Conditions: Alcohol-related Liver Disease
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 12
Healthy volunteers: no

Brief summary:
Is acamprosate safe to use in individuals with liver disease.

Detailed description:
Adult patients aged 21 or over with a diagnosis of alcohol-related liver disease and alcohol use disorder (AUD) and abstinent from alcohol for at least 2 weeks (but not more than 6 months) prior to initiating acamprosate treatment.

Arms:
arm 1: The first 5 patients enrolled = AUD (alcohol use disorder) w/MELD-Na (model for end stage liver disease sodium) score less than 20. arm 2: The second 5 patients enrolled = AUD (alcohol use disorder) w/MELD-Na (model for end stage liver disease sodium) score more than 20.

Interventions: intervention 1: Acomprosate
Intervention descriptions: intervention 1: Acamprosate will be administered orally and will be dosed at 333 mg three times a day, if tolerated it will be increased to 666 mg three times a day. Acamprosate will be administered for a total of 3 months

Protocol document:
Prot_SAP_000.pdf: 
 
 
A PHASE IIA STUDY 
EVALUATING THE SAFETY OF 
ACAMPROSATE FOR ALCOHOL 
USE DISORDER IN ALCOHOL-
RELATED LIVER DISEASE 
 
NCT04287920 
 
4/25/2022 


Acamprosate for alcohol use disorder in alcohol-related liver disease 
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Revised 04/25/2022 
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Douglas Simonetto 
 
CONFIDENTIAL 
 
 
A PHASE IIA STUDY EVALUATING THE SAFETY OF 
ACAMPROSATE FOR ALCOHOL USE DISORDER IN ALCOHOL-
RELATED LIVER DISEASE 
 
 
 
 
 
 
Regulatory Sponsor: 
Douglas Simonetto 
Division of Gastroenterology and Hepatology, Department of 
Medicine 
 
 
 
 
Study Product: 
Acamprosate 
Protocol Number: (IRBe) 
18-010902 
IND Number: 
n/a 
 
 
 
 
 
Initial version: 4/11/2019 Version (1.0) 
Revised: 
01/07/2020 Version (2.0) 
Revised: 
06/25/2020 Version (2a) 
Revised: 
04/25/2022 Version (3.0) 
 


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The table of contents headings and page numbers can be AUTOMATICALLY updated after all 
of the other changes have been made to the protocol template.  Right click on the Table of 
Contents field and use the “Update Field” function in MS-Word. 
 
Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................. 6 
1.1 
BACKGROUND ................................................................................................................................ 6 
1.2 
INVESTIGATIONAL AGENT ............................................................. ERROR! BOOKMARK NOT DEFINED. 
1.3 
PRECLINICAL DATA ........................................................................................................................ 7 
1.4 
CLINICAL DATA TO DATE ................................................................................................................ 7 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................. 7 
2 
STUDY OBJECTIVES .......................................................................................................................... 8 
3 
STUDY DESIGN ................................................................................................................................... 8 
3.1 
GENERAL DESIGN ........................................................................................................................... 9 
3.2 
PRIMARY STUDY ENDPOINTS ......................................................................................................... 10 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 10 
3.4 
PRIMARY SAFETY ENDPOINTS ........................................................................................................ 11 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 11 
4.1 
INCLUSION CRITERIA ..................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA .................................................................................................................... 12 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .................................................................. 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................ 12 
4.4.1 
When and How to Withdraw Subjects ........................................................................................ 12 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 13 
5 
STUDY DRUG .................................................................................................................................... 13 
5.1 
DESCRIPTION ................................................................................................................................ 13 
5.2 
TREATMENT REGIMEN ................................................................................................................... 14 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................................ 14 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................................... 14 
5.5 
SUBJECT COMPLIANCE MONITORING .............................................................................................. 15 
5.6 
PRIOR AND CONCOMITANT THERAPY .............................................................................................. 15 
5.7 
PACKAGING .................................................................................................................................. 15 
5.8 
BLINDING OF STUDY ..................................................................................................................... 15 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................. 15 
5.9.1 
Receipt of Drug Supplies .......................................................................................................... 15 
5.9.2 
Storage ................................................................................................................................... 15 
5.9.3 
Dispensing of Study Drug ......................................................................................................... 15 
5.9.4 
Return or Destruction of Study Drug ......................................................................................... 15 
6 
STUDY PROCEDURES ...................................................................................................................... 16 
6.1 
VISIT 1 ......................................................................................................................................... 16 
6.2 
VISIT 2-5 ...................................................................................................................................... 16 
6.3 
VISIT 6. ........................................................................................ ERROR! BOOKMARK NOT DEFINED. 
6.4 
VISIT 7. ........................................................................................ ERROR! BOOKMARK NOT DEFINED. 
6.5 
VISIT 8. ........................................................................................ ERROR! BOOKMARK NOT DEFINED. 
 
7 
STATISTICAL PLAN ......................................................................................................................... 19 


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7.1 
SAMPLE SIZE DETERMINATION ....................................................................................................... 19 
7.2 
STATISTICAL METHODS ................................................................................................................. 19 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ......................................................................................... 19 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 20 
8.1 
DEFINITIONS ................................................................................................................................ 20 
8.2 
RECORDING OF ADVERSE EVENTS .................................................................................................. 22 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ...................................... 22 
8.3.1 
Investigator reporting: notifying the Mayo IRB ........................................................................... 22 
8.3.2 
Investigator reporting: Notifying the FDA .................................................................................. 24 
8.4 
UNBLINDING PROCEDURES ............................................................................................................ 24 
8.5 
STOPPING RULES  .......................................................................................................................... 24 
8.6 
MEDICAL MONITORING ................................................................................................................. 25 
8.6.1 
Internal Data and Safety Monitoring Board ............................................................................... 25 
8.6.2 
Independent Data and Safety Monitoring Board ........................... Error! Bookmark not defined. 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 25 
9.1 
CONFIDENTIALITY ........................................................................................................................ 25 
9.2 
SOURCE DOCUMENTS .................................................................................................................... 25 
9.3 
CASE REPORT FORMS .................................................................................................................... 26 
9.4 
RECORDS RETENTION .................................................................................................................... 27 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 28 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 28 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 28 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 28 
12 
STUDY FINANCES ............................................................................................................................ 29 
12.1 
FUNDING SOURCE ......................................................................................................................... 29 
12.2 
CONFLICT OF INTEREST ................................................................. ERROR! BOOKMARK NOT DEFINED. 
12.3 
SUBJECT STIPENDS OR PAYMENTS .................................................. ERROR! BOOKMARK NOT DEFINED. 
13 
PUBLICATION PLAN ....................................................................................................................... 29 
14 
REFERENCES ................................................................................................................................... 29 
15 
ATTACHMENTS ............................................................................................................................... 31 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUD 
Alcohol use disorder 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSM 
Diagnostic and Statistical Manual 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HE 
Hepatic encephalopathy 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
 
