Safety of Acamprosate in Treating Alcohol Use Disorder in the Post Liver Transplant Populations
Phase: PHASE2
Conditions: Alcohol Use Disorder, Liver Transplant; Complications
Sponsor: University of Southern California

 
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TITLE: Safety of Acamprosate in Post-liver transplantation population with Alcohol-associated Liver 
disease  
 
 
STUDY PHASE: Enrollment  
 
 
STUDY ARMS: Acamprosate + Standard of Care, Standard of Care   
 
 
PRINCIPAL INVESTIGATOR(S):  
HYOSUN HAN  
C1, 2nd Floor 1510 San Pablo Street Los Angeles, CA 90033  
323-442-6171  
Hyosun.Han@med.usc.edu  
 
 
 
 
CO-INVESTIGATOR(S):  
Divya Ayyala-Somayajula MD 
 
Stephanie Cho MD 
 
Norah Terrault MD  
 
Vincent Tristan PA 
 
 
 
 
PARTICIPANTS/LOCATONS: Transplant patients from Liver Transplant Program from the USC KECK  
Transplant Institute’s patient census  
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
 
SCHEMA, SYNOPSIS, OR STUDY SUMMARY 
 
 
 
 
 
PAGE 
 
1.0 
BACKGROUND AND HYPOTHESES  
_____ 
 
2.0 
OBJECTIVES AND PURPOSE 
_____ 
 
3.0 
STUDY DESIGN  
_____ 
 
4.0 
DRUG/DEVICE INFORMATION 
_____ 
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
_____ 
 
6.0 
DESCRIPTIVE FACTORS/STRATIFICATION/RANDOMIZATION SCHEME 
_____ 
 
7.0  
STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY  
MANAGEMENT PLAN 
_____ 
 
 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
_____ 
 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS 
_____ 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
 
 
_____  
 
11.0 
SPECIAL INSTRUCTIONS 
 
 
 
 
 
 
 
_____ 
 
12.0 
DATA COLLECTION AND MONITORING 
_____ 
 
13.0 
STATISTICAL CONSIDERATIONS  
_____ 
 
14.0 
REGISTRATION GUIDELINES  
_____ 
 
15.0 
BIOHAZARD CONTAINMENT 
_____ 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
_____ 
 
17.0 
REFERENCES  
 
 
 
 
 
 
 
 
_____ 
 
APPENDICES 
 
 

 
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1.0 
BACKGROUND AND HYPOTHESES 
 
1.1  
The prevalence of alcohol-associated liver disease (ALD) has been increasing due to ongoing 
alcohol use and high-risk drinking over the past decade1. ALD now poses a significant burden to the 
US healthcare system, accounting for 5.4 per 100,00 deaths in 2012, and ALD mortality is increasing 
particularly in younger demographics2. Given the increased prevalence of ALD in conjunction with a 
5-fold increase in liver transplant (LT) for severe alcohol associated hepatitis (AH)3, ALD is now the 
leading indication for liver transplantation accounting for approximately 30% of LT waitlist additions 
and 24% of LT recipients in 2016 in the US1. Despite excellent surgical outcomes, ~50% liver graft 
recipients with alcohol use disorder (AUD) relapse (any alcohol use) by 5 years post- (LT)4. Those post-
LT patients that go on to develop harmful drinking patterns (early onset, moderate to heavy alcohol 
use) have increased rates of graft failure highlighting a population that would likely benefit from 
comprehensive treatment of AUD, including pharmacotherapy5.  Though not contraindicated, to 
date, no AUD medication has been FDA-approved for use in patients with ALD6. Naltrexone and 
disulfuram are both FDA approved but have a black box warning for hepatoxicity6. Although, small 
studies have shown the benefit of pharmacotherapy in patients with ALD, no studies have been done 
to validate the use of AUD pharmaceuticals in the post-LT population7. Due to combination of factors- 
provider discomfort, lack of data regarding pharmaceutical effectiveness and safety in this 
population, and lack of treatment protocols to treat AUD in this specific population, our post- LT 
population has not received standard of care for AUD7. Failure to utilize available and effective 
interventions predisposes this patient population to alcohol relapse (e.g. slips), subsequent harmful 
drinking patterns (early onset, moderate to heavy alcohol use), and ultimately graft dysfunction5.  
 
