Clinical trial NCT02445339
Conditions: Alcohol Dependence Alcohol Use Disorder
Keywords: Alcohol Dependence Alcohol Use Disorder Care Management Case Management Emergency Care Services Emergency Department Emergency Room Extended-release naltrexone Frequent Users Health Care Utilization Medical Management Naltrexone Population Health Public Health Vivitrol XR-NTX XR-NTX+CM Alcoholism Alcohol-Related Disorders Central Nervous System Agents Chemically-Induced Disorders Clinical Trial Emergency Medicine Mental Disorders Narcotic Antagonists Peripheral Nervous System Agents Pharmacologic Actions Physiological Effects of Drugs Sensory System Agents Substance-Related Disorders
Sponsor: NYU Langone Health
Start date: 2015-07-01; Completion date: 2019-02-08
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Our primary aim is to assess the feasibility of initiating treatment in the ED with extended-release naltrexone (XR-NTX) plus care management (CM) vs. standard care and continuing care in cooperation with clinic providers as well as how best to assess outcomes. Secondarily, the investigators will explore its effect on various health outcomes (healthcare utilization and engagement, expenditures, drinking and consequences, quality of life) as well as the association of patient-level characteristics (e.g. sex, race, baseline drinking, health and psychosocial factors, mu opioid receptor genotype) with effectiveness. Determining both how to implement XR-NTX+CM and rigorously test its effects in the ED (phase 1) is essential before planning a large-scale effectiveness trial (phase 2).

Detailed description:
Aim #1: To conduct a feasibility and acceptability study of XR-NTX+CM treatment in alcohol dependent patients with frequent ED use.

Hypothesis: Enrollment of a limited number of subjects will allow identification of optimal processes for a definitive trial.

Aim #2: To conduct an analysis of the effect of this intervention on healthcare utilization and engagement, drinking outcomes, quality of life, and consequences of drinking (initial analysis will be exploratory).

Hypothesis: Measuring changes in healthcare utilization, drinking metrics, and indicators of quality of life and consequences will provide preliminary data on intervention effect size on various outcomes of interest to inform the second phase, definitive trial.

Aim #3: To identify patient-level characteristics associated with effectiveness.

Hypothesis: Exploratory analysis of patient and system-level characteristics possibly associated with effectiveness will inform treatment choice to maximize the probability of successful outcome. Factors assessed will include data collected in ongoing investigations of pharmacotherapy for alcohol dependence, including mu opioid receptor (OPRM1) genotypes, to facilitate comparison across study populations and settings.

This a phase IV, randomized, open-label, non-placebo-controlled, single-center study of the feasibility, acceptability, and effect of initiating treatment in the ED with extended-release naltrexone 380mg intramuscular injection compared to standard care in subjects with severe alcohol use disorders (i.e. alcohol dependence) and frequent emergency department use. In the first two years, we will finalize study preparations, recruit and randomize 50 subjects for the pilot phase of this study. The duration of each subject's participation will be 12 months. Thereafter, in the second phase of study, we will enroll an additional 250 subjects (for a total of 300 subjects) to address remaining feasibility and acceptability concerns and test effects.

The study investigators (PI and RA) will collect process data, including barriers and facilitators encountered in the completion of all study procedures. For the following study procedures, study investigators (the PI and RAs) will enter data directly into New York University Langone Medical Center (NYULMC) internal REDCap system for use on portable tablet computers.

Synopsis of Study Procedures:

The following study procedures are described in greater detail elsewhere in this protocol.

Patients will be prescreened for potential eligibility and added to an automated alert system linked to ED registration by Bellevue Care Managers as part of an ongoing quality improvement initiative. When a potentially eligible patient presents to the ED, an automated page will be delivered to the study PI and Bellevue ED social work and care management staff, prompting consultation and potential referral of the patient to study investigators (PI/RA) for recruitment (See 4.3 Subject Recruitment and Screening). ED medical providers (inclusive of ED physicians, nurses, social workers, and care managers) will notify study investigators (PI/RA) when potentially eligible patients are present in the ED. The medical provider will introduce the PI/RA to clinically sober and medically stable patients who have given their permission to be approached. The PI/RA will describe the study, confirm capacity to consent using the University of California San Diego Brief Assessment of Capacity to Consent to Research (UBACC), and obtain written informed consent. The PI/RA will confirm eligibility by performing a chart and laboratory review (liver enzymes, pregnancy, urine drug screen), history and examination, and diagnostic interview to confirm alcohol dependence and assess for opioid use and chronic pain. The PI/RA will conduct research intake assessments and interview and collect blood for biomarker (5mL) and genetic (10mL) analyses. The PI/RA will randomize subjects to intervention (XR-NTX+CM) or Standard Care using a random number generator with randomly permuted blocks with allocations contained within opaque sealed envelopes.

1. For subjects randomized to the Intervention Arm, the PI/RA will confirm the drug screen is negative for opioids prior to administering XR-NTX 380mg as an intramuscular gluteal injection. The PI/RA will facilitate a person-centered, harm-reduction-based motivational interview, , and psychosocial assessment/interview to inform subjects' care-management plans. Subjects will receive a one-week referral to Bellevue ambulatory care for initial Alcohol-Medical Management (MM) and will also be scheduled every 4 weeks (after most recent XR-NTX injection) for MM and XR-NTX injections. When possible, participants who miss MM-injection visits will be navigated to clinic upon their next ED presentation and/or may receive MM and XR-NTX in the ED. XR-NTX will be administered by the PI or a provider (physician, physician assistant, or registered nurse) who is trained in the administration of XR-NTX. The schedule for MM-Injection visits is weeks 4, 8, 12, 16, 20, and 24. Participants may be offered to continue XR-NTX treatment through this study for as many has 12 injections in total as we explore the feasibility, acceptability and potential benefits of extending treatment duration to 12 months. The schedule for potential additional MM-Injection visits is weeks 28, 32, 36, 40, and 44. Research assessment visits will occur at weeks 12, 24, and 48 and may be conducted up to 28 days prior to- or 90 days after- date in which research visits are due. During research visits, the PI/RA will repeat the assessments that were conducted at the initial enrollment visit plus adverse events and participant satisfaction and we will collect a 5mL blood sample to examine alcohol consumption biomarkers. Subject participation ends after the week-48 research visit.
2. For subjects randomized to the Standard care arm, the PI/RA will provide referral to Bellevue ambulatory care for MM without further intervention. Research assessment visits will occur at weeks 12, 24, and 48 and may be conducted up to 28 days prior to- or 90 days after- date in which research visits are due. During research visits, the PI/RA will repeat the assessments that were conducted at the initial enrollment visit plus adverse events and participant satisfaction and we will collect a 5mL blood sample to examine alcohol consumption biomarkers. Subject participation ends after the week-48 research visit.