 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
MELD-Na 
Model for End Stage Liver Disease Sodium  
MMSE 
Mini mental state examination 
PACS 
Pennsylvania Alcohol Craving Scale 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
 
 
 
 
 


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Study Summary 
Title 
A phase IIa study evaluating the safety of acamprosate for alcohol use 
disorder in alcohol-related liver disease 
Running Title 
Acamprosate for alcohol use disorder in alcohol-related liver disease 
Protocol Number 
18-010902 
Phase 
Phase IIa 
Methodology 
Open label, pilot safety assessment 
Overall Study 
Duration 
12 months 
Subject Participation 
Duration 
6 months 
Single or Multi-Site  
Single site 
Objectives 
To evaluate the safety of acamprosate in individuals with alcohol-use 
disorder (AUD) and alcohol-related liver disease 
Number of Subjects 
10 
Diagnosis and Main 
Inclusion Criteria 
Adult patients aged 21 or over with a diagnosis of alcohol-related liver 
disease and AUD 
Study Product, Dose, 
Route, Regimen 
Acamprosate will be dosed at 333 mg TID, increased to 666 mg TID 
after 1 week if tolerated. If GFR is 30-50 ml/min, dosage will remain at 
333 mg TID throughout the study. 
Duration of 
Administration 
3 months 
Reference therapy 
No reference or control group 
Statistical 
Methodology 
Basic descriptive statistics and a qualitative analysis will be performed 
 


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1 Introduction 
This document is a clinical research 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.  
1.1 
Background 
Alcohol use disorder (AUD) is a common condition with a lifetime and 12-month prevalence of 
29.1% and 13.9%, respectively, identified in the US population (Grant et al., 2015). Although 
several effective treatments are available, less than one-fifth of individuals seek treatment over 
their lifetime; most seek help from physicians to manage comorbidities related to AUD (Grant et 
al., 2015; Lyon, 2017). Alcohol-related liver disease encompasses a wide spectrum of disease, 
ranging from steatosis and minimal fibrosis to alcoholic hepatitis, cirrhosis and sequelae of portal 
hypertension. Hepatic steatosis is common, seen in approximately 90% of longstanding heavy 
drinkers with recent binging (Edmondson et al., 1967). Ongoing alcohol consumption may result 
in steatohepatitis in one third of patients and an estimated 16% of those with steatohepatitis will 
develop cirrhosis over five years (Barrio et al, 2004; Deleuran et al., 2012). Individuals with 
alcohol-related cirrhosis are at high risk for complications from liver disease and death; these risks 
are increased in the setting of ongoing alcohol use (Jepsen et al., 2010; Jepsen et al., 2012). 
 
Despite the prevalence of liver disease complicating AUD, there are few prospective clinical 
studies evaluating the efficacy of pharmacologic treatments to promote abstinence and prevent 
relapse. Naltrexone and acamprosate have been found to be effective for AUD; however, 
naltrexone carries a significant risk of hepatocellular injury, and it is contraindicated in those with 
acute hepatitis or liver failure (Jonas et al., 2014; Alkermes, Inc., 2010). Other promising 
medications that require further study include baclofen, topiramate, gabapentin, varenicline and 
ondansetron, of which baclofen is the only drug that has been evaluated in liver disease 
(Addolorato et al., 2007). 
 
Acamprosate has not been evaluated formally in individuals with AUD and liver disease. It is an 
N-methyl-D-aspartate glutamate receptor antagonist approved by the Food and Drug 
Administration to aid in maintaining abstinence in individuals with alcohol dependence (Frye et 
al., 2016). Acamprosate has an unclear mechanism of action, although it is thought that its effect 
on decreased alcohol craving intensity is mediated through a reduction in glutamate levels (Frye 
et al., 2016). The efficacy of acamprosate has been demonstrated in several meta-analyses, most 
recently exhibiting a number needed to treat of 12 to prevent return to any drinking (Jonas et al., 
2014; Rosato et al., 2015). Acamprosate is not metabolized by the liver and thus has been 
considered as a potential therapeutic option in those with liver disease. However, as acamprosate 
antagonizes the glutamate receptor, there have been concerns it may increase the risk of hepatic 
encephalopathy. Previously, a single dose of acamprosate 666 mg was administered to 12 patients 
with Child-Pugh A or B cirrhosis with no identifiable induction of subclinical hepatic 
encephalopathy; however, transient diastolic hypotension was noted (Delgrange et al., 1992). No 
further studies on acamprosate have been performed in individuals with liver disease. 
 
To evaluate the safety of acamprosate in individuals with AUD and alcohol-related liver disease, 
an initial pilot study in five patients with a Model for End Stage Liver Disease Sodium (MELD-
Na) score less than 20 will be conducted. If no safety concerns are identified, the study will then 


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be performed in five patients with MELD-Na scores of 20 or more. If again no safety concerns are 
identified, a larger, placebo-controlled efficacy study is planned and will be submitted as a separate 
protocol. 
1.2 
Investigational Agent 
Per the manufacturer, Merck (2005): “CAMPRAL® (acamprosate calcium) is supplied in an 
enteric-coated tablet for oral administration. Acamprosate calcium is a synthetic compound with 
a chemical structure similar to that of the endogenous amino acid homotaurine, which is a 
structural analogue of the amino acid neurotransmitter γ-aminobutyric acid and the amino acid 
neuromodulator taurine. Its chemical name is calcium acetylaminopropane sulfonate. Its 
chemical formula is C10H20N2O8S2Ca and molecular weight is 400.48.  
 
Each CAMPRAL tablet contains acamprosate calcium 333 mg, equivalent to 300 mg of 
acamprosate. Inactive ingredients in CAMPRAL tablets include: crospovidone, microcrystalline 
cellulose, magnesium silicate, sodium starch glycolate, colloidal anhydrous silica, magnesium 
stearate, talc, propylene glycol and Eudragit® L 30 D or equivalent. The drug product will 
appear in tablet form.”  
 
