseline AST/ALT.  We will use 2-sides 5% type I error rate throughout.  
2 Study Objectives 
 
Primary: 
 
 Assess the safety and tolerability and find the MTD of F-652 in patients with 
alcoholic hepatitis as determined by: 
a. 
Absence of unexpected serious adverse events and,   
b. 
Absence of worsening of alcoholic hepatitis (as determined by increase in 
MELD score > 5) up to Day 56 following administration of first dose of study 
drug. 
 
      
Secondary: 
 
 Determine the pharmacokinetics (PK) and pharmacodynamics (PD) of F-652 in 
patients with alcoholic hepatitis. 
 
  
Additional: 
 
 Assess the efficacy signal of F-652 in patients with alcoholic hepatitis as determined 
by: 
a. Clinical: improvement in clinical status 
b. Biochemical: Improvement in liver biochemistry, MELD and Lille scores at 
days 7, 28, 42 and 56 
c. Biomarkers of Il 22 activity (CRP, SAA, triglycerides)  
2.1 Trial Design: 
 
 
The following study evaluations will be performed during the course of the 
Screening period (Day -3 to Day 0):   
 
 Signed informed consent 
Screening Phase                
-72hrs to Day 0 
Treatment 
Phase           
Days 1, 7 and 14 
Follow-up Phase         
Days 8-56 


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 Inclusion and exclusion criteria 
 Complete medical and surgical histories 
 Record of concomitant medication usage, including use of prescription and over-the-
counter medications, and vitamin and/or mineral supplements 
 Patient demographics 
 
Completion of questionnaires:  Alcohol Use Disorder Identification Test (AUDIT), Alcohol 
Use- NIAAA Six Question Set  
 
Alcohol consumption for the last 30 days assessed using the Timeline Follow Back 
Questionnaire 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 Complete physical examination, including height, weight, and BMI 
 12-lead ECG 
 Liver biopsy (if performed) 
 Chest X-ray 
 Assessment of MELD Score 
 Calculate Maddrey Score 
 Clinical chemistry, hematology, coagulation, lipid profile, CRP, SAA1 Nutritional 
Assessment and correction as necessary 
 Evaluation by Addiction Services and Social Services to outline rehabilitation plan 
for alcohol abuse. This may include pharmacotherapy. 
 Nutritional Assessment 
 Immunogenicity Testing 
 Urinalysis 
 Serum pregnancy test (for women of childbearing potential) 
 Collection of specimens (blood and urine) for bio-specimen banking (optional) 
 
The following study evaluations will be performed during the course of Dosing    
Day 1 (+1):   
 
 
 Review of inclusion and exclusion criteria 
 Update medical and surgical histories 
 Assess for Adverse Events 
 Update record of concomitant medication usage, including use of prescription and 
over-the-counter medications, and vitamin and/or mineral supplements 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) pre-dose  then 3 
hours post-infusion with blood pressure and heart rate monitoring every 30 
minutes.Weight and BMI 
 Assessment of MELD Score and recording of Lille score parameters 
 Clinical chemistry, hematology, and coagulation prior to study drug dosing 
 Urine pregnancy test (for women of childbearing potential) 
 Receive first dose of study drug 
 Pharmacokinetic testing 
 Confirmation that patient is abstinent from alcohol 


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The following study evaluations will be performed during Day 3 (+ 1 day): 
 
 Update medical and surgical histories 
 Update record of concomitant medication usage, including use of prescription and 
over-the-counter medications, and vitamin and/or mineral supplements 
 Update Adverse Events 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 Weight and BMI 
 Calculation of MELD Score 
 Clinical chemistry, hematology, and coagulation 
 Pharmacokinetic testing 
 Confirmation that patient is abstinent from alcohol 
 
The following study evaluations will be performed during the course of Dosing Day 
7 (+3 days):   
 
 Update medical and surgical histories 
 Update record of concomitant medication usage, including use of prescription and 
over-the-counter medications, and vitamin and/or mineral supplements 
 Confirmation that patient is abstinent from alcohol 
 Update Adverse Events 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) pre-dose then 3 
hours post-infusion with blood pressure and heart rate monitoring every 30 minutes. 
 12-Lead ECG 
 Complete physical examination, including weight and BMI 
 Calculation of MELD Score 
 Calculation of Lille Score 
 Clinical chemistry, hematology, coagulation, lipid profile, CRP, SAA1, total protein 
and albumin prior to study drug dosing 
 Urine pregnancy test prior to study drug dosing 
 Receive second dose of study drug  
 Pharmacokinetic testing 
 Collection of specimens (blood and urine) for bio-specimen banking 
 Nutritional Assessment 
 
The following study evaluations will be performed during the Follow-up Day 14 (+ 3 
days):   
 
 Update medical and surgical histories 
 Update record of concomitant medication usage, including use of prescription and 
over-the-counter medications, and vitamin and/or mineral supplements 
 Confirmation that patient is abstinent from alcohol 
 Update Adverse Events 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 Weight and BMI 


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 Calculation of MELD Score 
 Clinical chemistry, hematology and coagulation 
 Pharmacokinetic testing 
 Immunogenicity Testing 
 Collection of specimens (blood and urine) for bio-specimen banking 
 
The following study evaluations will be performed during the course of Dosing Day 
14 (+3 days):   
 
 Update medical and surgical histories 
 Update record of concomitant medication usage, including use of prescription and 
over-the-counter medications, and vitamin and/or mineral supplements 
 Confirmation that patient is abstinent from alcohol 
 Update Adverse Events 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) pre-dose then 3 
hours post-infusion with blood pressure and heart rate monitoring every 30 minutes. 
 12-Lead ECG 
 Complete physical examination, including weight and BMI 
 Calculation of MELD Score 
 Clinical chemistry, hematology, coagulation, lipid profile, CRP, SAA1, total protein 
and albumin prior to study drug dosing 
 Urine pregnancy test prior to study drug dosing 
 Receive third dose of study drug  
 Pharmacokinetic testing 
 Collection of specimens (blood and urine) for bio-specimen banking 
 Nutritional Assessment 
 
The following study evaluations will be performed during the follow-up Day 28 (+ 4 
days):   
 
 Update medical and surgical histories 
 Update record of concomitant medication usage, including use of prescription and 
over-the-counter medications, and vitamin and/or mineral supplements 
 Confirmation that patient is abstinent from alcohol 
 Update Adverse Events 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 Complete physical examination, including weight and BMI 
 12-Lead ECG 
 Alcohol consumption for the last 30 days assessed using the Timeline Follow Back 
Questionnaire 
 Calculation of MELD Score 
 Clinical chemistry, hematology, coagulation, lipid profile, CRP, SAA1, total protein 
and albumin 
 Pharmacokinetic Testing 
 Immunogenicity Testing 


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 Collection of specimens (blood and urine) for bio-specimen banking. 
 