Arms: arm 1: XR-NTX+CM (Extended Release Naltrexone + Care Management) arm 2: Standard Care/Alcohol-Medical Management (MM) Only
Interventions: intervention 1: XR-NTX+CM (Extended-Release Naltrexone plus Care Management)
Intervention descriptions: intervention 1: The intervention arm will receive extended-release naltrexone (XR-NTX) 380mg (4 mL) to be administered as an intramuscular gluteal injection every 28 days up to 12 doses total. Expedited referral to alcohol-medical management. Care Management will include coordination of health care and social services for at least 12 months. Harm-reduction counseling and motivational interviewing to identify and work towards goals. The Standard care arm will receive an expedited alcohol-medical management referral.

Protocol documents:
Prot_SAP_000.pdf: 
  
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
 
 
NCT02445339 
 
 
 
 
NOVEL INTERVENTIONS FOR ALCOHOL DEPENDENT 
FREQUENT EMERGENCY DEPARTMENT USERS: 
A phase IV, randomized, open-label, non-placebo-controlled, single-center study of the feasibility, 
acceptability, and effect of extended-release naltrexone 380mg intramuscular injection compared to 
standard care on healthcare utilization, drinking, and quality of life in subjects with severe alcohol use 
disorders and frequent emergency department use. 
 
 
 
 
Regulatory Sponsor: 
Ryan P. McCormack, MD 
Department of Emergency Medicine 
462 First Ave, OBV 345A 
New York, NY 10016 
212-562-6561 (office) 
646-812-0218 (mobile)  
 
Funding Sponsor: 
National Institute on Alcohol Abuse and Alcoholism 
Program Officer: Brett Hagman,  
301-443-0638,  
Brett.Hagman@nih.gov 
 
Study Product: 
Naltrexone, extended release (Vivitrol)  
Protocol Number: 
S13-00928 
IND Number: 
N/A 
 
 
Initial version: [09/17/2014] 
Amended: 
[10/09/2018] 
 
 
 
 
 
 
 
 
 
Clinical Research Protocol 


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Table of Contents 
 
STUDY SUMMARY .......................................................................... ERROR! BOOKMARK NOT DEFINED. 
1 
INTRODUCTION ...................................................................... ERROR! BOOKMARK NOT DEFINED. 
1.1 
BACKGROUND.............................................................................. ERROR! BOOKMARK NOT DEFINED. 
1.2 
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1.3 
PRECLINICAL DATA ...................................................................... ERROR! BOOKMARK NOT DEFINED. 
1.4 
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1.5 
DOSE RATIONALE ........................................................................ ERROR! BOOKMARK NOT DEFINED. 
1.6 
RESEARCH RISKS & BENEFITS ..................................................... ERROR! BOOKMARK NOT DEFINED. 
1.6.1 
Risk of Study Drug .................................................................. Error! Bookmark not defined. 
1.6.2 
Other Risks of Study Participation .......................................... Error! Bookmark not defined. 
1.6.3 
Potential benefits ..................................................................... Error! Bookmark not defined. 
2 
STUDY OBJECTIVES ............................................................. ERROR! BOOKMARK NOT DEFINED. 
3 
STUDY DESIGN ...................................................................... ERROR! BOOKMARK NOT DEFINED. 
3.1 
GENERAL DESIGN ........................................................................ ERROR! BOOKMARK NOT DEFINED. 
3.2 
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3.3 
SECONDARY STUDY ENDPOINTS................................................... ERROR! BOOKMARK NOT DEFINED. 
3.4 
PRIMARY SAFETY ENDPOINTS ...................................................... ERROR! BOOKMARK NOT DEFINED. 
4 
SUBJECT SELECTION AND WITHDRAWAL ....................... ERROR! BOOKMARK NOT DEFINED. 
4.1 
INCLUSION CRITERIA .................................................................... ERROR! BOOKMARK NOT DEFINED. 
4.2 
EXCLUSION CRITERIA ................................................................... ERROR! BOOKMARK NOT DEFINED. 
4.3 
SUBJECT RECRUITMENT AND SCREENING ..................................... ERROR! BOOKMARK NOT DEFINED. 
4.3.1 
Prescreen: ............................................................................... Error! Bookmark not defined. 
4.3.2 
Screen (in Bellevue ED): ......................................................... Error! Bookmark not defined. 
4.3.3 
Capacity Assessment, Informed Consent, and Enrollment .... Error! Bookmark not defined. 
4.3.4 
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4.3.5 
Subject Randomization ........................................................... Error! Bookmark not defined. 
4.3.6 
Expected Human Subjects Characteristics ............................. Error! Bookmark not defined. 
4.4 
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5.4 
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5.5 
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5.6 
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5.7 
PACKAGING ................................................................................. ERROR! BOOKMARK NOT DEFINED. 
5.8 
BLINDING OF STUDY DRUG ........................................................... ERROR! BOOKMARK NOT DEFINED. 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ......................... ERROR! BOOKMARK NOT DEFINED. 
5.9.1 
Receipt of Drug Supplies ........................................................ Error! Bookmark not defined. 
5.9.2 
Storage .................................................................................... Error! Bookmark not defined. 
5.9.3 
Dispensing of Study Drug ....................................................... Error! Bookmark not defined. 
5.9.4 
Return or Destruction of Study Drug ....................................... Error! Bookmark not defined. 
6 
STUDY PROCEDURES ........................................................... ERROR! BOOKMARK NOT DEFINED. 