Acamprosate is now available as a generic in the USA. 
1.3 
Preclinical Data 
 
n/a 
1.4 
Clinical Data to Date 
 
Acamprosate has been studied extensively in individuals without liver disease. The efficacy of 
acamprosate has been demonstrated in several meta-analyses, most recently exhibiting a number 
needed to treat of 12 to prevent return to any drinking (Jonas et al., 2014; Rosato et al., 2015).  
 
Previously, a single dose of acamprosate 666 mg was administered to 12 patients with Child-
Pugh A or B cirrhosis with no identifiable induction of subclinical hepatic encephalopathy; 
however, transient diastolic hypotension was noted (Delgrange et al., 1992). No further studies 
on acamprosate have been performed in individuals with liver disease. 
 
1.5 
Dose Rationale  
 
Acamprosate will be dosed at 333 mg TID, increased to 666 mg TID after 1 week if tolerated. If 
GFR is 30-50 ml/min, dosage will remain at 333 mg TID throughout the study. The dosing and 
dose regimen of acamprosate has varied in prior trials; however, the regimen used herein is largely 
considered standard for use in AUD (Plosker, 2015; Higuchi, 2015). Based on prior studies and 
for practical purposes, route of administration will be by mouth. 


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1.6 
Risks and Benefits 
 
Individuals with alcohol-related cirrhosis are at high risk for complications from liver disease and 
death; these risks are increased in the setting of ongoing alcohol use (Jepsen et al., 2010; Jepsen et 
al., 2012). A profound difference in five-year survival after an episode of alcoholic hepatitis in 
seen in those who are able to maintain abstinence compared to those who continue to drink or 
relapse, with rates of 75% and 21-27%, respectively (Potts et al., 2013).  
 
Adverse events associated with acamprosate use are considered minimal and primarily have 
included anxiety, diarrhea and vomiting (Jonas et al., 2014; Reus et al., 2018). Specific rates of the 
following adverse events have been reported: pruritus (4%), diarrhea (17%), flatulence (3%), 
nausea (4%), dizziness (3%), insomnia (7%), anxiety (6%) and depression (5%) (Merck, 2005). 
More rare risks include cardiomyopathy, deep thrombophlebitis, heart failure, mesenteric arterial 
occlusion, shock and suicide (Merck, 2005). There has been no increased risk of withdrawal from 
trials with acamprosate due to adverse events (Jonas et al., 2014). Given the high risk of adverse 
outcomes associated with ongoing alcohol consumption in this patient population, including death, 
the risks of acamprosate use are reasonable in comparison.  
2 Study Objectives 
Primary Objective: 
 
To assess the safety and tolerability of acamprosate for treatment of AUD in alcohol-related liver 
disease as measured by adverse event reporting. 
 
Secondary Objective: 
 
To assess treatment effect of acamprosate on alcohol relapse in alcohol-related liver disease as 
measured by Pennsylvania Alcohol Craving Scale (PACS) scores and reporting of alcohol use. 
 
3 Study Design 
 
This study is a phase IIa trial of the safety of acamprosate in treating AUD in alcohol-related liver 
disease. Subjects will be screened for eligibility at outpatient clinic visits and during 
hospitalizations; interested qualified subjects will be consented and offered participation in this 
trial. At study enrollment, initial MELD-Na score must be less than 20 for the five individuals 
enrolling in the first phase of the pilot safety assessment. The second phase of the pilot safety 
assessment will include individuals with a MELD-Na of 20 or more at enrollment. Once consent 
has been obtained, baseline characteristics will be established and then patients will be initiated on 
acamprosate treatment. Acamprosate will be administered for three months, during which time, 
patients will complete monthly blood work, weekly telephone assessments for the first month, 
followed by telephone assessments and urine testing on a monthly basis thereafter. A final clinic 
visit for evaluation and collection of lab samples will be conducted at the end of the study at 3 
months. Patients will be contacted by telephone at weeks 13 and 24 after study enrollment for final 
follow up assessments off of study medication. 


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3.1 
General Description 
 
Adult patients aged 21 or over with a diagnosis of alcohol-related liver disease and AUD will be 
identified in the outpatient clinic or while admitted to hospital and seen by the gastroenterology or 
hepatobiliary service at Mayo Clinic, Rochester. This population is evaluated for potential 
eligibility for other alcohol-related liver disease studies by a research coordinator on a weekly 
basis. The diagnosis of alcohol-related liver disease will be determined by a hepatologist based on 
history of regular and excessive alcohol consumption in the absence of other causes of liver 
cirrhosis or acute hepatitis, compatible clinical, imaging and laboratory findings and typical 
histology on liver biopsy, if performed. Underlying liver disease may include alcoholic hepatitis, 
advanced (F3-F4) fibrosis, and/or portal hypertension. The diagnosis of AUD will be determined 
by a hepatologist based on history obtained that is consistent with DSM-5 diagnostic criteria for 
AUD (all categories of mild, moderate and severe considered eligible). 
 
Patients need not be abstinent from alcohol prior to initiating acamprosate treatment (but not 
abstinent for more than 6 months). At study enrollment, initial MELD-Na score must be less than 
20 for the five individuals enrolling in the first phase of the pilot safety assessment. The second 
phase of the pilot safety assessment will include individuals with a MELD-Na of 20 or more at 
enrollment. Patients with heart failure (NYHA class II or higher) or hypotension requiring the use 
of vasoconstrictors (i.e. midodrine) will be excluded. Individuals with a glomerular filtration rate 
(GFR) of less than 30 ml/min will be excluded. Acamprosate will be dosed at 333 mg TID, 
increased to 666 mg TID after 1 week if tolerated. If GFR is 30-50 ml/min, dosage will remain at 
333 mg TID throughout the study. Acamprosate will be administered for a total of 3 months. 
 
Prior to enrollment, known risks and benefits of acamprosate in treating AUD will be discussed 
with patients including pruritus (4%), diarrhea (10% to 17%), flatulence (3%), nausea (4%), 
dizziness (3%), insomnia (7%), anxiety (6%) and depression (5%). More rare risks include 
cardiomyopathy, deep thrombophlebitis, heart failure, mesenteric arterial occlusion, shock and 
suicidal intent (1%). 
 