 
The following study evaluations will be performed during Day 42 (+2 days): 
 
 Update medical and surgical histories 
 Update record of concomitant medication usage, including use of prescription and 
over-the-counter medications, and vitamin and/or mineral supplements 
 Confirmation that patient is abstinent from alcohol 
 Update Adverse Events 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 Weight and BMI 
 Physical Examination 
 Calculation of MELD Score 
 Clinical chemistry, hematology, and coagulation 
 Complete Timeline Follow-back Questionnaire 
 Collection of specimens (blood and urine) for bio-specimen banking. 
 Pharmacokinetic Testing 
 Immunogenicity Testing 
 Nutritional Assessment 
 
The following study evaluations will be performed during Day 56 (+2 days) (Only 
completed if patient received three doses of study drug): 
 
 Update medical and surgical histories 
 Update record of concomitant medication usage, including use of prescription and 
over-the-counter medications, and vitamin and/or mineral supplements 
 Confirmation that patient is abstinent from alcohol 
 Update Adverse Events 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 Weight and BMI 
 Physical Examination 
 Calculation of MELD Score 
 Clinical chemistry, hematology, and coagulation 
 Complete Timeline Follow-back Questionnaire 
 Collection of specimens (blood and urine) for bio-specimen banking. 
 Nutritional Assessment 
 
 
 


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2.2 Study Design/Type 
 
 
Schedule of Procedures 
Safety Assessments 
Screening 
(-72 hrs) 
Day 
1 
(+ 1 
day)  
Day 
3  
(+ 1 
day) 
Day  
7   
(+3 
days) 
Day 
14  
(±3 
days) 
Day 
28  
(±4 
days) 
Day 
42  
(+2 
days) 
Day 
566 
(+2 
days) 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Physical Examination  
X 
 
 
X 
X5 
X 
X 
X 
Medical/Surgical History 
X 
 
X 
X 
X 
X 
X 
X 
Nutritional Assessment 
X 
 
 
 
X5 
 
X 
X 
AUDIT 
and 
NIAAA 
Questionnaires 
X 
 
 
 
 
 
 
 
Timeline 
Followback 
Questionnaire 
X 
 
 
 
 
X 
X 
X 
Vital Signs 
X 
 
X 
 
X 
X 
X 
X 
Serial Vital Signs 
 
X 
 
X 
X5 
 
 
 
Serum ChemistryA 
X 
X 
X 
X 
X 
X 
X 
X 
CoagulationA 
X 
X 
X 
X 
X 
X 
X 
X 
HematologyA 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
 
X 
X5 
 
 
 
Lipid profile, CRP, SAA1, total 
protein, albuminA 
X 
 
 
X 
X5 
X 
 
 
Calculate MELD Score 
X 
X 
X 
X 
X 
X 
X 
X 
Calculate Lille Score 
 
 
 
X 
 
 
 
 
Calculate Maddrey Score 
X 
 
 
 
 
 
 
 
Urinalysis1 
X 
 
 
 
 
 
 
 
ECG2 
X 
 
 
X 
X5 
X 
 
 
Chest X-ray3 
X 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dosing 
 
X 
 
X 
X5 
 
 
 
Pharmacokinetic 
Sample 
Collection7 
 
X 
X 
X 
X 
X 
X 
 
Immunogenicity Testing8 
X 
 
 
 
X 
X 
X 
 
Biomarkers(blood and urine) 
X7 
 
 
X 
X 
X 
X 
X 
Confirmation that patient is 
abstinent from alcohol 
 
X 
X 
X 
X 
X 
X 
X 
1. Urinalysis results can be used for Screening if tested within 7 days. 
2. ECG results can be used for Screening if tested within 7 days. 
3. Chest X-ray results can be used for Screening if tested within 30 days.  
4. Day 1, Day 7 and Day 14 labs and testing must be completed prior to dosing. 
5. These tests/procedures will occur only on Day 14 if the patient is receiving a 3rd dose at that visit.  
6. Day 56 will only occur if the patient received a 3rd dose on Day 14. 
7. Biomarkers are optional at Screening. 
 
 


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AClinical Laboratory Tests 
 
Hematology 
Coagulation 
Serum Chemistry 
Urinalysis 
Other 
Liver  
Function 
Tests 
Other Chemistry 
Complete 
Blood Count 
with 
differential, 
Platelet count, 
MCV 
PT, INR 
AST, ALT, 
Total 
Bilirubin, 
Direct 
Bilirubin 
Sodium, Potassium, 
Chloride, 
Bicarbonate, 
Calcium, 
Magnesium, 
Phosphate, 
Creatinine, BUN, 
Glucose, Total 
protein, Albumin, 
Lipid profile, CRP, 
SAA1 
Specific 
gravity, pH, 
Blood, 
Protein, 
Glucose, 
Ketones  
β-HCG 
serum 
pregnancy 
test 
 
Urine 
pregnancy 
test 
 
 
 
Blood will be collected for PK sampling per the schedule below:   
 
8Pharmacokinetic Sampling Schedule 
Study Visit Day 
Study 
Visit 
Day 
+0* 
Study 
Visit 
Day 
+2* 
Study 
Visit 
Day 
+3* 
Study 
Visit 
Day  
+4* 
24 hrs 
48 hrs 
72 hrs 
96 hrs 
 
Pre-dose 
30 mins 
(±5 mins) 
1 hr  
(±10 mins)  
8 hr  
(±30 mins) 
 
 
 
 
Day 1 
X 
X 
X 
X 
 
 
X 
 
Day 7 
X 
X 
X 
X 
X 
X 
X  
X 
Follow-Up Visit Day 
 
 
 
 
Day 14 
X 
 
 
 
 
Day 28 
X 
 
 
 
 
Day 42 
X 
 
 
 
 
* +/- 2 hour window for PK points > 8 hours after dosing 
 


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9Immunogenicity Sampling Schedule 
 
Dosing Day 
Baseline 
Day 14 
Day 28 
Day 42 
X 
X 
X 
X 
 
 
2.3 Primary Study Endpoints/Secondary Endpoints 
 
Primary: 
 
 Absence of unexpected serious adverse events. 
 
       Secondary: 
 
 Pharmacokinetics (PK) and pharmacodynamics (PD) of F-652 in patients with 
alcoholic hepatitis. 
 
Efficacy Signal endpoints: 
 
 Decrease in MELD score, Lille score, triglyceride, CRP, AST, ALT and SAA1  
2.4 Trial Treatment 
 
Participants will receive 10 μg/kg, 30 μg/kg or 45 μg/kg of F-652 on Day 1 and Day 7 via 
slow intravenous infusion.  Three patients will receive 10 μg/kg of F-652.  
Pharmacokinetic testing will be completed on these subjects.  If evaluations demonstrate 
safety and efficacy signals, the next 3 patients will receive 30 μg/kg.  If pharmacokinetic 
testing demonstrates safety and efficacy signals, the next 3 patients will receive 45 μg/kg.  
If evaluations demonstrate safety and efficacy signals, patients with a MELD score of 21-
28 will receive a third dose of the study drug at the maximum tolerated dose on Day 14. 
2.5 Remuneration 
 
Each site will compensate participants for their time, travel and parking.  The amount will 
be determined by the site study team and reflected in the consent form. 
2.6 Duration 
The screening process will occur in the 72 hrs leading up to Day 1.  The dosing phase will 
occur from Day 1 to Day 14.  Follow-up will occur between Day 14 to Day 56.  Visit 
activities are described in the previously mentioned Schedule of Procedures.   