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6.1 
Visit 1:  Day 0 .............................................................................. Error! Bookmark not defined. 
6.2 
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6.13 
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6.14 
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7 
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7.2 
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Data Collection and Variables: (Table 2) ................................ Error! Bookmark not defined. 
7.2.2 
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7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ...................................... ERROR! BOOKMARK NOT DEFINED. 
8 
SAFETY AND ADVERSE EVENTS ........................................ ERROR! BOOKMARK NOT DEFINED. 
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DEFINITIONS ................................................................................ ERROR! BOOKMARK NOT DEFINED. 
8.2 
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8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMSERROR! BOOKMARK NOT 
DEFINED. 
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Investigator reporting: notifying the study sponsor ................. Error! Bookmark not defined. 
8.3.2 
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8.3.3 
Sponsor reporting: Notifying the FDA ..................................... Error! Bookmark not defined. 
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8.4 
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MEDICAL MONITORING ................................................................. ERROR! BOOKMARK NOT DEFINED. 
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Data Monitoring Committee .................................................... Error! Bookmark not defined. 
9 
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9.1 
CONFIDENTIALITY......................................................................... ERROR! BOOKMARK NOT DEFINED. 
9.2 
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9.3 
SOURCE DOCUMENTS .................................................................. ERROR! BOOKMARK NOT DEFINED. 
9.4 
CASE REPORT FORMS ................................................................. ERROR! BOOKMARK NOT DEFINED. 
9.5 
RECORDS RETENTION .................................................................. ERROR! BOOKMARK NOT DEFINED. 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ........ ERROR! BOOKMARK NOT DEFINED. 
10.1 
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10.2 
AUDITING AND INSPECTING ........................................................... ERROR! BOOKMARK NOT DEFINED. 
11 
ETHICAL CONSIDERATIONS ................................................ ERROR! BOOKMARK NOT DEFINED. 
12 
MANDATORY BIOMARKER AND GENETIC TESTING ........ ERROR! BOOKMARK NOT DEFINED. 
 
13 
INCLUSION OF PRISONERS ............................................................................................................ 48 
14 
AUDIO RECORDING .......................................................................................................................... 51 
15 
STUDY FINANCES ............................................................................................................................. 51 
15.1 
FUNDING SOURCE ........................................................................................................................ 51 


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15.2 
CONFLICT OF INTEREST ................................................................................................................. 51 
15.3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................ 51 
16 
PUBLICATION PLAN ......................................................................................................................... 51 
17 
REFERENCES .................................................................................................................................... 52 
18 
ATTACHMENTS ................................................................................................................................. 58 
 


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authorized in writing by the study sponsor 
 
 
List of Abbreviations 
 
 
 
 
 
AASE  
Alcohol Abstinence Self-efficacy Scale 
AST, ALT 
Liver transaminase serum concentration (Aspartate and Alanine aminotransferase)  
AUD 
 
Alcohol Use Disorder 
CBRD  
Center for Biospecimen Research and Development 
CDT 
 
Carbohydrate deficient transferrin (quantitative measure of drinking) 
CM 
 
Care Management 
CoC 
 
Certificate of Confidentiality 
CTSI 
 
Clinical and Translational Science Institute 
DSMB  
Data and Safety Monitoring Board 
DSM-IV/V 
Diagnostic and Statistical Manual of Mental Disorders (versions 4 and 5) 
EtG 
 
Ethyl glucuronide concentration test (quantitative measure of drinking) 
ED 
 
Emergency Department  
EQ-5D  
EuroQoL-5D  
GGT 
 
Gamma-glutamyl transpeptidase  
hcG 
 
Pregnancy test (human chorionic gonadotropin)  
HHC 
 
New York City Health and Hospitals Corporation  (Public Hospital System) 
HIPAA  
Health Insurance Portability and Accountability Act  
IM 
 
Intramuscular injection 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
IV 
 
Intravenous injection 
MM 
 
Medical Management (largely based on the COMBINE study model) 
MUSC  
Medical Center of the University of South Carolina Laboratory 
NIAAA  
National Institute of Alcohol Abuse and Alcoholism 
NIH 
 
National Institutes of Health 
NYU 
 
New York University 
PHI 
 
Protected Health Information 
SCID 
 
Structured Clinical Interview for DSM disorders 
SIP-2R  
Short Inventory of Problems 
TLFB 
 
Timeline Follow Back 
UBACC  
University of California-San Diego Brief Assessment of Capacity to Consent to Research 
XR-NTX 
Naltrexone, extended release preparation (brand name Vivitrol) 
XR-NTX+CM 
Intervention arm of enhanced care consisting of XR-NTX plus care management and  
 
 
harm-reduction based motivation interviewing 
 
 
 
 
 


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Study Summary 
Title 
Novel Interventions for Alcohol Dependent Frequent Emergency 
Department Users: A phase IV, randomized, open-label, non-placebo-
controlled, single-center study of the feasibility, acceptability, and effect of 
extended-release naltrexone 380mg intramuscular injection compared to 
standard care on healthcare utilization, drinking, and quality of life in subjects 
with severe alcohol use disorders and frequent emergency department use. 
Short Title 
XR-NTX in ED users with AUDs 
Protocol Number 
S13-00928 
Phase 
4 
Methodology 
Randomized, Open Label, non-placebo (compared to standard care)  
Study Duration 
8 years 
Study Center(s) 
Single-center 
Objectives 
To conduct a feasibility and acceptability study of XR-NTX+CM treatment in 
alcohol dependent patients with frequent ED use and explore its effect on 
healthcare utilization, drinking, and quality of life. 
Number of Subjects 
300 (Pilot, N=50; Subsequent trial N=250) 
Diagnosis and Main 
Inclusion Criteria 
Alcohol use disorder and frequent emergency department use 
Study Product, Dose, 
Route, Regimen 
Extended-release naltrexone (Vivitrol) 380mg intramuscular injection every 4 
weeks  
Duration of 
administration 
12 months 
Reference therapy 
Reference is treatment as usual (No medications) 
Statistical 
Methodology 
 Formal statistical analysis is not planned for the primary aim, in which we will 
a) further develop and pilot procedures and b) descriptively document 
feasibility and acceptability of XR-NTX for frequent ED users with alcohol use 
disorders. To explore the intervention effect, we will generate descriptive 
statistics and calculate changes in scores within and between groups. 
 