At enrollment, collected baseline characteristics will include patient age, sex, race, martial and 
employment status, education level, social support, presence of children, age of children, 
underlying liver disease etiology, MELD-Na score, presence of ascites, esophageal varices, 
spontaneous bacterial peritonitis, diabetes, corticosteroid or other medical treatment for alcoholic 
hepatitis (Maddrey and Lille scores if relevant), medical comorbidities, prescription and non-
prescription medications. With regard to alcohol use, patients will have the 11 DSM-5 questions 
regarding AUD answered at screening (American Psychiatric Association, 2013), as well as the 
following history obtained: duration of excess alcohol consumption in years, level of alcohol 
consumption prior to study enrollment, interval of alcohol abstinence prior to study enrollment, 
family history of alcoholism, history of alcohol-related legal issues, psychiatric comorbidity 
(requiring medication, outpatient care or hospitalization), other addictions including smoking and 
number of prior rehabilitation attempts for alcohol or other addictions. The PACS questionnaire 
will be administered. Vital signs and a physical examination will be performed. West Haven HE 
score will be graded and modified telephone version of MMSE completed. Blood work will be 
completed including a complete blood count, electrolytes, creatinine, blood urea nitrogen, total 
bilirubin, direct bilirubin, albumin, INR, AST, ALT and alkaline phosphatase. A urine ethyl 


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glucuronide will be performed. A urine pregnancy test will be conducted before admission into 
the trial for women of child-bearing potential. 
 
Study duration will be six months. During the study, patients will complete monthly MELD-Na 
labs and receive a phone call weekly for the first month, then monthly for a total of 3 months. 
Urine ethyl glucuronide will be done at enrollment and once monthly. Patients will then have a 
follow up visit at 12 weeks, with labs, urine ethyl glucuronide, vital signs and physical exam. 
During telephone assessments and at the follow up visit, patients will be asked about potential side 
effects and hepatic decompensation. Other variables to be collected at enrollment and at the 3 
month visit include Child-Pugh score, West Haven grading of HE, vital signs at enrollment and 
current medications. At enrollment, during phone calls and at the follow up visit, patients will be 
asked standardized questions to assess for HE based on the abbreviated telephone version of the 
mini-mental state examination (MMSE). Follow up telephone visits at 13 and 24 weeks will be 
conducted, primarily to monitor for adverse events and alcohol relapse. 
 
The Pennsylvania Alcohol Craving Scale (PACS) will be applied before treatment initiation, 
weekly for the first month on treatment, then monthly thereafter. This will include the need severity 
scale (mild, moderate, severe) at baseline and at each assessment by phone call and in clinic. 
 
Alcohol use relapse will be monitored. Any amount of alcohol use as revealed during follow-up 
considered a relapse event. Alcohol use will be captured and categorized as none, slip (no longer 
drinking at most recent follow up) or sustained alcohol use (minimum 100 days drinking). Slips 
and sustained alcohol use will be categorized as binge drinking, frequent drinking, or both (binge 
drinking as more than 6 units/day for men and 4 units/day for women and frequent drinking as 
alcohol use in 4 or more days/week regardless of quantity per day) (Lee et al., 2018). 
 
Basic descriptive statistics and a qualitative analysis will be performed. Analyses will be 
performed using SPSS 25 (Chicago, IL). Results will not contain any patient-specific information.  
3.2 
Number of Subjects 
 
10 individuals. 
3.3 
Duration of Participation 
 
6 months. 
3.4 
Primary Study Endpoints 
 
The primary endpoint is an estimation of the safety profile of acamprosate for treatment of AUD 
in alcohol-related liver disease as measured by adverse event reporting. The safety parameters to 
be measured include clinical symptoms, vital signs, physical examination, blood work and urine 
testing. 
3.5 
Secondary Study Endpoints 
 


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Secondary endpoints will detail extent of alcohol cravings and relapse during treatment with 
acamprosate for treatment of AUD in alcohol-related liver disease as measured by Pennsylvania 
Alcohol Craving Scale (PACS) scores and reporting of any amount of alcohol use. 
3.6 
Primary Safety Endpoints 
 
See 3.4. 
3.7 
Identification of Source Data 
 
The following source data will be directly recorded on the Case Report Form (CRF):  
• Vital signs 
• Weight 
• Clinical history 
• Adverse events 
• Medication list including new medications, change in medications 
• Alcohol use 
• Other substance use including nicotine and recreational drug use 
• PACS responses and score 
• MMSE responses and score 
• West Haven HE grade 
• Laboratory results and clinical interpretation of the values. 
• Clinical significance of observations (when applicable) 
 
The following source data will not be directly collected in the Case Report Form (CRF), but will 
be captured in supportive documentation (Demographics form, Concurrent Medications form): 
• All data to be obtained at enrollment as detailed in 6.1. 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
Eligible individuals: 
• Aged 21 or over  
• Diagnosis of alcohol-related liver disease and AUD.  
o The diagnosis of alcohol-related liver disease will be determined by a hepatologist 
based on history of regular and excessive alcohol consumption in the absence of 
other causes of liver cirrhosis or acute hepatitis, compatible clinical, imaging and 
laboratory findings and typical histology on liver biopsy, if performed. Underlying 
liver disease may include alcoholic hepatitis, advanced (F3-F4) fibrosis, and/or 
portal hypertension.  
o The diagnosis of AUD will be determined by a hepatologist and/or addiction 
psychiatrist based on history obtained that is consistent with DSM-5 diagnostic 
criteria for AUD (all categories of mild, moderate and severe considered eligible) 
(American Psychiatric Association, 2013; questions from NIH, 2016).  


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• Patients need not be abstinent from alcohol prior to initiating acamprosate treatment (but 
not abstinent for more than 6 months).  
• At study enrollment, initial MELD-Na score must be less than 20 for the five individuals 
enrolling in the first phase of the pilot safety assessment. The second phase of the pilot 
safety assessment will include individuals with a MELD-Na of 20 or more at enrollment. 
• Have capacity to provide consent themselves 
4.2 
Exclusion Criteria 
 
Exclusion criteria: 
• Individuals with a glomerular filtration rate (GFR) of less than 30 ml/min 
• Congestive heart failure (NYHA class II or higher) 
• Hypotension, requiring the use of vasoconstrictors (i.e. midodrine) 
• Pregnancy, lactation or refusal to use a reliable method of birth control if a sexually active 
female of childbearing potential. Although no human trial data is available, animal studies 
suggest possible teratogenic effects of acamprosate (Merck, 2005).   
4.3 
Subject Recruitment, Enrollment and Screening 
 
Patients will be identified in the outpatient hepatobiliary clinic or while admitted to hospital and 
seen by the gastroenterology or hepatobiliary service at Mayo Clinic, Rochester. This population 
is evaluated for potential eligibility for other alcohol-related liver disease studies by a research 
coordinator on a weekly basis. Physicians that identify eligible patients that are not captured by 
the research coordinator may refer the patient. Both male and female subjects must use 2 reliable 
forms of birth control from screening to at least up to 4 weeks after the study treatment is over. 
No recruitment material will be created. 
 