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2.7 Discontinuation  
 
Discontinuation of the F-652 will occur if a participant experiences a Serious Adverse 
Event or UPIRTSO AND, in the opinion of the investigator and study ajudicator, is related 
to the study drug.  Patients will be discontinued if grade 3 or higher CTCAE develop that 
are determined to be possibly or likely attributable to study drug. 
2.8 Product Accountability 
 
The study drug product will be manufactured, labeled, and supplied by AAI Pharma 
Services Corporation on behalf of Generon (Shanghai) Corporation, Ltd.  The drug will be 
managed and accounted for by each site’s Research or Clinical Pharmacy. 
2.9 Data Identification 
 
During the Screening phase, patients will be identified by a unique screening number and 
by their initials (first and last).  On Day 1, patients will be identified by a unique five-digit 
patient number and initials.  Only qualified patients will be assigned a patient number.  
3 Subject Selection Enrollment and Withdrawal 
3.1 Inclusion Criteria 
 
To participate in this study, patients must meet all of the following criteria: 
 
1. Able to provide written informed consent (either from patient or patient’s legally 
acceptable representative) 
2. Male or female patients 21 years of age or older 
3. Patients with alcoholic hepatitis defined as:  
a. History of heavy alcohol abuse use: >40 g/day in females and >60 g/day in 
males for a minimum period of 6 months 
b. Consumed alcohol within 6 weeks of entry into the study 
c. Serum bilirubin > 3mg/dL AND AST >ALT, but less than 500 U/L 
d. MELD score between 11-28 
e. Liver biopsy will be carried out to confirm diagnosis in all patients except 
those who meet criteria a-c and in whom other causes of liver disease have 
been excluded (viral, drug, autoimmune etc). 
4. Women of child-bearing potential must utilize appropriate birth control. 
 
*Patients on steroids and/or pentoxifylline will not be excluded from the study. 
3.2 Exclusion Criteria 
 
1. Other or concomitant cause of liver disease as a result of:  
a. 
Autoimmune liver disease  


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b. 
Wilson disease  
c. 
Vascular liver disease 
d. 
Drug induced liver disease 
Note: Concurrent viral hepatitis is not excluded. 
2. Co-infection with human immunodeficiency virus (HIV) 
3. Any active malignancies other than curatively treated skin cancer (basal cell or 
squamous cell carcinomas) or any other malignancy diagnosed within the last five 
years. 
4. Active tuberculosis on chest x-ray at study entry 
5. Significant systemic or major illness other than liver disease, including coronary 
artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious 
psychiatric disease, that, in the opinion of the Investigator would preclude the patient 
from participating in and completing the study 
6. Patients requiring the use of vasopressors or inotropic support 
7. Liver biopsy, if carried out, showing findings not compatible with alcoholic hepatitis 
8. Any patient that has received any investigational drug or device within 30 days of 
dosing or who is scheduled to receive another investigational drug or device in the 
course of the study 
Note: Investigational drug includes any drug that is used off-label. 
9. If female, known pregnancy, or has a positive urine or serum pregnancy test, or 
lactating/breastfeeding 
10. Serum creatinine >2.5 mg/dL 
3.3 Subject Recruitment, Enrollment and Screening 
 
Subjects will be recruited, enrolled and screened using the following resources: 
 
 From the Principal Investigator or Co-Investigator clinical practices 
 Referring physicians, advertisement, etc. 
 Information that is to be given to potential subjects (handouts, brochures, etc.) 
 Advertisements 
 Screening requirements or qualifying lab values 
 Evaluation and documentation of inclusion/exclusion criteria 
3.4 Subject Withdrawal 
 
A subject may be withdrawn from the study prior to that subject completing all of the 
study-related procedures.  Some reasons include: 
 
Criteria for Subject Withdrawal  
 
The following are criteria for subject discontinuation from the study:  
 
1. Subject withdraws study consent. 


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2. Subject is found to be ineligible for the protocol as per the Inclusion/Exclusion 
criteria.  
3. Subject experiences disease progression.  
4. Lille scores at any time are >0.45 (treatment failure).  Patient will be taken off 
study drug, however, we will request that they complete follow-up. 
5. Failure of the subject to comply with protocol requirements.  
6. Exhibition of unacceptable toxicity which would make it difficult or dangerous to 
comply with further protocol requirements such as study visits, blood draws, etc.  
7. There are changes in medical status of the subject such that the Investigator 
believes that subject safety will be compromised or that it would be in the best 
interest of the subject to stop participation in the study. 
8. Death of the subject. 
9. Subjects with a test consistent with pregnancy such as a positive beta-hCG. 
10. Subject is lost to follow-up. 
11. Any complication that requires prolongation of the hospitalization or change in 
treatment and in the opinion of the investigator is related to the study drug. 
Procedures for Subject Withdrawal  
 
At the time of study withdrawal, subjects, if capable, will be asked to complete all of the 
procedures that would normally be performed at the Day 42 assessment. Withdrawn 
subjects will have a 30-day follow up phone call after their last clinical assessment. 
3.5 Data Collection and Follow-up for Withdrawn Subjects 
Even though a subject has withdrawn from the study, these patients will be followed up in 
the hospital and to  42 days following the last administration of the study drug.  Such data 
is important to the integrity of the final study analysis since early withdrawal could be 
related to the safety profile of the study drug.  If a subject withdraws consent to participate 
in the study, for subject safety reasons, attempts should be made to obtain permission to 
collect follow up information whenever possible.  
4 Study Drug 
4.1 Description 
 
F-652 (Recombinant human IL-22)  
 
The drug product (DP) was manufactured by AAIPharma Services Corp, Charleston, South 
Carolina under Good Manufacturing Practice for pharmaceutical products (GMP).  
F-652 drug substance (DS) used to manufacture the DP was produced using standard 
monoclonal antibody manufacturing process. The drug substance is sent from China at -77 
degrees F to South Carolina.  In South Carolina, it is defrosted and lyophilized into a cake.  
This will be then be shipped at -2 degrees F to the sites and reconstituted. 
  


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The F-652 DP in lyophilized formulation is stored at 2–8°C prior to reconstitution.  F-652 
is supplied lyophilized white cake in 2 mL glass vials. Each vial contains 5 mg/mL when 
reconstituted with 1 mL of sterile water.  
4.2 Packaging, Labeling and Storage  
 
The Generon Corporation, Ltd. or its Agent will provide labeled study medication for the 
clinical trial. The investigational drug is supplied as 5 mg/vial lyophilized product in 2-mL 
clear glass vials. A unique number is associated with each vial and is the means of drug 
assignment and inventory. A sample label is provided in the figure below. Please note that 
the label is subject to change format but the information contained therein will not change. 
The label has a tear off section that should be used to identify which drug was distributed 
to which subject and remain with the source documentation. 
Sample F-652 Product Label 
 
 
Study drug should be stored and maintained between 2°–8°C prior to dispensing. The 
product should not be frozen at any time. 
4.3 Treatment Regimen 
 
F-652 will be administered by slow intravenous infusion over approximately 100 
minutes.  The study medication is reconstituted as per the protocol in 100 ml of 5% 
dextrose in water.  To monitor, as well as prevent hypersensitivity reactions, the infusion 
rate will be as follows: 
 