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1 Introduction 
 
This document is a protocol for a human research study. This study is to be conducted in accordance with 
US government research regulations, and applicable international standards of Good Clinical Practice, 
and institutional research policies and procedures. 
1.1 Background 
Alcohol use disorders (AUDs) are common, costly, and undertreated. They exact a tremendous toll in 
morbidity, mortality, and suffering with far reaching implications for patients, families and society.1-15 In the 
US, excessive alcohol use is the third leading cause of preventable death and accounts for an estimated 
$223.5 billion annual cost to society. 16,17  An estimated 4% of U.S. adults meet DSM-IV criteria for alcohol 
dependence,18 and the vast majority of persons with AUDs do not succeed in accessing specialty 
treatment.19,20  
 
Alcohol dependent patients with frequent emergency department (ED) use often receive their care 
exclusively in EDs. They account for a disproportionate share of healthcare visits and costs, leading to 
increased service demands for treatment settings and suboptimal healthcare delivery for these patients.21-
36 Typically, these individuals are brought to the ED involuntarily by EMS for public intoxication and have 
not sought care. Almost always, the ED visit represents a missed intervention opportunity as these 
patients are dismissed quickly with limited medical or social interventions.32 Their unabated frequent ED 
visits further providers’ therapeutic nihilism, patients’ loss of motivation for treatment, and stigma32,37-39 
Despite the extraordinarily high prevalence of alcohol use among ED patients, treatment or referrals for 
AUDs are rarely initiated in the ED, and research to develop and practically implement effective 
interventions is even less common.36,40,41 In fact, ED patients with severe AUDs are currently excluded 
from most research studies as they are often difficult to engage in care, are non-adherent to treatment, 
and suffer from alcohol-related and other comorbidities, as well as psychosocial dysfunction.32,42,43 
 
 
The infrastructure to support timely data-sharing and coordination of services between health and social 
service institutions is underdeveloped, resulting in failed navigation, frustrating providers and patients. By 
helping to address these difficulties, care management (CM) interventions targeting frequent ED users, 
including our pilot, have demonstrated reductions in the use of costly health services but have not 
reported an effect on drinking.21,32-34,44-46 Low-barrier, non-abstinence based, housing programs that 
include intensive care management (e.g. Housing First) have been associated with reduced use of costly 
public resources as well as alcohol use and alcohol-related harm.29,35,47-49 These community-based 
programs, however do not yet partner directly with EDs to coordinate care or to identify program subjects.  
 
Well-controlled clinical trials– such as the “Combining Medications and Behavioral Interventions for 
Alcoholism” (COMBINE) study– have demonstrated the efficacy of behavioral and pharmacologic 
treatments for alcohol dependence.50-53 Specifically, naltrexone, an FDA-approved opioid receptor 
antagonist, has been shown to reduce craving, heavy drinking, and healthcare utilization and associated 
costs.51,53-63 The pharmacokinetic properties of the extended-release preparation (XR-NTX), providing 
steady-state medication concentrations with injections every 4 weeks, are promising and particularly well 
suited for this often medically disengaged population at risk of non-adherence.64 It is safe and effective 
among both individuals who are abstinent and actively drinking.54  Its feasibility in primary care and other 
non-specialized medical settings has been demonstrated at our institution, where effectiveness studies 
are ongoing.57,65,66 A recent pilot of XR-NTX plus harm reduction counseling in a community-based low-
barrier housing program (in which abstinence is not required and intensive care management is provided) 
suggests a potentially more robust effect and high acceptability among a population similar to the one we 
are studying.67 However, neither XR-NTX nor other pharmacotherapy for alcohol dependence has been 
studied in the ED.  A critical need exists to refine and test the use of medications to treat alcohol 
dependent individuals in clinical settings where they frequently present, such as the ED. 
Demonstrating that efficacious pharmacotherapy can be initiated practically in the ED, ideally as a bridge 
to ambulatory care, would offer a powerful boost to efforts to expand the delivery and impact of evidence-


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based alcohol treatment. 
 
In preparation for a large definitive trial of a multimodal intervention that includes XR-NTX, we developed 
and tested a multidisciplinary CM intervention targeting homeless, alcohol dependent frequent ED users 
that coordinated healthcare, housing, and other social services through collaboration with NYC health and 
public health agencies.31  Upon each ED visit, prompted by an automated page, our ED social worker and 
the homeless outreach team met with participants, guided by previously developed care plans, to help 
coordinate ED care and offer shelter upon discharge. Assigned outreach caseworkers attempt to relocate 
participants into increasingly supportive settings. Care plans are informed by a cross-departmental, 
multidisciplinary team and updated with community partners during biweekly meetings. Plans were 
updated based on participants’ medical, psychosocial, and housing needs, safety, and barriers to 
rehabilitation. In this prospective, nonequivalent pre-test post-test control group trial, we consecutively 
enrolled 20 participants with alcohol dependence, chronic homelessness, and 2 years of frequent ED use 
to receive the CM intervention. We compared this group to 20 patients recruited prospectively who 
received standard care, and 20 patients identified retrospectively from the previous year using the same 
algorithm for patient identification. ED visits, inpatient days, and direct hospital costs were reduced by 
medians of 35%, 56%, and 50% respectively in the six-month period after intervention (p= 0.024; 0.20; 
0.09). The differences-in-differences of visits in the 6 months before and after intervention compared to 
the two control groups are shown below (and published). Eighteen participants accepted shelter; no 
controls were housed. No deaths occurred in the CM group, whereas in the 2 control groups, 9 subjects 
died and were excluded from the visit analysis.31 
We now propose an ED-based feasibility study comparing enhanced care that includes XR-NTX to 
standard care.  Our study incorporates components of efficacious interventions into a multimodal 
intervention customized for this unique population, including CM, housing facilitation, and 
pharmacological and behavioral therapy (XR-NTX, harm reduction-based motivational interview, CM). 
Our overarching hypotheses are that XR-NTX + multidisciplinary care management (CM) will be 
feasible and will decrease acute healthcare utilization, days of heavy drinking, and improve quality 
of life in a population of alcohol dependent frequent ED users.  
 