1.2   
Acamprosate is an effective FDA approved adjunct therapy for alcohol dependence in adults8. 
However, there is limited literature on the use of acamprosate in patients with ALD, and there is no 
literature on the use of acamprosate in post-LT ALD patients7,8. It is well established that 
acamprosate is not metabolized by the liver and unlikely to interfere with medications metabolized 
via cytochrome P4508. Given this unique pharmacokinetic property of acamprosate, there should be 
no drug-drug interactions with its use in LT recipients9. 
 
1.3  
We hypothesize that acamprosate will be a feasible AUD therapy for post-LT patients.  
 
2.0  
OBJECTIVES AND PURPOSE 
Keck Medicine of USC’s Liver Transplant Program will develop a pilot study to incorporate 
acamprosate use in suitable post-LT individuals. A research team will provide weekly appointments to 
administer surveys to assess for alcohol use, alcohol cravings, acamprosate compliance, and drug 
side-effects. Patients will obtain laboratory values and visit their transplant hepatologist monthly as is 
standard of care. Patients will also receive a consultation with the program’s transplant pharmacist to 
reconcile medications to avoid drug-drug interactions.  
The primary goals of this study are:  
2.1 
To evaluate the feasibility and safety of acamprosate for management of AUD in post-liver 
transplant patients  
2.2 
To determine whether acamprosate use in combination with standard of care (weekly 
telephone visit) reduces the frequency of alcohol relapse  
 

 
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3.0 
STUDY DESIGN 
Procedure: Each patient eligible for the study will be contacted by a research assistant via telephone 
or in-person in the transplant clinic. If patients state they are not interested, we will provide an email 
address to reach if the patient decides in the future to participate. Interested patients will be 
consented for study participation. Baseline demographic, social, and medical history, laboratory data, 
and current medications will be abstracted from the electronic medical record. Baseline alcohol use 
will be assessed with TLFB and last drink of alcohol. Baseline alcohol cravings will be assessed with 
PACS survey. Patients randomized to acamprosate arm will then be contacted by a transplant 
pharmacist to perform a medication reconciliation regardless of whether they are randomized to the 
acamprosate plus standard of care (SOC) vs SOC alone group. The cost of the medication will be 
covered by the insurance. Patients without insurance or that decline to use insurance will be 
excluded or withdrawn if they have already signed consent.  Randomization will occur via a 2:1 ratio 
of acamprosate plus SOC versus SOC alone respectively stratified by sex. The study team and 
participants will not be blinded to treatment group. For those randomized to the acamprosate plus 
SOC group, they will be counseled to start acamprosate 666 mg three times daily after this initial visit. 
All patients (both groups) will undergo weekly phone visits with the research team where interval 
medical history will be obtained (changes in medications, hospitalizations, and emergency 
department visits), assessment of alcohol use (TLFB), alcohol craving (PACS), acamprosate side effects 
(GASE), and acamprosate compliance (self-reported number of missed doses) for those randomized 
to the acamprosate arm will be obtained. If at any time, patients report side effects to acamprosate 
or any new symptoms, these will be communicated to the patients’ transplant hepatologist to advise 
appropriate medical care. Patients will then receive standard of care laboratory testing including 
alcohol metabolites and routine clinic visits with a transplant hepatologist where medication 
compliance will be assessed (number of pills left and number of refills obtained).  This part of the 
study will last 14 weeks. If patients choose to continue acamprosate they will continue with their 
primary hepatologist and continue monthly visits, those in the control arm will resume standard of 
care visits with their primary hepatologist. At 1 year, 3 years, and 5 years, we will abstract data from 
the electronic medical record (interval social history, medical history, laboratory data, current 
medications, graft function, pertinent transplant history, continuation of acamprosate or intiation of 
AUD therapy since time of the study, and current alcohol use). All data will be recorded in the 
REDCap database.  
  