1. 10 ml/hr for 15 minutes 
2. 20 ml/hr for 15 minutes 
3. 40 ml/hr for 15 minutes 
4. 80 ml/hr for 15 minutes 
5. 100 ml/hr until infusion complete 
That is, the total infusion will be over approximately 100 minutes.  Patients will be 
monitored for 3 hours post-infusion with blood pressure and heart rate monitoring every 
30 minutes. 
Lot # : XXXXXXX 
 
Manufacturing Date: 
XXXXXXX 
 
Expiry Date: XXXXXXX 
F-652 for IV Infusion, 5mg/vial 
Protocol No.: TREAT-008 
Caution: New Drug-Limited by Federal (US) 
Law to Investigational Use. 
Store at: 2°C to 8°C. Protect from Light. 
Prepare in accordance with protocol
Manufactured by AAIPharma Services Corp, 
Charleston, South Carolina for Generon 
(Shanghai) Corporation, Shanghai, China 
Vial #: XXXX 
Lot # : XXXXXXX 
Manufacturing
Date: 
XXXXXXX 
Expiry Date: XXXXXX 


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Patients will receive two separate IV infusions separated by 6-10 days (i.e. one infusion 
on Day 1 and a repeat infusion approximately one week later depending on outpatient 
scheduling). After information is received regarding the primary end point (safety) at the 
first dose (10ug/kg), and the 10ug/kg dose determined to be safe, the 2nd cohort of patient 
will be administered the 30ug/kg dose.  Further escalation will follow this scheme.  If 
evaluations demonstrate safety and efficacy signals, patients in the final dose escalation 
cohort will receive a third dose of the study drug at the maximum tolerated dose on Day 
14. 
 
Medications allowed:  Corticosteroids, pentoxifylline, antibiotics, acamprosate, and 
Baclofen, as well as any other medication deemed to be essential for the treatment of the 
patient will be allowed. 
 
Prohibited medications:  Biological agents and any other concomitant investigational 
agents. 
 
4.4 Preparation and Administration of Study Drug 
 
Reconstitution of F-652:  
 
Remove the F-652 vial from the refrigerator. Using an appropriately sized syringe and 
needle, withdraw 1.0 mL of water for injection. Reconstitute the vial by slowly adding the 
1.0 mL of water for injection into the interior of the vial's neck. Gently dissolve the drug 
powder with a slow swirling motion. This results in a solution of F-652 at a concentration 
of 5 mg/mL. Allow up to 2 minutes for the F-652 to dissolve. The solution should not be 
used if discolored or cloudy, or if particulate matter remains.  
 
IV Preparation:  
 
The research or clinical pharmacist will withdraw a volume of Baxter 5% Glucose IV 
solution and insert into the Baxter Empty Viaflex bag (PVC) 150mL. Based on the weight 
dose provided by the study team, withdraw the required volume of F-652 from the vial 
containing 5 mg/mL F-652 drug solution. Slowly add the appropriate volume of F-652 into 
the Baxter Empty Viaflex bag 150 mL containing 5% dextrose in water (D5W) to make the 
volume up to 100 mL, then gently invert the IV bag up to 5 times to ensure that the 
investigational product and Baxter 5% Glucose IV solution are well mixed.  
 
Investigational Product at Study Site: 
 
Study medication will be shipped to each institution site upon site initiation. The 
Investigator is responsible for monitoring the inventory of medication supplies, in order to 
ensure sufficient supply for the site. The study monitors will also verify the drug 
accountability during each site-monitoring visit. At the end of the study, all study drug 
supplies will be returned to the Sponsor/designee by the study monitor for each site. 


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Test Article Accountability: 
 
The Investigator will maintain accurate records of the receipt of all study medication.  In 
addition, accurate records will be kept regarding when and how much study medication is 
dispensed and used by each subject in the study.  Drug accountability and distribution of 
drug will be done at each visit as needed during the course of the study.  Reasons for 
deviation from the expected dispensing regimen must also be recorded.  A storage 
temperature log is to be maintained to document proper storage conditions. Malfunctions 
must be reported to the sponsor immediately. The clinical supplies for this study must be 
maintained under adequate security and stored under conditions specified on the label. 
Investigational Product at Study Site at Study Conclusion: 
 
At completion of the study, all study medication will be reconciled by the designee and 
then returned, retained, or destroyed according to applicable country regulations. Prior to 
any action being taken with study medication after the study is completed; the investigator 
will contact the Generon Corporation, Ltd. or the contracted CRO for approval of such 
action. 
4.5 Immunogenicity Testing 
 
Immunogenicity testing will occur at Baseline, on Day 14, Day 28 and Day 42.  Three 
assays will be used to evaluate the anti-F-652 antibodies in serum samples collected in this 
trial. The first assay is a Bridging ELISA binding assay which screens antibody binding 
activities in the serum samples. Positive samples identified in the binding assay will be 
analyzed in the confirmatory assay, in which a serum sample is first incubated with F-652 
in vitro, and the sample is then analyzed by the binding assay. Positive samples identified 
in the confirmatory assay will be further analyzed in the cell-based neutralizing assay, in 
which the neutralizing bioactivity to F-652 (IL-22) in the serum samples is analyzed. The 
binding and confirmatory assay have been developed and validated in minimal required 
dilution (MRD), cut point and cut point correction factor, sensitivity, specificity, 
selectivity, inter and intra precision, and drug tolerance followed “Guidance for Industry, 
Assay Development for Immunogenicity Testing of Therapeutic Proteins” (FDA, CMC, 
2009). The neutralizing assay has been developed and under validating. The validation 
reports have been sent to FDA in the IND 121673 Serial Number 0004. 
5 Assessment of Efficacy Signals 
5.1 Efficacy Parameters 
 
 Change in MELD score, Lille score, triglycerides, CRP, AST, ALT and SAA1. 
5.2 Method and Timing 
 
1. MELD score will be calculated at each visit. 
2. Lille score will be calculated on Day 7. 


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3. Triglycerides, CRP and SAA1 will be collected at Screening, Day 7, Day 14 (if 
dosed) and Day 28. 
4. AST and ALT will be collected at Screening, Day 3, Day 7, Day 14, Day 28, Day 35, 
Day 42 and Day 56 (if applicable). 
5. Adverse events will be evaluated at each study visit per the Schedule of Procedures 
by the study coordinator and reviewed by the investigator 
6 Assessment of Safety 
6.1 Safety Variables 
 
During study drug infusion:  Patients will be monitored as per our standard protocol 
followed for a biological agent such as infliximab.  The protocol is as follows: 
a. 
Intravenous access.  Peripheral intravenous access is started for those who do not 
have an intravenous access.  Central lines may be used for administration of 
intravenous fluids, medications and blood draws unless otherwise specified.   
b. 
Pre-medication.  Acetaminophen 500 mg and diphenhydramine 25 mg will be 
given by mouth prior to the infusion. 
c. 
Infusion- related reaction medication.  The following would be the medications 
used: 
i. Diphenhydramine 25 mg intravenously for skin rashes 
ii. Demerol 25 mg intravenously single dose and repeated every 15 
minutes if ineffective for rigors. 
iii. Methylprednisone (Solu-Medrol) 1 mg/kg intravenously as a bolus 
for more severe infusion-related reactions like hypotension or 
severe bronchospasm. 
Monitoring for hypersensitivity reactions:  The infusions are all carried out at the clinical 
research center under the direction of trained personnel who have expertise in 
recognizing hypersensitivity reasons, as well as in treating these reactions.  
Hypersensitivity reactions may also occur when the patient is at home.  Preliminary 
studies in normal volunteers have indicated that the only possible hypersensitivity 
reactions noted in these patients are skin rashes.  The care giver will be instructed on skin 
rashes and will be shown flash cards to facilitate recognition of reactions. 
 