Several aspects of this study are novel, including:  
• 
Initiation of pharmacotherapy for alcohol dependence in the ED. There are no published studies 
of initiating treatment for alcohol or drug dependence in the ED (excluding withdrawal).  
• 
Potential use of ED observation to facilitate alcohol treatment, research enrollment and procedures, 
and aftercare coordination. Observation units are becoming increasingly common for patients whose 
length of stay is expected to require 8 - 23 hours, which supports the generalizability of this 
model.68,69 
• 
High degree of collaboration between health and public health institutions. Our innovative 
service model will use existing social services through collaboration with the NYC Departments of 
Homeless Services, Fire and EMS, and Health and Mental Hygiene, as well as with community 
outreach providers. It is therefore feasible given limited resources. Receiving data from collaborators, 
Table 1: Acute healthcare use was reduced in those receiving CM. The difference-in-differences 
of visits in the 6 months before and after intervention were compared to 2 control groups to 
attenuate the threat of regression to internal validity. 


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through agreements that include database management support, will allow more robust tracking and 
outcomes analysis. 
• 
We will use an adapted, validated case-finding algorithm to identify a cohort whose ED use is 
less likely to decline based on their past utilization patterns and comorbidities.28,70-74 
• 
We will use an innovative, automated alert system, linked to hospital registration, to recruit 
and track participants. This will allow us to communicate with partnering institutions and intervene in 
the ED, 24-hours/day, 7 days/week, rather than directing subjects to social and medical services 
elsewhere, when they have failed to adhere to referrals in the past.  
 
This work is of great significance because it may provide efficacious treatment and social stability to a 
population that has a disproportionate impact on healthcare and societal costs, and one that traditionally 
does not seek or receive care in medical settings offering addiction treatment. This proposal supports the 
National Institute of Health–National Institute on Alcohol Abuse and Alcoholism’s (NIAAA’s) priorities to 
limit health disparities by expanding access to effective alcohol treatments in general clinical settings 
through the increased use of emerging pharmacotherapies, while disseminating treatment principles 
endorsed by the NIAAA Clinicians Guide.75,76 It has the potential to transform revolving door ED visits into 
an effective point of public health intervention and to incorporate the ED and its unique populations into a 
more integrated healthcare system.  
 
Background: Alcohol Biomarkers 
Laboratory measures of heavy drinking are needed to assist clinicians in identifying and monitoring the 
treatment of patients suffering from alcohol use disorders and to provide investigators with objective 
outcome measures in clinical trials.  Recent research has provided new insights into the relationships 
between alcohol intake, biomarkers, and factors affecting their diagnostic validation.  However, the 
diagnostic validation of alcohol biomarkers is incomplete and information on the sensitivities and 
specificities of the even the most commonly used tests have remained controversial.77  
 
Currently, carbohydrate-deficient transferrin (CDT) is the most specific indicator of heavy drinking and is 
used as a marker of excessive and chronic alcohol consumption.77,78 Based on the literature, the 
correlation between the CDT level and self-reported alcohol consumption using validated, reliable 
methods among alcohol consumption in alcohol dependent patients ranges from approximately r= .35 to 
r=.60.79-85  However, the relationship between CDT levels and alcohol intake may be influenced by age, 
gender, BMI, cirrhosis, smoking status, flushing, and other factors, such that the correlation among these 
subgroups groups is less (although, typically not powered to reach statistical significance).81,84 Because of 
potential inter-individual variation, measuring the change in CDT from an individual’s baseline as a 
continuous variable appears to improve performance.  Recent studies have also suggested that the 
combination of CDT and gamma-glutamyl transpeptidase (GGT), via the equation [0.8*ln(GGT) + 
1.3*ln(CDT)], has higher diagnostic sensitivity and stronger correlation with the actual amount of alcohol 
consumed than either of the parent compounds alone; in one study the correlation of CDT-GGT was  
r=.76; p<.001.79,82,84,86 CDT represents a ‘cutting edge’ alcohol biomarker, and one not previously studied 
in the context of an XR-NTX treatment trial until a current trial being conducted by Joshua Lee, MD from 
NYU (R01AA020836; S12-02263). 
 
Background: OPRM1 Genomic Polymorphism 
Naltrexone’s relative ineffectiveness in African American clinical trial sub-populations, including in the 
COMBINE trial,87 is possibly mediated by low rates of the Asp40 OPRM1 functional allele in persons of 
African descent, who are primarily Asn40 homozygous.88 This Asp40 (A118G, ‘G’ allele) OPRM1 
functional single nucleotide polymorphism has been shown to be associated with successful treatment 
with naltrexone.89,90 Currently, Joshua Lee, MD from NYU (R01AA020836; S12-02263) in partnership with 
Charles O’Brien and Dr. Wade Berrettini’s lab from the University of Pennsylvania are prospectively 
assessing whether this allele is associated with retention and treatment effectiveness, potentially 
representing one of the first studies to assess the impact of Asp40 on XR-NTX treatment outcomes.  
 


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1.2 Investigational Agent 
 
Naltrexone is a pure opioid antagonist that acts as a competitive antagonist at opioid receptor sites, 
showing the highest affinity for mu opioid receptors. 
 
Naltrexone for extended-release injectable suspension (XR-NTX, Vivitrol®) is an FDA-approved alcohol 
treatment medication.  It is supplied as a microsphere formulation of naltrexone for suspension, to be 
administered by intramuscular injection. Naltrexone is an opioid antagonist with little, if any, opioid agonist 
activity.  
 