4.0 
DRUG/DEVICE INFORMATION 
4.1 Acamprosate is the drug that will be utilized in the proposed study. This is an FDA approved 
commercially available drug for alcohol dependence and abuse in the United States since 2004. 
Acamprosate is available in delayed release tablets of 333 mg generically and under the brand name 
campral. The typical maintenance dose is 666 mg three times daily.  
 
4.2 Acamprosate will be the only drug being utilized in this study.  
 
4.3 IND/IDE number not applicable.  
 
4.4 Acamprosate will be prescribed and sent to patients preferred pharmacy. 
 
4.5 Acamprosate (a kam' proe sate) is N-acetylhomotaurine, a synthetic amino acid analogue similar 
to gamma aminobutyric acid (GABA) and taurine that has been shown to decrease alcohol craving in 

 
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animal models. Acamprosate appears to function as a neurotransmitter with GABA agonist and 
partial glutamate (N-methyl-D-aspartate [NMDA]) antagonist activity, but its precise mechanism of 
action in decreasing alcohol craving is unknown10. Acamprosate appears safe and well-tolerated for 
the maintenance of abstinence in alcohol-dependent patients across a wide range of patient 
groups8.Flatulence is the only other adverse effect that has been significantly associated with 
acamprosate over placebo11 with no statistically significant differences were observed between 
groups (acamprosate versus placebo) of premature withdrawals from treatment due to adverse 
effects12.  
 
Acamprosate has a low propensity for interactions with other drugs8.Acamprosate is contraindicated 
in patients with hypersensitivity to acamprosate calcium or any of its components and patients with 
severe renal impairment (CrCl of 30 mL/min or less) as Acamprosate is primarily renally excreted13. 
There were no sex differences in safety or tolerability for acamprosate8. Acamprosate appears 
generally safe in patients with impaired hepatic function8.  
 
5.0  
SELECTION AND WITHDRAWAL OF SUBJECTS 
Beginning January 1st, 2022, we will recruit patients from Liver Transplant Program from the USC 
Transplant Institute’s patient census. We will target at least 25-30 patients for this study with 2:1 
randomization (acamprosate plus SOC vs SOC alone). All patients must have history of LT with a pre-
LT diagnosis of ALD. As our usual number of transplants per year is 120 and 30% of patients have ALD 
(includes AH) as a diagnosis, we do not anticipate any difficulties in identifying 30 participants for this 
study.  
 
Enrollment will be on a rolling basis.  
 
5.1 Patients must have received a transplant for liver disease secondary to alcohol-associated 
hepatitis or alcohol-associated cirrhosis.  
 
5.2 We will exclude patients with hypersensitivity to acamprosate calcium or any of its components, 
severe renal impairment (creatinine clearance ≤30 mL/min), psychopathology under treatment with 
psychoactive drug, substance dependence other than THC, alcohol, or nicotine, need for inpatient 
detoxification or inpatient treatment of alcohol use, participation in a clinical trial within the past 30  
days, and women of childbearing potential who do not practice a medically acceptable form of 
contraception will be excluded.  
 
We will obtain an informed consent for all patients. As part of the informed consent, participants will 
be expected to complete a weekly telemedicine visit with a research member for at least 3 months, 
required to fill out weekly surveys (Appendix III) (Penn Alcohol Craving Scale (PACS), Alcohol Timeline 
Followback (TLFB), and Generic Assessment of Side Effects in Clinical Trials (GASE) prior to these visits 
and expected to be compliant with acamprosate if randomized to that group. The proportion of 
patients eligible but who did not agree to participate will be captured. 
 
5.3 Patients may withdraw from study at any time. If patients suffer any severe adverse effects from 
acamprosate they will be advised to stop the drug immediately and withdraw from the study.  
 
6.0 
 STRATIFICATION/DESCRIPTIVE FACTORS/RANDOMIZATION SCHEME 

 
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6.1  
Sex will be balanced across treatment arms – due to the pilot nature of this study, age, race 
ethnicity and time from transplant will be recorded for planning of future trials.   
 
6.2  
Drinking history, social history, pre- liver transplant relapse probability scores, medical history, 
and medication history will be obtained.  
 