During follow-up:  Safety will be determined based on clinical and laboratory 
monitoring. 
 
Clinical: At each study follow-up visit, patients will have a physical examination with 
specific attention to skin changes, hypersensitivity reactions, pulmonary abnormalities, 
worsening in liver function as noted by increasing jaundice, ascites, or hepatic 
encephalopathy and presence of infection. 
 


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Laboratory: Biochemical parameters that are monitored include CRP, liver biochemistry, 
creatinine, and electrolytes. The study will be stopped if two or more patients have 
either A. AST or ALT > 500 U/L or B. Lille score > 0.85.  The study will also be 
stopped if more than one patient (that is, two or more) has an adverse event grade 3 or 
above on the CTCAE scale that is determined to be possibly or likely attributable to study 
drug as per the study adjudicator.  A patient will be WITHDRAWN from the dosing 
phase if Lille scores at any time are > 0.45 (treatment failure).  
 
We recognize that determination of whether worsening of liver biochemical tests is due 
to the alcoholic hepatitis or study drug induced liver injury (DILI) is very difficult. An 
AST or ALT increase >500 IU/L would be considered an indication that the patient might 
have DILI since AST and ALT are typically < 250 U/L in AH.  Such an increase of > 500 
IU/L would trigger prompt evaluation and consideration of discontinuation of the study 
drug.  A Lille score > 0.85 and an increase in MELD score >10 would also warrant 
discontinuation of the study drug.  Considering how difficult it is to distinguish potential 
DILI from worsening of the underlying liver disease, we have incorporated an external 
adjudication of all suspected DILI events.  This external adjudication is in addition to the 
data safety monitoring board (DSMB) which will monitor the entire study.  A renowned 
hepatologist, Dr. Willis Maddrey, who is an internationally renowned expert both in the 
field of alcoholic hepatitis and DILI, has kindly agreed to serve as the external 
adjudicator for this IL 22 study.  He will be contacted on an as needed basis when there is 
question of symptom causality. 
The following parameters will be recorded for the safety evaluation: 
 Adverse events 
 Vital signs (pulse, heart rate, respiration) 
 Physical examinations 
 Clinical chemistry, hematology, coagulation, and urinalysis 
 ECGs 
 Chest X-Ray 
6.2 
Method and Timing 
 
1. Adverse events, vital signs, chemistry, hematology and coagulation will be assessed 
at each study visit. 
2. Urinalysis will be assessed at Screening. 
3. ECG will be assessed at Screening, Day 7, Day 14 (if dosing) and Day 28. 
6.3 Adverse Event Reporting 
 
Definitions 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
 
Any unanticipated problem or adverse event that meets the following three criteria:  


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 Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: 
(1) death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, 
or prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or new 
information (i.e. publications, DSMB reports, interim findings, product labeling 
change) that in the opinion of the local investigator may adversely affect the rights, 
safety, or welfare of the subjects or others, or substantially compromise the research 
data, AND 
 Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
 Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
Adverse Event 
 
An untoward or undesirable experience associated with the use of a medical product (i.e. 
drug, device, biologic) in a patient or research subject. 
Serious Adverse Event 
 
Adverse events are classified as serious or non-serious.  Serious problems/events can be 
well defined and include: 
 
 death 
 life threatening adverse experience 
 hospitalization 
 inpatient, new, or prolonged; disability/incapacity 
 persistent or significant birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-
investigator may have adversely affected the rights, safety, or welfare of the subjects or 
others, or substantially compromised the research data. 
 
Other important medical events are those that may not be immediately life threatening, 
but are clearly of major clinical significance.  They may jeopardize the subject, and may 
require intervention to prevent one of the other serious outcomes noted above.  For 
example, drug overdose or abuse, a seizure that did not result in in-patient hospitalization 
or intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 


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All adverse events that do not meet any of the criteria for serious, should be regarded as 
non-serious adverse events.  
 
Adverse Event Reporting Period 
 
For this study, the study treatment follow-up period is defined as 42 days following the 
last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
General Physical Examination Findings 
 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as an 
adverse event.  
 
Post-study Adverse Event 
 
All unresolved adverse events should be followed by the sponsor-investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the sponsor-investigator should instruct each 
subject to report, to the sponsor-investigator, any subsequent event(s) that the subject, or 
the subject’s personal physician, believes might reasonably be related to participation in 
this study.  
 
Abnormal Laboratory Values 
 
A clinical laboratory abnormality should be documented as an adverse event after the 
screening visit.  For this study, clinically significant laboratory abnormalities will be 
defined as abnormal laboratory values that in the opinion of the site investigator are not 
explained by alcoholic hepatitis, underlying liver disease or other underlying health 
conditions. 
 
All patients with laboratory tests containing clinically significant abnormal values should 
be followed regularly until the values return to normal ranges, until a valid reason for the 
AE (other than study medication related AE) is identified, or until further follow up is 
deemed medically unnecessary.  
 
Hospitalization, Prolonged Hospitalization or Surgery 
 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 


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otherwise in this protocol.  Any condition responsible for surgery should be documented 
as an adverse event if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances:  
 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an outcome 
of an adverse event if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator.  
6.4 Recording of Adverse Events 
 
At each contact with the subject, the study team must seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Information on all adverse 
events should be recorded immediately in the source document, and also in the Adverse 
Event Case Report Form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic, laboratory or procedure results should recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has been 
ultimately determined that the study treatment or participation is not the probable cause.  
Serious adverse events that are still ongoing at the end of the study period must be 
followed up, to determine the final outcome.  Any serious adverse event that occurs after 
the study period and is considered to be at least possibly related to the study treatment or 
study participation should be recorded and reported immediately. 
6.5 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
The sponsor-investigator is responsible to evaluate all adverse events to determine 
reporting requirements to the IRB and FDA.  When an adverse event has been identified, 
the study team will take appropriated action necessary to protect the study participant and 
then complete the Study Adverse Event Worksheet and log.  The sponsor-investigator 
will evaluate the event and determine the necessary follow-up and reporting required.  
The reporting will need to occur within two working days. 
 
 


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6.6 
Sponsor-Investigator Reporting: Notifying the Mayo IRB  
 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-
UPIRTSOs according to the Mayo IRB Policy and Procedures. 
 
Any serious adverse event (SAE) which the Principal Investigator has determined to be a 
UPIRTSO must be reported to the Mayo IRB as soon as possible but no later than five 
working days after the investigator first learns of the problem/event. 
 