Naltrexone is designated chemically as morphinan-6-one, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-
dihydroxy-(5α) (CAS Registry # 16590-41-3). The molecular formula is C20H23NO4 and its molecular 
weight is 341.41 in the anhydrous form (i.e., < 1% maximum water content).  XR-NTX is provided as a 
carton containing a vial each of XR-NTX microspheres and diluent, one 5-mL syringe, one ½-inch 20-
gauge preparation needle, and two 1½-inch 20-gauge administration needles with safety device.  
 
XR-NTX microspheres consist of a sterile, off-white to light tan powder that is available in a dosage 
strength of 380 mg naltrexone per vial. Naltrexone is incorporated in 75:25 polylactide-co-glycolide (PLG) 
at a concentration of 337 mg of naltrexone per gram of microspheres. The diluent is a clear, colorless 
solution. The composition of the diluent includes carboxymethylcellulose sodium salt, polysorbate 20, 
sodium chloride, and water for injection. The microspheres must be suspended in the diluent prior to 
injection. 
 
CLINICAL PHARMACOLOGY:  
 
Pharmacodynamics  
Mechanism of Action: Naltrexone is an opioid antagonist with highest affinity for the mu opioid receptor.  
Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties. However, it does 
produce some pupillary constriction, by an unknown mechanism. The administration of XR-NTX is not 
associated with the development of tolerance or dependence. In subjects physically dependent on 
opioids, XR-NTX will precipitate withdrawal symptomatology.  
 
Occupation of opioid receptors by naltrexone may block the effects of endogenous opioid peptides. The 
neurobiological mechanisms responsible for the reduction in alcohol consumption observed in alcohol-
dependent patients treated with naltrexone are not entirely understood. However, involvement of the 
endogenous opioid system is suggested by preclinical data.   Naltrexone blocks the effects of opioids by 
competitive binding at opioid receptors. This makes the blockade produced potentially surmountable, but 
overcoming full naltrexone blockade by administration of opioids may result in non-opioid receptor-
mediated symptoms such as histamine release. 
 
XR-NTX is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate 
use or ethanol ingestion.  
 
Pharmacokinetics  
Absorption  
XR-NTX is an extended-release, microsphere formulation of naltrexone designed to be administered by 
intramuscular (IM) gluteal injection every 4 weeks or once a month.  
After IM injection, the naltrexone plasma concentration time profile is characterized by a transient initial 
peak, which occurs approximately 2 hours after injection, followed by a second peak observed 
approximately 2 - 3 days later. Beginning approximately 14 days after dosing, concentrations slowly 
decline, with measurable levels for greater than 1 month. Maximum plasma concentration (Cmax) and 
area under the curve (AUC) for naltrexone and 6β-naltrexol (the major metabolite) following XR-NTX 
administration are dose proportional. Compared to daily oral dosing with naltrexone 50 mg over 28 days, 
total naltrexone exposure is 3 to 4-fold higher following administration of a single dose of XR-NTX 380 


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mg. Steady state is reached at the end of the dosing interval following the first injection. There is minimal 
accumulation (<15%) of naltrexone or 6β-naltrexol upon repeat administration of XR-NTX.  
 
Distribution 
In vitro data demonstrate that naltrexone plasma protein binding is low (21%). 
 
Metabolism 
Naltrexone is extensively metabolized in humans. Production of the primary metabolite, 6β-naltrexol, is 
mediated by dihydrodiol dehydrogenase, a cytosolic family of enzymes. The cytochrome P450 system is 
not involved in naltrexone metabolism. Two other minor metabolites are 2-hydroxy-3-methoxy-6β-
naltrexol and 2-hydroxy-3-methoxynaltrexone. Naltrexone and its metabolites are also conjugated to form 
glucuronide products. Significantly less 6β-naltrexol is generated following IM administration of XR-NTX 
compared to administration of oral naltrexone due to a reduction in first-pass hepatic metabolism. 
 
Elimination 
Elimination of naltrexone and its metabolites occurs primarily via urine, with minimal excretion of 
unchanged naltrexone. The elimination half-life of naltrexone following XR-NTX administration is 5 to 10 
days and is dependent on the erosion of the polymer. The elimination half-life of 6β-naltrexol following 
XR-NTX administration is 5 to 10 days. 
 
Special Populations 
Hepatic Impairment: The pharmacokinetics of XR-NTX are not altered in subjects with mild to moderate 
hepatic impairment (Groups A and B of the Child-Pugh classification). Dose adjustment is not required in 
subjects with mild or moderate hepatic impairment. XR-NTX pharmacokinetics were not evaluated in 
subjects with severe hepatic impairment. 
Renal Impairment: A population pharmacokinetic analysis indicated mild renal insufficiency (creatinine 
clearance of 50-80 mL/min) had little or no influence on XR-NTX pharmacokinetics and that no dosage 
adjustment is necessary. XR-NTX pharmacokinetics have not been evaluated in subjects with moderate 
and severe renal insufficiency. 
Gender: In a study in healthy subjects (n=18 females and 18 males), gender did not influence the 
pharmacokinetics of XR-NTX. 
Age: The pharmacokinetics of XR-NTX have not been evaluated in the geriatric population. 
Race: The effect of race on the pharmacokinetics of XR-NTX has not been studied. 
Pediatrics: The pharmacokinetics of XR-NTX have not been evaluated in a pediatric population.  
Drug-Drug Interactions 
Clinical drug interaction studies with XR-NTX have not been performed. 
Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and cold remedies, 
antidiarrheal preparations and opioid analgesics. 
 