Using clinical information obtained from the electronic medical record, patients will be screened 
for eligibility. Documentation of inclusion and exclusion criteria will be included in the participant 
database. 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 
Patients will be withdrawn from the study prior to study completion if: 
1. Subjects elect to withdraw consent 
2. Subject is found to be ineligible for the protocol as per the Inclusion/Exclusion criteria. 
3. Subjects experience a serious adverse event felt to possibly be related to acamprosate 
administration as determined by PI and/or DSMB. 
4. Failure of the subject to comply with protocol requirements. 
5. Exhibition of unacceptable toxicity which would make it difficult or dangerous to comply 
with further protocol requirements such as study visits, blood draws, etc. 
6. 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. 


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7. Death of the subject. 
8. Subjects with a test consistent with pregnancy such as a positive beta-hCG. 
9. Subject is lost to follow-up. 
10. 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. 
 
If subjects are withdrawn from the study, they will be replaced to ensure a total of 10 patients 
complete the study in its entirety. The data collected up until the time of withdrawal from the 
study will be included in analysis. 
 
Follow up from subjects withdrawn from study treatment will include: 
• Clinic visit at time of withdraw from study will be recommended. Beyond risk of 
returning to alcohol consumption, sudden study treatment termination should not include 
any subject safety considerations. 
• Follow up phone call 3 months after withdrawal from study 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
If a subject withdraws consent to participate in the study, for subject safety reasons, attempts will 
be made to obtain permission to collect follow up information whenever possible. Attempt will 
be made when the patient reports withdrawal of consent. 
5 Study Drug  
5.1 
Description 
 
Per Merck manual (2005): 
“CAMPRAL® (acamprosate calcium) is supplied in an enteric-coated tablet for oral 
administration. Acamprosate calcium is a synthetic compound with a chemical structure similar 
to that of the endogenous amino acid homotaurine, which is a structural analogue of the amino 
acid neurotransmitter γ-aminobutyric acid and the amino acid neuromodulator taurine. Its 
chemical name is calcium acetylaminopropane sulfonate. Its chemical formula is 
C10H20N2O8S2Ca and molecular weight is 400.48.  
 
Acamprosate calcium is a white, odorless or nearly odorless powder. It is freely soluble in water, 
and practically insoluble in absolute ethanol and dichloromethane. Each CAMPRAL tablet 
contains acamprosate calcium 333 mg, equivalent to 300 mg of acamprosate. Inactive ingredients 
in CAMPRAL tablets include: crospovidone, microcrystalline cellulose, magnesium silicate, 
sodium starch glycolate, colloidal anhydrous silica, magnesium stearate, talc, propylene glycol 
and Eudragit® L 30 D or equivalent. The drug product will appear in tablet form. 
 
CLINICAL PHARMACOLOGY  
Pharmacodynamics  
The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely 
understood. Chronic alcohol exposure is hypothesized to alter the normal balance between 


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neuronal excitation and inhibition. In vitro and in vivo studies in animals have provided evidence 
to suggest acamprosate may interact with glutamate and GABA neurotransmitter systems 
centrally, and has led to the hypothesis that acamprosate restores this balance.  
 
Pharmacodynamic studies have shown that acamprosate calcium reduces alcohol intake in 
alcohol-dependent animals in a dose-dependent manner and that this effect appears to be specific 
to alcohol and the mechanisms of alcohol dependence. Acamprosate calcium has negligible 
observable central nervous system (CNS) activity in animals outside of its effects on alcohol 
dependence, exhibiting no anticonvulsant, antidepressant, or anxiolytic activity.  The 
administration of acamprosate calcium is not associated with the development of tolerance or 
dependence in animal studies.  CAMPRAL is not known to cause alcohol aversion and does not 
cause a disulfiram-like reaction as a result of ethanol ingestion.  
 
Pharmacokinetics 
Absorption: The absolute bioavailability of CAMPRAL after oral administration is about 11%. 
Steady-state plasma concentrations of acamprosate are reached within 5 days of dosing. Steady-
state peak plasma concentrations after CAMPRAL doses of 2 x 333 mg tablets three times daily 
average 350 ng/mL and occur at 3-8 hours post-dose. Coadministration of CAMPRAL with food 
decreases bioavailability as measured by Cmax and AUC, by approximately 42% and 23%, 
respectively. The food effect on absorption is not clinically significant and no adjustment of dose 
is necessary. 
Distribution: The volume of distribution for acamprosate following intravenous administration is 
estimated to be 72-109 liters (approximately 1 L/kg). Plasma protein binding of acamprosate is 
negligible.  
Metabolism: Acamprosate does not undergo metabolism. 
Elimination: After oral dosing of 2 x 333 mg of CAMPRAL, the terminal half-life ranges from 
approximately 20 - 33 hours. Following oral administration of CAMPRAL, the major route of 
excretion is via the kidneys as acamprosate.” 
5.2 
Treatment Regimen 
Acamprosate will be dosed at 333 mg PO TID, increased to 666 mg PO TID after 1 week if 
tolerated. If GFR is 30-50 ml/min, dosage will remain at 333 mg PO TID throughout the study. 
Treatment duration is 3 months. 
5.3 
Method for Assigning Subjects to Treatment Groups 
 
n/a 
5.4 
Preparation and Administration of Study Drug 
 
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5.5 
Subject Compliance Monitoring 
 
At weekly telephone assessments for the first month, and then monthly telephone assessments 
and then clinic visit at 3 months, the study team will ask the patient if he or she has missed any 
acamprosate doses. Subjects will be asked to count their remaining pills and detail how many 
they were initially prescribed and when. If patients are significantly non-compliant, defined as 
taking less than 75% of prescribed medication, they will be withdrawn from the study. 
5.6 
Prior and Concomitant Therapy 
 
All prescription and non-prescription medications will be documented at enrollment and 
throughout the study. There are no known significant drug interactions and no concomitant 
medications will be considered exclusion criteria to the study (Merck, 2005). 
5.7 
Packaging 
 
Acamprosate will be administered in tablets by mouth. The drug will be picked up at the 
patient’s preferred pharmacy. The study is not blinded. Labeling will be per manufacturer.  
5.8 
Masking/Blinding of Study  
 
The study is not blinded. 
5.9 
Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
 
The drug will be picked up by the patient at the patient’s preferred pharmacy. 
5.9.2 Storage 
 
It will be recommended that patients store acamprosate at room temperature. Merck indicates 
recommended storage at 25ºC (77ºF); excursions permitted to 15º - 30ºC (59º - 86ºF). 
5.9.3 Dispensing of Study Drug 
 
Regular study drug reconciliation will be performed during assessments to document drug 
remaining, and will be logged on the Case Report Form.   
5.9.4 Return or Destruction of Study Drug 
 
Study drug is an FDA-approved prescription medication that patients will be picking up at their 
local pharmacies. Should the patient stop taking the study drug for any reason, it will be 
recommended that they return the drug to their local pharmacy for disposal. 
 