Information collected on the adverse event worksheet (and entered in the research 
database):  
 
 Subject’s Name 
 Medical record number:  
 Disease/histology (if applicable):  
 The date the adverse event occurred:  
 Description of the adverse event:  
 Relationship of the adverse event to the research (drug, procedure, or 
intervention):  
 If the adverse event was expected:  
 The severity of the adverse event: (use a table to define severity scale 1-5) 
 If any intervention was necessary:  
 Resolution: (was the incident resolved spontaneously, or after discontinuing 
treatment) 
 Date of Resolution:  
 
The sponsor-investigator will review all adverse event reports to determine if specific 
reports need to be made to the IRB and FDA.  The sponsor-investigator will sign and date 
the adverse event report when it is reviewed.  For this protocol, only directly related 
SAEs/UPIRTSOs will be reported to the IRB. 
6.7 
Sponsor-Investigator Reporting: Notifying the FDA 
 
The sponsor-investigator will report to the FDA all unexpected, serious suspected adverse 
reactions according to the required IND Safety Reporting timelines, formats and 
requirements. 
 
Unexpected fatal or life threatening suspected adverse reactions where there is evidence 
to suggest a causal relationship between the study drug/placebo and the adverse event, 
will be reported as a serious suspected adverse reaction.  This will be reported to the FDA 
on FDA Form 3500A, no later than 7 calendar days after the sponsor-investigator’s initial 
receipt of the information about the event. 
 
 
Other unexpected serious suspected adverse reactions where there is evidence to suggest 
a causal relationship between the study drug/placebo and the adverse event, will be 


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reported as a serious suspected adverse reaction.  This will be reported to the FDA on 
FDA Form 3500A, no later than 15 calendar days after the sponsor-investigator’s initial 
receipt of the information about the event. 
 
Any clinically important increase in the rate of serious suspected adverse reactions over 
those listed in the protocol or product insert will be reported as a serious suspected 
adverse reaction.  This will be reported to the FDA on FDA Form 3500A no later than 15 
calendar days after the sponsor-investigator’s initial receipt of the information about the 
event. 
 
Findings from other studies in human or animals that suggest a significant risk in humans 
exposed to the drug will be reported.  This will be reported to the FDA on FDA Form 
3500A, no later than 15 calendar days after the sponsor-investigators initial receipt of the 
information about the event. 
 
For this multi-center clinical trial, in addition to reporting certain unanticipated problems 
and adverse events noted above to the FDA, it is the responsibility of the study sponsor to 
report those same adverse events or findings to participating investigators.  
 
 


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FDA Definitions (21 CFR 312.32(a)) 
 
A. Adverse Event: any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
B. Suspected Adverse Reaction: any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Adverse Reaction: any adverse event caused by a drug. Adverse reactions are a subset of 
all suspected adverse reactions where there is reason to conclude that the drug caused the 
event. 
 
D. Unexpected: An adverse event or suspected adverse reaction is considered “unexpected” 
if it is not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. For example, under this definition, 
hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator 
brochure referred only to elevated hepatic enzymes or hepatitis. 
 
E. Serious: An adverse event 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 patient or subject 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. 
 
F. Life-Threatening: An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the investigator or sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
 
 


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6.8 Stopping Rules 
 
The study will stop if any of the following occur: 
 
1. The participant decides to withdraw from the study. 
2. The participant experiences a Serious Adverse Event (SAE) that, in the opinion of 
the investigator, is possibly, probably or definitely related to the study drug 
utilizing the National Cancer Institute’s CTCAE system as a guide. 
3. The participant experiences a medical condition that, in the opinion of the 
investigator, continuation on the study drug would be detrimental. 
4. At least two patient have either: 
a. AST or ALT >500 U/L or 
b. Lille score >0.85. 
In the event of a SAE, the site will report this to the Mayo Clinic study team.  If the SAE 
is attributable to study drug, the Mayo Clinic study team will report the event to the 
Institutional Review Board and the FDA.  
6.9 Individual Stopping Rules 
 
The following are criteria for subject discontinuation from the study:  
 
1. Subject withdraws study consent. 
2. Subject is found to be ineligible for the protocol as per the Inclusion/Exclusion 
criteria.  
3. Subject experiences disease progression.  
4. Lille scores at any time are >0.45 (treatment failure).  Patient will be taken off 
study drug, however, we will request that they complete follow-up. 
5. A subject that requires more than 2 investigation drug (F-652) dose reductions.  
6. Failure of the subject to comply with protocol requirements.  
7. Exhibition of unacceptable toxicity which would make it difficult or dangerous to 
comply with further protocol requirements such as study visits, blood draws, etc.  
8. There are changes in medical status of the subject such that the Investigator 
believes that subject safety will be compromised or that it would be in the best 
interest of the subject to stop participation in the study. 
9. Death of the subject. 
10. Subjects with a test consistent with pregnancy such as a positive beta-hCG. 
11. Subject is lost to follow-up. 
12. Any complication that requires prolongation of the hospitalization or change in 
treatment and in the opinion of the investigator is related to the study drug. 
The investigator will utilize the National Cancer Institute’s CTCAE system as a guide 
when determining the need for an individual participant to stop the study. 


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7 
Statistical Plan 
7.1 
Statistical Methods 
 
Primary endpoint (safety): The number and percentage of patients with SAE and 
increase in MELD score > 5 up to Day 56 following administration of first dose of study 
drug will be summarized by each dose level. Ninety-five percent confidence interval of 
the percentage will be calculated too.  
 
Summary of adverse event will also be provided by each dose level. 
 
Secondary endpoint: Pharmacokinetics (PK) and pharmacodynamics (PD) of F-652 in 
patients with alcoholic hepatitis at the first dose level (10ug/kg) and subsequent dose 
levels will be determined by the study sponsor using standard pharmacological tools.  
The total exposure (area under the curve), maximum serum concentration, time at 
maximum concentration, last measurable serum concentration, time at last measurable 
concentration, clearance, volume of distribution, elimination half-life, accumulation ratio 
and dose proportionality will be calculated. 
 
Efficacy signal endpoint: The main efficacy end point is the reduction of AST/ALT or 
serum triglycerides. If patients show a reduction of AST/ALT or serum triglyceride by 
30% at day 42, the drug shows efficacy in this patient. We will calculate the percentage 
of patients with efficacy (rate) and its 95% confidence interval for each dose level.  
 
We will also use the proportion of patients with 30% change of AST, ALT from baseline 
to Day 3, Day7, Day14, Day 28, Day 42 and Day 56 as the dependent variable, dose level 
and baseline AST, ALT and other patients’ characteristic at baseline as the covariates to 
evaluate the change (efficacy) or drug by dose level.  A random intercept will be included 
for accommodating the correlation among the repeated measurement.  
 
Other efficacy endpoints: Paired t-test or signed-rank test will be used to compare the 
level Lille score. Linear mixed-effect models will be used to analyze the MELD score, 
triglycerides, CRP, and SAA1 in a similar way to the AST/ALT. 
7.2 
Termination Criteria 
 
The study will be terminated when accrual is completed. Patients may be terminated from 
this study according to the criteria discussed in Section 4.4 Subject Withdrawal whether 
voluntarily or by the recommendation of the site investigator. 
7.3 
Deviation Reporting 
 
Any change from the study design will be reported to the IRB according to institutional 
policy. 