6.3  
Randomization will occur via an unblinded 2:1 ratio of acamprosate plus SOC versus SOC 
alone respectively stratified by sex.  
 
7.0 
STUDY AGENT ADMINISTRATION OR INTERVENTION AND TOXICITY MANAGEMENT PLAN 
 
7.1 Treatments 
 
A. Standard of Care (SOC): Participants will be expected to complete a weekly telemedicine 
visit with a research member for at least 3 months, required to fill out weekly surveys (figure 2) (Penn 
Alcohol Craving Scale (PACS), Alcohol Timeline Followback (TLFB), and Generic Assessment of Side 
Effects in Clinical Trials (GASE) prior to these visits and expected to be compliant with acamprosate if 
randomized to that group. 
 
B. SOC+ Acamprosate: Participants randomized to this arm will participate in SOC + take 
acamprosate 666 mg TID daily for three months.  
 
7.21 
AGENT 
DOSE 
ROUTE 
DAYS 
ReRx INTERVAL 
NOTES 
Acamprosate  666 mg  
PO TID  
Daily  
4 weeks  
maximum cumulative dose 500 mg/m2 
 
7.31 A patient may always be removed from treatment whenever he/she wishes 
 
7.32 Treatment will be discontinued or held at discretion of investigators if patients experience any 
moderate-severe side effects as evaluated in section 8.0 thought to be secondary to acamprosate.  
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
 
8.1 Acamprosate’s package insert includes a comprehensive list of adverse events in over 7000 
patients exposed to acamprosate14. However, adverse events are listed without regard to the causal 
relationship of the events to the drug14. Only diarrhea and flatulence appear to be  
significantly associated with acamprosate14. There is no evidence that acamprosate has 
additional risks in the liver transplant population8.  Multiple meta analyses have found that the 
only side effect significantly associated with acamprosate over placebo is diarrhea8,15.  
Flatulence is the only other adverse effect that has been significantly associated with  
acamprosate over placebo11.  In a review of clinical trials, diarrhea was observed in 10-17% of 
patients treated with acamprosate (versus 10-11% in placebo)11,12. Diarrhea appears to be  
acamprosate dose dependent, settles within a few days, and mostly mild or moderate in  
severity11. If diarrhea was severe, temporary dose reduction was beneficial8. Of note, no  
statistically significant differences were observed between groups (acamprosate versus  
placebo) in terms of premature withdrawals from treatment due to adverse effects12. No  
clinically meaningful differences have been found comparing acamprosate and placebo  
regarding the incidence of clinically significant postbaseline abnormalities for any hematology  

 
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parameter measured: including mean values for the liver function tests aspartate 
aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase  
(GGT)11. Acamprosate therapy has not been associated with serum enzyme elevations over and  
above rates that occur with placebo therapy. Despite wide-scale use in alcohol treatment 
programs, there have yet to be published reports of clinically apparent acute liver injury  
attributed to acamprosate therapy10. Pharmacovigilance data in 1.5 million patients has  
indicated no serious adverse events8.   
 
Acamprosate’s package insert includes a precaution for suicidality due to an increase in adverse 
events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) in  
acamprosate treated patients. The insert recognizes the complex and well-recognized  
interrelationship between alcohol dependence, depression and suicidality and encourages that  
“all alcohol-dependent patients, including those patients being treated with CAMPRAL should  
be monitored for the development of symptoms of depression or suicidal thinking.” There is no 
evidence of a statistically significant association between treatment with acamprosate and  
adverse events of a suicidal nature8,14,11,12.  Acamprosate has a low propensity for interactions  
with other drugs, including those likely to be administered as concomitant drugs in alcohol- 
dependent patients, including alcohol, diazepam, disulfiram or naltrexone. In vitro studies  
indicate that acamprosate does not induce cytochrome P450 (CYP) 1A2 or 3A4 isoenzymes, nor  
does it inhibit the metabolism of drugs that are substrates for CYP1A2, 2C9, 2C19, 2D6, 2E1 or  
3A416. Micromedex has no reported drug interactions with acamprosate13. However, co- 
administration of naltrexone with acamprosate significantly increased the maximum plasma  
concentration and the area under the plasma concentration-time curve of acamprosate14,17. No  
adverse effects were documented17. No adjustment of dosages is recommended in patients  
with co-administration of naltrexone with acamprosate14.  
 