 
 


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6 Study Procedures 
6.1 
Visit 1 – Screening/enrollment day 
 
Informed consent will be obtained. Inclusion and exclusion criteria will be evaluated. Collected 
baseline characteristics will include patient age, sex, race, martial and employment status, 
education level, social support, presence of children, age of children, underlying liver disease 
etiology, MELD-Na score, presence of ascites, esophageal varices, spontaneous bacterial 
peritonitis, diabetes, corticosteroid or other medical treatment for alcoholic hepatitis (Maddrey and 
Lille scores if relevant), medical comorbidities, prescription and non-prescription medications. 
With regard to alcohol use, patients will fill out the Alcohol Use Disorder Identification Test 
(AUDIT) and the following history will be obtained: duration of excess alcohol consumption in 
years, level of alcohol consumption prior to study enrollment, interval of alcohol abstinence prior 
to study enrollment, family history of alcoholism, history of alcohol-related legal issues, 
psychiatric comorbidity (requiring medication, outpatient care or hospitalization), other addictions 
including smoking and number of prior rehabilitation attempts for alcohol or other addictions. The 
PACS questionnaire will be administered. 
 
Vital signs and a physical examination will be performed. West Haven HE score will be graded 
and modified telephone version of MMSE completed. Blood work will be completed including a 
complete blood count, electrolytes, creatinine, blood urea nitrogen, total bilirubin, direct bilirubin, 
albumin, INR, AST, ALT and alkaline phosphatase. A urine ethyl glucuronide will be performed. 
A urine pregnancy test will be conducted before admission into the trial for women of child-
bearing potential.  
6.2 
Visit 2-5 
 
Visits 2-5 will be conducted by telephone and include data to be included on the Case Report Form 
including  
• Clinical history 
• Adverse events 
• Medication list including new medications, change in medications 
• Alcohol use 
• Other substance use including nicotine and recreational drug use 
• PACS responses and score 
• MMSE responses and score 
• West Haven HE grade 
• Laboratory results and clinical interpretation of the values. 
• Clinical significance of observations (when applicable) 
6.3 
Visit 6 
 
Visit 6 will occur at week 12 of acamprosate therapy. Interval clinical history, adverse events, 
medication list and alcohol and other substance use will be detailed. PACS score will be 
evaluated. Case Report Form will be completed. 
 


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Vital signs and a physical examination will be performed. West Haven HE score will be graded 
and modified telephone version of MMSE completed. Blood work will be completed including a 
complete blood count, electrolytes, creatinine, blood urea nitrogen, total bilirubin, direct bilirubin, 
albumin, INR, AST, ALT and alkaline phosphatase.  
 
6.4 
Visit 7 Follow up 
Patients will receive a telephone call at week 13 for reassessment. Interval clinical history will be 
obtained, all adverse events, medication list and alcohol and other substance use will be detailed. 
PACS score, modified telephone version of MMSE and West Haven HE score will be calculated. 
Case Report Form will be completed.  
 
6.5 
Visit 8 Follow up 
Patients will receive a telephone call at week 24 for reassessment. Interval clinical history will be 
obtained, history of any serious adverse events, medication list and alcohol and other substance 
use will be detailed. PACS score, modified telephone version of MMSE and West Haven HE 
score will be calculated. Case Report Form will be completed. Final blood tests will be 
requested. 
 
  
Scree
ning/ 
Enroll
ment 
day 
Treatment Period 
Test/Procedure Name 
(D1) 
W1 
W
2 
W
3 
W
4 
W
5 
W
6 
W
7 
W
8 
W
9 
W
10 
W
11 
W
12 
W
13 
W
24 
Study Visit 
x 
  
  
  
  
  
  
  
  
  
  
  
x 
  
  
Follow-Up Phone Calls 
  
x 
x 
x 
x 
  
  
  
x 
  
  
  
  
x 
x 
Physical Exam 
x 
  
  
  
  
  
  
  
  
  
  
  
x 
  
  
Complete blood count 
x 
  
  
  
  
  
  
  
  
  
  
  
x 
 
x 
Electrolytes 
x 
 
 
 
x 
  
  
  
x 
  
  
  
x 
 
x 
Creatinine 
x 
 
 
 
x 
  
  
  
x 
  
  
  
x 
 
x 
Urea 
x 
  
  
  
  
  
  
  
  
  
  
  
x 
 
x 
Total Bilirubin 
x 
 
 
 
x 
  
  
  
x 
  
  
  
x 
 
x 
Direct bilirubin 
x 
  
  
  
  
  
  
  
  
  
  
  
x 
 
x 
INR 
x 
 
 
 
x 
  
  
  
x 
  
  
  
x 
 
x 
Urine Ethyl Glucuronide 
x 
  
  
  
x 
  
  
  
x 
  
  
  
x 
 
x 
Albumin 
x 
  
  
  
  
  
  
  
  
  
  
  
x 
 
x 
AST, ALT, alkaline 
phosphatase 
x 
  
  
  
  
  
  
  
  
  
  
  
x 
 
x 
Child Pugh Score 
x 
  
  
  
  
  
  
  
  
  
  
  
x 
 
x 
West Haven HE Score 
x 
  
  
  
  
  
  
  
  
  
  
  
x 
x 
x 
MMSE 
x 
x 
x 
x 
x 
  
  
  
x 
  
  
  
x 
x 
x 
Med Review 
x 
x 
x 
x 
x 
  
  
  
x 
  
  
  
x 
x 
x 
Pennsylvania Alcohol 
Craving Scale 
x 
x 
x 
x 
x 
  
  
  
x 
  
  
  
x 
x 
x 


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Adverse event evaluation 
x 
x 
x 
x 
x 
  
  
  
x 
  
  
  
x 
x 
x 
Alcohol consumption 
documentation 
x 
x 
x 
x 
x 
  
  
  
x 
  
  
  
x 
x 
x 
 
 
 
 
 


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7 Statistical Plan 
7.1 
Sample Size Determination 
 
As the study is a phase IIa safety trial, no power analysis was completed.  
7.2 
Statistical Methods 
 
Descriptive Statistics 
 
Univariate descriptive statistics and frequency distributions will be calculated, as appropriate for 
all variables.  Baseline values for demographic, clinical, and outcome variables (primary and 
secondary) will be tabulated.   
 