1.3 Preclinical Data 
According to the FDA prescribing information in all controlled and uncontrolled trials during the 
premarketing development of XR-NTX, more than 1100 patients with alcohol and/or opioid dependence 
have been treated with XR-NTX. Approximately 700 patients have been treated for 6 months or more, 
and more than 400 for 1 year or longer. In controlled trials of 6 months or less in alcohol-dependent 
patients, 9% of alcohol-dependent patients treated with XR-NTX discontinued treatment due to an 
adverse event, as compared to 7% of the alcohol-dependent patients treated with placebo. Adverse 
events in the XR-NTX 380 mg group that led to more dropouts than in the placebo-treated group were 
injection site reactions (3%), nausea (2%), pregnancy (1%), headache (1%), and suicide-related events 
(0.3%). In the placebo group, 1% of patients withdrew due to injection site reactions, and 0% of patients 
withdrew due to the other adverse events.87  
 


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1.4 Clinical Data to Date 
A recently published meta-analysis of XR-NTX found an association with reduction in heavy drinking days 
(weighted mean difference -4.6%; 95% CI, -8.5% to -0.56%).88 XR-NTX is safe and effective among 
both individuals who are abstinent and actively drinking.54   
 
The efficacy of XR-NTX in the treatment of alcohol dependence was evaluated in a 24 week, placebo-
controlled, multi-center, double-blind, randomized trial of alcohol-dependent (DSM-IV criteria) outpatients. 
Subjects were treated with an injection every 4 weeks of XR-NTX 190 mg, XR-NTX 380 mg or placebo. 
Oral naltrexone was not administered prior to the initial or subsequent injections of study medication. 
Psychosocial support was provided to all subjects in addition to medication. Subjects treated with XR-
NTX 380 mg demonstrated a greater reduction in days of heavy drinking than those treated with placebo. 
Heavy drinking was defined as self-report of 5 or more standard drinks consumed on a given day for male 
patients and 4 or more drinks for female patients. Among the subset of patients (n=53, 8% of the total 
study population) who abstained completely from drinking during the week prior to the first dose of 
medication, compared with placebo-treated patients, those treated with XR-NTX 380 mg had greater 
reductions in the number of drinking days and the number of heavy drinking days. In this subset, patients 
treated with XR-NTX were also more likely than placebo-treated patients to maintain complete abstinence 
throughout treatment. The same treatment effects were not evident among the subset of patients (n=571, 
92% of the total study population) who were actively drinking at the time of treatment initiation.87 
 
There are no published trials of pharmacotherapy for alcohol dependence that have been conducted in 
the ED. Its feasibility in primary care and other non-specialized medical settings has been demonstrated 
at our institution, where effectiveness studies are ongoing.57,65,66 Our team’s studies of XR-NTX for 
alcohol treatment include participating as a site in Garbutt’s pivotal trial, an observational study 
demonstrating the feasibility, acceptability and likely effectiveness of 3- and 15-month courses of XR-NTX 
among 72 adults in Bellevue primary care clinics, and a newly initiated NIAAA R01 trial comparing it to 
oral NTX in primary care. Opioid treatment studies have included 4 recently completed or on-going XR-
NTX vs. no medication or Buprenorphine (Joshua Lee, MD). All studies have used a simple Medical 
Management platform to deliver XR-NTX in general care settings. A recent pilot of XR-NTX plus harm 
reduction counseling in a community-based Housing First program suggests a potentially more robust 
effect and high acceptability among a population similar to the one we are studying.67  
 
1.5 Dose Rationale 
XR-NTX 380mg intramuscular injection every 4 weeks is the FDA approved and recommended dosage 
for the treatment of alcohol dependence.  We will administer XR-NTX according to these guidelines.  As 
per the above data, the extended release preparation is favorable to the oral formulation because it helps 
address non-adherence.  The dosage of XR-NTX 380mg has demonstrated the best efficacy while 
maintaining safety.  The treatment duration is variable in research and clinical practice; the minimum 
duration is typically 3 months.  Duration is generally extended in patients with more severe or refractory 
alcohol dependence, such as the patients we will be studying. We will plan for each subject to receive 6 
months of medication and will explore continuing treatment for up to 12 months of XR-NTX. 
1.6 Research Risks & Benefits 
1.6.1 Risk of Study Drug 
The study medication (XR-NTX, Vivitrol) was FDA approved in 2006 and will be used for the approved 
indication(s), so it is not an investigational drug, per se. The FDA has reviewed the protocol and 
determined that it meets all of the requirements for exemption from the Investigational New Drug (IND) 
regulations and, therefore, an IND is not required to conduct the investigation. This exemption was 
requested by the PI because the administration of XR-NTX may deviate slightly from its labeled-use.  
 
XR-NTX is typically recommended for people who are able to abstain from alcohol in an outpatient setting 
prior to initiation of treatment. The duration of abstinence is not specified.  Patients who receive XR-NTX 


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in the study may be intoxicated from alcohol when they arrive in the emergency department, but will not 
be enrolled until medically stable and clinically sober.  Patients (potential subjects) may be placed into ED 
observation for the extended duration of care necessary to achieve this state. If this represents a minor 
deviation from the VIVITROL labeling, it may affect efficacy but should not represent an additional safety 
concern.  XR-NTX is not aversive therapy and does not cause a disulfiram-like reaction as a result of 
ethanol ingestion. XR-NTX has been shown to be safe and effective among both individuals who are 
abstinent and actively drinking.54  A subject’s ability to abstain from drinking prior to an initial XR-NTX 
injection may predict treatment response.89 However, this association has not been seen in all studies, 
including an XR-NTX pilot conducted in Bellevue Hospital primary care.65 Further, the administration of 
XR-NTX for the treatment of alcohol dependence users in this study is consistent with current clinical care 
for alcohol dependent patients in other clinical settings, including Bellevue Hospital Ambulatory care.  The 
administration of XR-NTX in our protocol is based on protocols of ongoing studies of XR-NTX for alcohol 
dependence in other clinical and community settings, including Dr. Joshua Lee’s XR-NTX study in 
Bellevue Hospital ambulatory care (R01AA020836; S12-02263) and Susan Collins’ study in a Seattle 
community housing program (R01 AA022309), which the FDA also determined was exempt from IND 
reporting. Also of note, the investigation is not intended to be reported to FDA as a well-controlled study 
in support of a new indication and there is no intent to use it to support any other significant change in the 
labeling or advertising of the drug. The investigation does not involve a route of administration, dose, 
patient population, or other factor that significantly increases the risk associated with the use of the drug 
product. 
 