Acamprosate is contraindicated in patients with hypersensitivity to acamprosate calcium or any  
of its components and patients with severe renal impairment (CrCl of 30 mL/min or less)13.  
Acamprosate is primarily renally excreted. Peak plasma concentrations after administration of a  
single dose of 2 x 333 mg Acamprosate tablets to patients with moderate or severe renal  
impairment were about 2-fold and 4-fold higher, respectively, compared to healthy subjects13.  
Acamprosate is known to be substantially excreted by the kidney, and the risk of toxic reactions  
to this drug may be greater in patients with impaired renal function13. There were no sex  
differences in safety or tolerability for acamprosate8. Acamprosate appears generally safe in  
patients with impaired hepatic function8.  There is no evidence, clinical or theoretical, that  
Acamprosate is not safe in the liver transplant population. Acamprosate may improve  
morbidity and mortality in liver transplant patients by mitigating the risks associated with  
continued alcohol use.   
 
The greatest proportion of deaths or re-transplants after liver transplantation occur soon after 
initial transplantation. The causes of death and graft loss vary according to the interval from  
transplantation, with infection and intraoperative and perioperative causes accounting for nearly 60% 
of deaths and graft losses in the first posttransplant year. After the first year, death due to acute 
infections declines, whereas malignancies and cardiovascular causes account for a greater proportion 
of deaths. The recurrence of the pretransplant condition, especially hepatitis C virus (HCV) or 
autoimmune liver disease, is an increasingly important cause of graft loss the longer the patient 

 
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survives transplantation for these etiologies [10]. There is no evidence, clinical or theoretical, of a link 
between acamprosate and any of the above causes of morbidity and mortality in liver  
transplant patients in the first-year post-transplant8,15,11,12.   
 
Though no causal relationships to acamprosate have been found, the adverse of acute kidney  
failure has been reported to be temporally associated with acamprosate in several patient13.  
There is no evidence of a link between acamprosate and any of the other above causes of  
morbidity and mortality in liver transplant patients following the first-year post-transplant8,15,11,12. 
 
8.11 Patients will undergo a self-administered weekly survey, Generic Assessment of Side Effects in  
Clinical Trials (GASE) to evaluate for potential side effects and toxicities. They will also undergo  
standard of care laboratory testing as well to check renal function and graft function along with  
immunosuppression levels.  Details regarding the survey are listed in Appendix III.  
 
8.12 There are no known long term drug toxicities associated with acamprosate. The recommended 
long-term dose for acamprosate is 666 mg TID PO daily unless the patient has severe renal 
impairment (CrCl of 30 mL/min or less) or levels hypersensitivity to acamprosate calcium or any of its 
components, in which case, acamprosate is contraindicated.  If the patients choose to continue 
acamprosate after this study, they will continue to follow with their primary transplant hepatologist 
who can monitor for adverse side effects such as kidney dysfunction, hypersensitivity, diarrhea, and 
flatulence.  
 
 
8.2 Complete discontinuation is advised if the patient experiences any drug toxicities related to 
acamprosate. Patients should not restart treatment if toxicity is thought to be related to 
acamprosate. 
 
8.3 
8.31 If a patient experiences an adverse event such as an unexpected or fatal toxicity, the event will 
be immediately (within 24 hours) reported to the primary medical care team so patient can receive 
the appropriate care.  
8.32 We will then report the event to the IRB and FDA.  
 