Safety analyses will be conducted using all subjects, and presented overall. Safety data will be 
analyzed using descriptive statistics and tabulation. 
 
7.3 
Subject Population(s) for Analysis 
 
All subjects that received at least one dose of study drug will be evaluated. 
 


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8 Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• 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) breach of confidentiality 
and (6) 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 include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
 
and/or per protocol may be problems/events that in the opinion of the investigator may have 
adversely affected the rights, safety, or welfare of the subjects or others, or substantially 
compromised the research data. 
 
All adverse events that do not meet any of the criteria for serious, will be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
 
For this study, the study treatment follow-up period is defined as 12 weeks following the last 
administration of study treatment.  


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Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
will 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 will 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 will be followed by the 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 investigator should instruct each subject to report, to the 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 
Determination of whether worsening of liver biochemical tests is due to the alcohol-related 
hepatitis or study drug induced liver injury (DILI) is 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 < 300-400 U/L in AH. Such an increase of > 500 IU/L would trigger prompt evaluation 
and consideration of 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. An increase in MELD-Na score >5 points 
from baseline, or doubling bilirubin (2 times the baseline level at enrollment) would warrant 
urgent review by the DSMB.  
 
The study will be stopped if three or more patients develop AST or ALT > 500 U/L or as or as 
determined by the DSMB. 
. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be documented 
and reported as a serious adverse event unless specifically instructed otherwise in this protocol.  
Any condition responsible for surgery will 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 will 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. 


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• 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. 
8.2 
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 appropriate adverse 
event section of the 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 will 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 will be followed up to determine the 
final outcome.  Any serious adverse event that occurs during the Adverse Event Reporting 
Period and is considered to be at least possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 
Adverse events will be classified per the CTCAE Version 5.0, November 27, 2017. 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
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 investigator will evaluate the event and determine the necessary follow-up and 
reporting required. 
8.3.1 Investigator reporting: notifying the Mayo IRB 
 
The investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs according to 
the Mayo IRB Policy and Procedures. 
 
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:  
• 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:  
 


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The investigator will review all adverse event reports to determine if specific reports need to be 
made to the IRB.  The 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. 
 
* Relationship Index  
The relationship of an AE to the Investigational Drug is a clinical decision by the principal 
investigator (PI) based on all available information at the time of the completion of the CRF and 
is graded as follows: 
 
1. Not related: a reaction for which sufficient information exists to indicate that the etiology is 
unrelated to the study drug; the subject did not receive the study medication or the temporal 
sequence of the AE onset relative to administration of the study medication is not reasonable or 
the event is c1early related to other factors such as the subject' s clinical state, therapeutic 
intervention or concomitant therapy. 
 
2. Unlikely: a clinical event, including laboratory test abnormality, with a temporal relationship 
to drug administration which makes a causal relationship improbable and in which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
 
3. Possible: a clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug but which could also be explained by concurrent disease 
or other drugs or chemicals; information on drug withdrawals may be lacking are unclear. 
 
4. Probable: a clinical event including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other 
drugs or chemicals and which follows a clinically reasonable response on withdrawal (de-
challenge): re-challenge information is not required to fulfi1 this definition. 
 
5. Definite: a reaction that follows a reasonable temporal sequence from administration of the 
drug, or in which the drug level has been established in body fluids or tissues, that follows a 
known or expected response pattern to the suspected drug, and that is confirmed by improvement 
on stopping or reducing the dosage of the drug, and reappearance of the reaction on repeated 
exposure (re-challenge). 
 
Severity Index  
The maximum intensity of an AE during a day will be graded according to the definitions below 
and recorded in details as indicated on the CRF. If the intensity of an AE changes over a number 
of days, then separate entries should be made having distinct onset dates.  
 
1. Mild: AEs are usually transient, requiring no special treatment, and do not interfere with 
patient’s daily activities. 
 
2. Moderate: AEs typically introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities, but are usually ameliorated by simple therapeutic measures. 
 


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3. Severe: AEs interrupt a patient's usual daily activity and traditionally require systemic drug 
therapy or other treatment. 
 
8.3.2 Investigator reporting: Notifying the FDA 
 
n/a 
8.4 
Unmasking/Unblinding Procedures 
 
n/a 
8.5 
Stopping Rules  
 
The study will stop for an individual patient 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 UPIRTSO AND, in the opinion of the investigator and 
study adjudicator, is related to the study drug 
4. The participant experiences a grade 3 or higher CTCAE develop that are determined to be 
possibly or likely attributable to study drug 
5. The participant experiences a medical condition that, in the opinion of the investigator, 
continuation on the study drug would be detrimental. 
6. Decision by the DSMB. If a participant experiences a MELD-Na score increase by more 
than 5 points from baseline or doubling bilirubin level from enrollment, the DSMB will 
review the records to determine whether DILI is suspected or changes are attributed to 
natural course of disease 
7. The participant experiences an increase of AST or ALT >500 U/L 
 
Determination of whether worsening of liver biochemical tests is due to the alcoholic hepatitis or 
study drug induced liver injury (DILI) is 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 < 
300-400 U/L in AH. Such an increase of > 500 IU/L would trigger prompt evaluation and 
consideration of 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. An increase in MELD-Na score >5 points from 
baseline, or doubling bilirubin (2 times the baseline level at enrollment) would warrant urgent 
review by the DSMB.  
  
The study will be put on hold for review with the DSMB if one patient experiences a serious 
adverse event.  The study will be restarted if the DSMB considers the serious adverse events to 
be unrelated to study drug. 
 
The study will stop overall if any of the following occur: 


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1. 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. 
2. Two or more patients have 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.   
3. Three or more patients develop AST or ALT > 500 U/L. 
4. If recommended by the DSMB. 
 
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. 
8.6 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
8.6.1 Internal Data and Safety Monitoring Board 
 
See DSMB charter. 
9 Data Handling and Record Keeping 
9.1 
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. 
9.2 
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 


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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. 
9.3 
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. 
 
Data Management 
 
Source documents will be kept that include, but are not limited to, medical records, charts, 
appointment books, patient questionnaires, original laboratory records, equipment printouts. 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 
- 
Patient questionnaires responses  
- 
Issues with protocol compliance 
- 
Completion of, or withdrawal from, trial 
- 
Entirety of Case Report Forms  
 
Data Processing 
 
This is a single center study. Flow of data will be between study coordinators and PIs. De-
identified data will be available to DSMB. 
 