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8 
Direct Access to Source Data/Documentation 
 
Direct access to source data and documentation will be readily available to the study 
teams at each site through use of the OnCore electronic data capture system. 
9 
Quality Control and Quality Assurance 
 
One of the investigators and a study coordinator will maintain quality control.  All data 
entered will be reviewed by the investigator and the study statistician.  Quality assurance 
of data accuracy will occur routinely through monthly checks for completeness and edits 
and form audits.  Quality assurance of data analysis is achieved by independent replication 
of key analyses within the DCC and review reports by multiple individuals before 
distribution. 
 
9.1 Monthly check for completeness and edits 
 
On a monthly basis, the DCC will generate a database report of: 
 Subject Accrual: Number of patients enrolled, number of subjects on/off study  
 Data Entry timeliness (% of data entered within 2 weeks from subject visit) 
 Quality of data/Edits (see below) 
 Protocol Deviations: Number of deviations in each category, by site.  
 Missed visits 
 Incomplete visits 
 Missed specimen collection or shipment 
 Serious Adverse Events 
 Site responsiveness to resolving edits (data queries and/or errors) 
 
Edits are run on the database of the keyed forms monthly. Checks for missing, out of 
range, unusual and inconsistent values, cross-form checks and arithmetic errors are some 
of the type of checks performed. The Data Manager will record the edits to be resolved in 
the OnCore system. The site must respond within 2 weeks to each edit by making 
appropriate changes to the forms and database, provide documentation on each change, and 
file the documentation with the edited data collection form. 
9.3 Form Audits 
 
On a periodic basis the DCC selects and requests copies of forms for specific participants 
be sent by each clinical center to the DCC for auditing. 
 Audited forms are compared with the database 


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 Discrepancies are noted and queried 
9.4 Performance Monitoring 
 
The DCC will generate recruitment and retention reports that will provide a count of 
participants enrolled at each site. 
On approximately a bimonthly basis, the DCC will generate reports summarizing the 
performance of all sites. These reports will be reviewed by each site Principal Investigator, 
Consortium Coordinator and by the NIAAA program official. 
9.5 Site Visits 
 
Prior to commencement of the study, representatives of Generon and/or the Mayo Clinic 
will visit the study site to verify adequacy of facilities to conduct the protocol, and to 
review with the Investigator the general obligations regarding studies with investigational 
new drugs. 
During on-site visits, case report forms will be reviewed for completeness and for 
adherence to the protocol. As part of the data review, it is expected that source documents 
(e.g., hospital records, office records, etc.) will be made available for review by the 
representatives of Generon and/or the Mayo Clinic. The representatives will also perform 
drug accountability checks and may periodically review the Investigator’s study file to 
assure completeness of documentation in all aspects of the conduct of the study. The 
Investigator (or appointed delegate) will be available to the representatives of Generon 
and/or the Mayo Clinic during these on-site visits, will provide necessary study documents 
for inspection, and will respond to all inquiries that may arise as part of this review. 
On completion of the study, the representatives of Generon and/or the Mayo Clinic will 
arrange for a final review of the study files, after which the study files should be secured 
for the appropriate time period.  The Investigator will also permit inspection of the study 
files by the Sponsor’s Quality Assurance auditors, IRB/IEC, authorized representatives of 
the FDA, and/or other applicable regulatory agencies. 
10    Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
Study monitoring will occur both on-site and remotely.  The Investigator will ensure that 
the monitor or other compliance or quality assurance reviewer is given access to all the 
study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
 


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Clinical trial monitoring will include review of the study documents and data generated 
throughout the duration of the study to help ensure the validity and integrity of the data 
along with the protection of human research subjects.  This will assist sponsor-
investigators in complying with Food and Drug Administration regulations. 
 
10.2 Data and Safety Monitoring Board (DSMB) for the TREAT Consortium 
 
The Data and Safety Monitoring Board (DSMB) for the TREAT Consortium will be 
reviewing the data for this study every six months.  The charter will be reported to the 
Mayo Clinic IRB and shared with each site. 
10.3 Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, and government regulatory agencies, of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.). 
 
11 Ethical Considerations 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
 
This study will be conducted according to US and international standards of Good Clinical 
Practice (FDA regulations 21 CFR 312 for IND studies and FDA guidance E6) for all 
studies.  Applicable government regulations and institutional research policies and 
procedures will also be followed. 
 
This protocol and any amendments will be submitted to the Institutional Review Board 
(IRB) for formal approval to conduct the study.  The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator.   
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review 
and approval by the IRB.  The formal consent of a subject, using the IRB-approved consent 
form, will be obtained before that subject is submitted to any study procedure.  This consent 
form must be signed by the subject or legally acceptable surrogate, and the investigator-
designated research professional obtaining the consent.  


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12 Data Handling and Record Keeping 
12.1 Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
 What protected health information (PHI) will be collected from subjects in this 
study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term 
survival status that the subject is alive) at the end of their scheduled study period. 
12.2 Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial. 


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12.3 Case Report Forms 
 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If a 
space on the CRF is left blank because the procedure was not done or the question was not 
asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All 
entries should be printed legibly in black ink.  If any entry error has been made, to correct 
such an error, draw a single straight line through the incorrect entry and enter the correct 
data above it.  All such changes must be initialed and dated.  Do not erase or use “white-
out” for errors.  For clarification of illegible or uncertain entries, print the clarification 
above the item, then initial and date it.  If the reason for the correction is not clear or needs 
additional explanation, neatly include the details to justify the correction. 
12.4 Data Management and Processing 
 
Source documents will be kept that include, but are not limited to, medical records, charts, 
appointment books, patient questionnaires, original laboratory records, equipment print-
outs.  All source documents must be made available to the CRA.  The following data must 
be included in the source data: 
 
 Consent to participate in Trial 
 Letter to Primary Care Physician, if applicable 
 Patient visit dates 
 Screening Numbers 
 Demographic Information 
 Medical history 
 Disease history 
 Physical examination 
 Vital signs 
 Laboratory assessments (copy of laboratory reports) 
 AEs and concomitant medications 
 Dates of administering study medication 
 ECGs 
 Liver biopsy reports (if applicable) 
 Patient questionnaires 
 Issues with protocol compliance 
 Completion of, or withdrawal from, trial 
 
 


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12.5 Data Security and Confidentiality 
 
All information obtained during the conduct of the trial with respect to the patient will be 
regarded as confidential and confidentiality of all patients will be maintained.  Clinical 
monitors (e.g. CRAs), auditors and inspectors will require access to a patient’s medical 
notes for the purpose of source document verification source document verification but the 
patient’s confidentiality will be maintained at all times.  An agreement for disclosure of 
any such information will be obtained in writing and is included in the statement of 
informed consent.  The trial data shall not be disclosed to a third party (with the exception 
of auditors and/or regulatory authorities) without the written consent of the TREAT 
consortium.  All data shall be secured against unauthorized access. 
 
Apart from the site investigators, no one will have access to participant’s identity.  Each 
site will securely maintain the code that links participants’ identity to their study numbers 
to prevent access to unauthorized third parties.  Participants will be identified according to 
their study numbers in the data management system (OnCore) and by the investigators 
during any communications. 
 