9.0 CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR 
 
Parameter 
Pre- 
Treatment 
Day 1 
Weekly 
 
Bi-monthly 
Targeted History (alcohol history,  
psychiatric history, liver transplant 
history, medications history, social  
history, abdominal imaging, pregnancy 
test if 
indicated) 
 
X 
 
 
 
Complete Blood Count (CBC) 
X 
 
 
X 
Complete Metabolic panel (CMP)  
X 
 
 
X 
Alcohol Metabolites  
x 
 
 
X 

 
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Immunosuppression levels 
X 
 
 
X 
Penn Alcohol Craving Scale (PACS) 
X 
 
X 
 
Quick Drinking Screen 
X 
 
X 
 
Timeline Follow back  
X 
 
X 
 
General Assessment of Side Effects in 
Clinical Trials (GASE)  
 
 
X 
 
Agent administration  
 
X1 
 
 
Interval history (hospitalizations, 
medication changes)  
 
 
X 
 
1daily  
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
Outcomes assessed will include feasibility, safety, and efficacy. Feasibility will be assessed via 
completion rates, number of missed doses per patient, and number of patients who completed 3 
monthly refills for the study. Safety will be measured via % total, minor, moderate, and major side-
effects documented via the GASE survey and mortality during the time of the study. Finally, efficacy 
will be measured via % maintained abstinence, reduction in alcohol cravings determined via PACS 
score, and % of alcohol relapses determined via TLFB survey, PeTh, and self-reporting. We will then 
examine acamprosate use and its effect on 1-, 3-, and 5- year graft survival and alcohol usel in our 
patients transplanted for ALD. Efficacy and safety outcomes will be compared to control group to 
determine if acamprosate itself is helpful and safe for alcohol use reduction post-LT. 
 
11.0 
SPECIAL INSTRUCTIONS: 
This is not applicable for this study.   
 
12.0 
DATA COLLECTION AND MONITORING 
All data collection will be done using the REDCAP database. Only those involved in data collection and 
analysis who are included on the IRB will have access to the data.  
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1  The goal of this study is to evaluate the feasibility, safety, and efficacy of acamprosate for 
management of AUD in post-liver transplant patients. All patients will be post-LT with a pre-LT 
diagnosis of ALD. As our usual number of transplants per year is 120 and 30% of patients have ALD 
(includes AH) as a diagnosis, we do not anticipate any difficulties in identifying 30 participants for this 
study.  Feasibility will be assessed via completion rates, number of missed doses per patient, and 
number of patients who completed 3 monthly refills for the study. Safety will be measured via % 
total, minor, moderate, and major side-effects documented via the GASE survey. Finally, efficacy will 
be measured via % maintained abstinence, reduction in alcohol cravings determined via PACS score, 
% of alcohol relapses determined via TLFB survey, PEth, and self-reporting and patient and graft 
survival in our patients transplanted for ALD. Demographic variables will be compared between SOC 
and acamprosate+SOC groups using descriptive statistics. Efficacy and safety outcomes will be 
compared to control group using wilcoxan pair rank sum. Cox regression analysis will be done to 
determine determinants of alcohol relapse and graft failure in both SOC and SOC+acamprosate 

 
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group. Finally, time to relapse will be measured in both SOC and SOC+acamprosate group via Kaplan 
meier plots.  
 
13.2  Given the small number of patients (30), we will not perform a stratified randomization based 
upon age, race, ethnicity and timing from transplant but rather compare frequencies of different 
ethnicities in our descriptive statistics section.  
 
14.0 
REGISTRATION GUIDELINE 
 
14.1 
Patients will be contacted by our research coordinator.  Patients will be randomized in a 2:1 
fashion and stratified based upon sex.  
 
14.2 
Patients will undergo an intake session where an informed consent and HIPPA release form 
will be signed.  All patients will receive a signed and dated copy of the Informed Consent Form once 
enrolled. 
 
 
 
15.0  BIOHAZARD COMTAINMENT 
No biohazard materials will be produced during this study,hus containment protocol is not applicable.  
 
 
16.0  ETHICAL AND REGULATORY CONSIDERATIONS 
` 
All institutional and Federal regulations concerning the Informed Consent form will be 
fulfilled.  The study will be conducted in adherence to ICH Good Clinical Practice. 
 