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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 PIs. All data shall be secured against unauthorized 
access. 
 
Apart from the investigators, no one will have access to participant’s identity. The 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 and by the investigators during any communications. 
 
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, instruction manuals, data verification, cross-
checking and data audits will be performed to ensure quality of all trial data.  
 
Data Clarification Process 
 
The data manager for the study will conduct periodic data queries. 
9.4 
Records Retention 
 
The 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). 
 
All research documentation during the duration of the study will be kept in both secured binders 
by the study coordinator and in a secured electronic environment (electronic data capture). 
Documents stored in the secured binders will be kept for the duration of the study. Once the 
study has been completed, the information in these binders (should it be less than 15 years since 
the start of the study) will be sent to a medical record warehouse as indicated by Mayo Clinic or 
stored in a locked research cabinet in the clinical area for at least 15 years. Access to the source 
documents in study binders will be monitored and only granted on an as needed basis to ensure 
the welfare of the patients and regulatory responsibilities are maintained through monitoring. 
There will be a list maintained by study personnel with patient names and identifying 
information (clinic number, unique patient number), this will not be given to monitors. Those 
who require access to patient records will be required to sign an agreement for disclosure of any 


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such information and will not be left unattended by study staff with the records. No copies will 
be authorized to be made by monitors. 
 
The electronic data capture system will only have de-identified data from subjects as qualified 
patients will be assigned a unique four-digit number and their initials. This electronic system will 
be secure meeting the federal requirements and access will be limited only on an authorized basis 
from the system administrator for purposes of the study.  
 
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 as above 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also 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. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 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.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the investigator before commencement of this study. 
 
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 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 


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obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject, and the individual obtaining the informed consent. 
 
It will be made clear throughout the consent process that subjects are under no obligation to 
participate in the study and that participation will not affect the health care they receive 
otherwise. Spoken and written communication during consent and throughout the study will be 
targeted at a maximum sixth grade reading level.  
12 Study Finances 
12.1 Funding Source 
 
The study is not financed.  
 
13 Publication Plan 
 
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.  This study will be planned for publication in a peer-reviewed journal. Dr. 
Douglas Simonetto holds the primary responsibility for publication of the results of the study and 
will be the primary responsible party from whom approval will need to be obtained before any 
information can be used or passed onto a third party. 
14 References 
Addolorato G, Leggio L, Ferrulli A, et al. Effectiveness and safety of baclofen for maintenance 
of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-
blind controlled study. Lancet 2007;370(9603):1915-1922. 
 
Alkermes, Inc. Naltrexone (Vivitrol®) [product monograph]. Waltham, MA; 2010. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021897s015lbl.pdf 
 
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. 
Washington, DC: American Psychiatric Association; 2013. 
 
Barrio E, Tomé S, Rodríguez I, et al. Liver disease in heavy drinkers with and without alcohol 
withdrawal syndrome. Alcohol Clin Exp Res. 2004;28(1):131-136. 
 
Deleuran T, Grønbaek H, Vilstrup H, Jepsen P. Cirrhosis and mortality risks of biopsy-verified 
alcoholic pure steatosis and steatohepatitis: a nationwide registry-based study. Aliment 
Pharmacol Ther. 2012;35(11):1336.  
 
Delgrange T, Khater J, Capron D, Duron B, Capron J-P. Effect of acute administration of 
acamprosate on the risk of hepatic encephalopathy and on blood pressure in alcoholic cirrhotic 
patients. Gastroenterol Clin Biol 1992;16(8-9):687-691. 
 


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Edmondson HA, Peters RL, Frankel HH, Borowsky S. The early stage of liver injury in the 
alcoholic. Medicine 1967;46(2):119-129. 
 
Frye MA, Hinton DJ, Karpyak VM. Anterior cingulate glutamate is reduced by acamprosate 
treatment in patients with alcohol dependence. J Clin Psychopharmacol 2016;36(6):669-674. 
 
Grant BF, Goldstein RB, Saha TD, et al. Results from the National Epidemiologic Survey on 
Alcohol and Related Conditions III. JAMA Psychiatry 2015;72(8):757-766. 
 
Higuchi S, for the Japanese Acamprosate Study Group. Efficacy of acamprosate for the 
treatment of alcohol dependence long after recovery from withdrawal syndrome: a randomized, 
double-blind, placebo-controlled study conducted in Japan (Sunrise Study). J Clin Psychiatry 
2015;76(2):181-188. 
 
Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Clinical course of alcoholic liver 
cirrhosis: a Danish population-based cohort study. Hepatology 2010;51(5):1675-1682. 
 
Jepsen P, Ott P, Andersen PK, Vilstrup H. The clinical course of alcoholic cirrhosis: effects of 
hepatic metabolic capacity, alcohol consumption and hyponatremia – a historical cohort study. 
BMC Res Notes 2012;5:509. 
 
Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in 
outpatient settings: a systematic review and meta-analysis. JAMA 2014;311(18):1889-1900. 
 
Lee BP, Mehta N, Platt L, et al. Outcomes of early liver transplantation for patients with severe 
alcoholic hepatitis. Gastroenterol 2018;155:422-430. 
 
Lyon J. More treatments on deck for alcohol use disorder. JAMA 2017;317(22):2267-2269. 
 
Merck Santé s.a.s., subsidiary of Merck KGaA. Acamprosate (Campral®) [product monograph]. 
Lyon, France; 2005. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021431s013lbl.pdf  
 
National Institutes of Health. Alcohol use disorder: a comparison between DSM-IV and DSM-5. 
NIH Publication No. 13-7999. Reviewed July 2016. 
 
Plosker GL. Acamprosate: a review of its use in alcohol dependence. Drugs 2015;75:1255-1268. 
Potts JR, Goubet S, Heneghan MA, Verma S. Determinants of long-term outcome in severe 
alcoholic hepatitis. Aliment Pharmacol Ther. 2013;38(6):584-595. 
 
Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association practice 
guideline for the pharmacological treatment of patients with alcohol use disorder. Am J 
Psychiatry 2018;175(1):86-90. 
 
Rosato V, Abenavoli L, Federico A, Masarone M, Persico M. Pharmacotherapy of alcoholic liver 
disease in clinical practice. Int J Clin Pract 2016;70(2):119-131. 


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15 Attachments 
 
- 
DSMB 
- 
Case report form 
- 
Adverse event form 
- 
Con Med Form