The written ICF will explain that, for data verification purposes, authorized representatives 
of the funding agency, IRB or Generon which is supplying the study medicine, may 
require direct access to parts of the hospital or practice records relevant to the trial, 
including patient’s medical history. 
12.6 Data Quality Assurance 
 
Logic and consistency checks will be performed on all data entered into the CRF to ensure 
accuracy and completeness. 
 
Training sessions, regular monitoring of the trial at the trial sites, instruction manuals, data 
verification, cross-checking and data audits will be performed to ensure quality of all trial 
data.  Investigators’ meetings and/or on-site trial initiations will be performed to prepare 
investigators and other trial site personnel for appropriate collection of trial data. 
12.7 Data Clarification Process 
 
The data manager for the TREAT consortium will conduct periodic data queries.  Each site 
will be responsible for reconciling these queries. 
12.8  Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the       
conduct of the study.  These will include subject case histories and regulatory documents. 
The investigator should retain all correspondence relating to this trial in the Investigator 
Site File (ISF).   
 


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All documents relating to the trial including the ISF itself, source documents and patient 
medical files (retained per country specific regulations), completed trial patient log and 
confidential patient identification list will be retained by the investigator for a minimum 
period of 15 years, in accordance with regulations.  In the event that storage of records 
becomes a problem at any time during this period, the Sponsor should be consulted for 
assistance.  At the end of the minimum period, the investigator should obtain written 
authorization form the Sponsor prior to the destruction of any records.  The investigator will 
notify the Sponsor if ownership documents or responsibility for the trial site is transferred.  
The sponsor will inform investigators should it become aware of any changes in storage 
requirements.   
13 Finance and Insurance 
 
This study is being funded by a grant from the National Institute on Alcohol Abuse and 
Alcoholism (NIAAA), one of the institutes that comprise the National Institutes of Health 
(NIH).   
 
Care for research-related injuries will be billed in the ordinary manner, to the participant or 
the participant’s insurance.  The participant will be responsible for all treatment costs not 
covered by their insurance, including deductibles, co-payments and coinsurance.  No 
compensation will be provided for losses related to the subject’s participation in this study 
(such as time off from work, disability, discomfort due to any research-related injury, etc.).  
14 Publication Plan 
 
No data is to be made public or published without prior knowledge and written approval by 
the TREAT Consortium Steering Committee. 
 
The TREAT consortium publication policies will be applied.  Generon will have the 
opportunity to review each paper prior to its submission for publication. 
 
The study will be registered to ClinicalTrials.gov prior to subject recruitment and 
enrollment, as well as posting of results to ClinicalTrials.gov within 12 months of final data 
collection for the primary outcome.   
 
 
 


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15 List of Planned Laboratory Analytes 
 
Serum Chemistry 
  
1. Sodium 
2. Potassium 
3. Calcium 
4. Chloride 
5. Bicarbonate 
6. Albumin 
7. BUN 
8. Creatinine 
9. Total bilirubin 
10. Direct bilirubin 
11. Aspartate aminotransferase (AST) 
12. Alanine transaminase (ALT) 
13. Alkaline phosphatase 
14. Glucose  
15. Total Protein 
Hematology 
 
1. Hemoglobin 
2. Hematocrit 
3. White Blood Cell Count 
4. Platelets 
5. MCV 
6. Prothrombin Time (PT and INR) 
Urine and Serum Pregnancy Test 
 
Special Investigations 
 
1. Lipid profile 
2. CRP 
3. SAA1 
 
 


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16 References 
 
1. Dhanda AD, Lee RW, Collins PL, McCune CA. Molecular targets in the treatment of 
alcoholic hepatitis. World J Gastroenterol. 2012 Oct 21;18(39):5504-13. doi: 
10.3748/wjg.v18.i39.5504. 
2. Dugum M, Zein N, McCullough A, Hanouneh I. Alcoholic hepatitis: Challenges in 
diagnosis and management. Cleve Clin J Med. 2015 Apr;82(4):226-236. doi: 
10.3949/ccjm.82a.14048. 
3. Gao B. Hepatoprotective and anti-inflammatory cytokines in alcoholic liver disease. J 
Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:89-93. doi: 10.1111/j.1440-
1746.2011.07003.x. 
4. Gao, B. Interplay of interleukin-22 and its binding protein in controlling liver scarring. 
Hepatology. 2015 Apr;61(4):1121-3. doi: 10.1002/hep.27688. Epub 2015 Mar 10. 
5. Haber PS, Warner R, Seth D, et al. Pathogenesis and management of alcoholic hepatitis. J 
Gastroenterol Hepatol. 2003 Dec;18(12):1332-44.  
6. Kong X, Feng D, Mathews S, Gao B. Hepatoprotective and anti-fibrotic functions of 
interleukin-22: therapeutic potential for the treatment of alcoholic liver disease.  J 
Gastroenterol Hepatol. 2013 Aug;28 Suppl 1:56-60. doi: 10.1111/jgh.12032. 
7. Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis N Engl J Med 2009; 360:2758-
2769. 
8. Madhotra R, Gilmore IT. Recent developments in the treatment of alcoholic hepatitis. 
QJM. 2003 Jun;96(6):391-400. 
9. Menon KV, Gores GJ, Shah VH. Pathogenesis, diagnosis, and treatment of alcoholic 
liver disease. Mayo Clinic. Proc. 2001;76(10):1021-9. 
10. Orman ES, Odena G, Bataller R. Alcoholic liver disease: pathogenesis, management, and 
novel targets for therapy. J Gastroenterol Hepatol. 2013 Aug;28 Suppl 1:77-84. doi: 
10.1111/jgh.12030. 
11. O’Shea RS, McCullough AJ. Treatment of alcoholic hepatitis. Clin Liver Dis. 2005 
Feb;9(1):103-34.  
12. Pan CX, Tang J, Wang XY, Wu FR, Ge JF, Chen FH. Role of interleukin-22 in liver 
diseases.  Inflamm Res. 2014 Jul;63(7):519-25. doi: 10.1007/s00011-014-0727-3. Epub 
2014 Mar 13. 
13. Paula H, Asrani SK, Boetticher NC, et al. Alcoholic liver disease-related mortality in the 
United States. Am J Gastroenterol. 2010; 1980-2003. 
14. Støy S, Sandahl TD, Dige AK, Agnholt J, Rasmussen TK, Grønbæk H, Deleuran B, 
Vilstrup H. Highest frequencies of interleukin-22-producing T helper cells in alcoholic 
hepatitis patients with a favourable short-term course.  PLoS One. 2013;8(1): e55101. 
doi:10.1371/ journal.pone.0055101.  Epub 2013 Jan 25. 
15. Williams JA, Manley S, Ding WX. New advances in molecular mechanisms and 
emerging therapeutic targets in alcoholic liver diseases. World J Gastroenterol. 2014 Sep 
28;20(36):12908-33. doi: 10.3748/wjg.v20.i36.12908. 


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16. Xing WW, Zou MJ, Liu S, Xu T, Wang JX, Xu DG. Interleukin-22 protects against acute 
alcohol-induced hepatotoxicity in mice. Biosci Biotechnol Biochem. 2011;75(7):1290-4. 
Epub 2011 Jul 7.