 
17.0 
REFERENCES 
(1) Cholankeril G and Ajaz A. Alcoholic Liver Disease Replaces Hepatitis C Virus Infection as the 
Leading Indication for Liver Transplantation in the United States. Clinical Gastroenterol 
Hepatol. 2020.  
(2) Guirguis J, Chhatwal J, Dasarathy J et al. Clinical impact of alcohol-related cirrhosis in the next 
decade: estimates based on current epidemiological trends in the United States. Alcohol Clin 
Exp Res 2015.  
(3) Cotter T, Burhaneddin S, Paul S, et al. Liver Transplantation for alcoholic hepatitis in the 
United States: Excellent outcomes with profound temporal and georgraphic variation in 
frequency. Am J Transplant. 2021.  
(4) Heyes CM, Schofield T, Gribble R, et al. Reluctance to Accept Alcohol Treatment by Alcoholic 
Liver Disease Transplant Patients: A Qualitative Study. Transplant Direct. 2016. 
(5) DiMartini A, Dew MA, Day N, et al. Trajectories of alcohol consumption following liver 
transplantation. Am J Transplant. 2010.   
(6) Yoo ER, Cholankeril G, Ahmed A. Treating Alcohol Use Disorder in Chronic Liver Disease. Clin 
Liver Dis. 2020.  
(7) Im GY, Mellinger JL, Winters A, et al. Provider Attitudes and Practices for Alcohol Screening, 
Treatment, and Education in Patients with Liver Disease: A Survey from the American 
Association for the Study of Liver Diseases Alcohol- Associated Liver Disease Special Interest 
Group. Clinical Gastrenterol Hepatol. 2020.  
(8) Sinclair JM, Chambers SE, Shiles CJ, et al. Safety and Tolerability of Pharmacological Treatment 
of Alcohol Dependence: Comprehensive Review of Evidence. Drug Saf. 2016. 

 
Version 4 
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11 
(9) Venkataramanan, R, Swaminathan, A, Prasad, T, et al. Clinical Pharmacokinetics of Tacrolimus. 
Clin Pharmacokinet. 1995.  
(10) LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda 
(MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from: 
https://www.ncbi.nlm.nih.gov/books 
(11) . Rosenthal RN, Gage A, Perhach JL, Goodman AM. Acamprosate: safety and tolerability in the 
treatment of alcohol dependence. J Addict Med. 2008;2(1):40-50. PMID 21768971  
(12) Bouza C, Angeles M, Magro A, Muñoz A, Amate JM. Efficacy and safety of naltrexone and 
acamprosate in the treatment of alcohol dependence: a systematic review. Addiction. 
2004;99(7):811-28. PMID 15200577  
(13) ACAMPROSATE. Micromedex Solutions. Greenwood Village, CO: Truven Health Analytics. 
http://micromedex.com/. Updated December 2019. Acessed December 2019.  
(14) CAMPRAL® (acamprosate calcium) Delayed-Release Tablets. 
https://www.accessdata.fda.gov/. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021431s013lbl.pdf.    
(15) . Rösner S, Hackl-herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol 
dependence. Cochrane Database Syst Rev. 2010;(9):CD004332. PMID 20824837   
(16) Plosker GL. Acamprosate: A Review of Its Use in Alcohol Dependence. Drugs. 
2015;75(11):1255-68. PMID 26084940   
(17) Drug-drug interactions in the treatment for alcohol use disorders: A comprehensive review. 
Guerzoni S, Pellesi L. Pharmacological Research. 2018.   
(18) Flannery BA, Volpicelli JR, Pettinati HM. Psychometric properties of the Penn Alcohol Craving 
scale. Alcoholism: Clinical and Experimental Research. 1999.  
(19) Robinson SM, Sobell LC, Sobell MB, Leo GI. Reliability of the Timeline Followback for Cocaine, 
Cannabis, and Cigarette Use. Psychol Addict Behav. 2014.  
(20) Rief W, Glombiewski JA, Barsky AJ. Generic Assessment of Side Effects. 2009.  
 
APPENDICES 
 
Appendix I: informed consent and HIPAA form 
Appendix II: 
Questionnaires &/or Survey Forms (if applicable) 
 
 
 
 
 
 
 
 
 
 
 
 

 
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