XR-NTX: This study provides enhanced care management and XR-NTX for treatment of alcohol 
dependence. According to the FDA prescribing information in all controlled and uncontrolled trials during 
the premarketing development of XR-NTX, more than 1100 patients with alcohol and/or opioid 
dependence have been treated with XR-NTX. Approximately 700 patients have been treated for 6 months 
or more, and more than 400 for 1 year or longer. In controlled trials of 6 months or less in alcohol-
dependent patients, 9% of alcohol-dependent patients treated with XR-NTX discontinued treatment due 
to an adverse event, as compared to 7% of the alcohol-dependent patients treated with placebo. Adverse 
events in the XR-NTX 380 mg group that led to more dropouts than in the placebo-treated group were 
injection site reactions (3%), nausea (2%), pregnancy (1%), headache (1%), and suicide-related events 
(0.3%). In the placebo group, 1% of patients withdrew due to injection site reactions, and 0% of patients 
withdrew due to the other adverse events. Theoretically naltrexone can cause transient liver inflammation 
and its packaging has a boxed warning regarding the possibility of serious injury to those with active liver 
disease and liver function. However, recent clinical trials have demonstrated that does not appear to be 
hepatoxic 
at 
recommended 
doses, 
including 
in 
individuals 
with 
mild-moderate 
liver 
impairment.50,54,57,65,90,91  Liver function will be monitored throughout the trial. We will accommodate (in the 
ED or clinic) unexpected visits related to side effects and adverse events, and the PI will be available by 
phone for emergency consultation at any time.  
  
It is thought that mis-injection of XR-NTX into subcutaneous adipose tissue may cause injection site 
reactions. The PI has been carefully trained on the proper techniques of medication administration, 
including in his role as medical clinician for the National Institute on Drug Abuse Clinical Trials Network 
#0048 CURB study (August 2011).  Any provider administering XR-NTX to study subjects will receive 
training as well. The PI will providing training personally and has access to supplemental webinar training 
resources as part of his membership in the National Institute on Drug Abuse Clinical Trials Network. 
Providers administering XR-NTX may include physicians, physician assistants, and registered nurses.   
 
XR-NTX also introduces a prolonged mu opioid antagonist blockade, complicating the treatment of acute 
or chronic pain with opioid medications. Persons receiving XR-NTX will be provided a wallet card 
identifying them as an XR-NTX patient and containing the PI’s name and study phone number. XR-NTX 
blockade can be ‘overridden’ due to competitive mu receptor pharmacodynamics with increasing doses of 
full mu agonists, which should be provided only in a monitored medical setting such as an ED. Persons 
with chronic pain conditions requiring opioid medications are excluded from enrollment. 
  
Otherwise this is a study of treatment for alcohol dependence, and there is no guarantee subjects will 
benefit from the intervention, and thus remain chronic, heavy drinkers, with all of the short- and long-term 


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risks and hazards alcohol dependence entails. The XR-NTX study represents an evidence-based, FDA 
approved intervention designed to treat alcohol dependence and minimize these risks, and the PI expects 
most subjects to derive some minimal benefit from treatment. At the index visit and any point in the trial, 
subjects who appear to be unable to stop drinking due to severe withdrawal symptoms or who are 
experiencing severely detrimental consequences of heavy drinking (i.e., job loss, homelessness) will be 
encouraged to seek admission to inpatient detoxification and specialty treatment through Bellevue 
Hospital. Withdrawal will be treated in the ED during the index visit as needed per standard of care. As 
per usual care, detoxification and intensive outpatient alcohol specialty services are immediately available 
to all subjects through the Bellevue Hospital Chemical Dependency programs, including same-day 
admissions to our detoxification unit, regardless of insurance status or ability to pay. Most of the risks 
described are well defined side effects naltrexone and XR-NTX or of on-going alcohol dependence. The 
additional risks of naltrexone treatment are small. 
 
Protection against Risk (XR-NTX): As per exclusion criteria, the PI will avoid administering XR-NTX in 
patients with medical conditions that would contraindicate its use. Specifically, XR-NTX will not be used 
in: active opioid dependence (including any individual whose urine drug screen is positive for opioids), 
acute or chronic pain requiring opioid treatment, acute liver injury/failure (liver aminotransferase 
concentrations >5 times the upper limit of normal), any medical condition considered by the PI to be 
incompatible with or unsafe for study inclusion (e.g. expectation of future opioid needs), lack of decisional 
capacity, refusal to consent, currently being prescribed outpatient addiction pharmacotherapy (other than 
treatment of alcohol withdrawal), previous significant adverse reaction to naltrexone, polylactide-co-
glycolide, carboxymethylcellulose, or any other components of the diluent, body habitus that precludes 
safe injection, children, or pregnancy. The PI will assess liver function prior to enrollment; persons with 
liver aminotransferase concentrations >5 times the upper limit of normal will not be eligible for enrollment. 
Subjects will be monitored for signs and symptoms of liver injury at subsequent XR-NTX administration 
visits and research visits. Subjects in both arms will have their liver enzymes tested at enrollment and at 
the 3-, 6-, and 12-month research visits. The PI will repeat liver enzyme testing if subject receiving XR-
NTX through the study has signs or symptoms of liver injury. If the liver aminotransferase concentrations 
rise to >5 times the upper limit of normal, the laboratory tests will be repeated in one week. If liver 
enzymes are persistently elevated or if the individual is symptomatic, study medication will be 
discontinued and the subject will be referred for a Hepatology evaluation.  
  
In case of an emergency situation requiring opioids, subjects will be provided with a card showing that 
they have (or have not) received XR-NTX. This card will provide detailed information to medical personnel 
describing the special precautions necessary in the event that the subject should require pain 
management. Specifically, the amount of opioids necessary for analgesia may be greater than usual, and 
the resulting respiratory depression may be deeper and more prolonged. As a result, a rapidly acting 
analgesic that minimizes respiratory depression is preferred and the amount of the analgesic 
administration titrated to the needs of the patient in a setting equipped and staffed for cardiopulmonary 
resuscitation. The name of and contact information for the study PI and phone number of will be listed on 
the card in the event of an emergency. Unexpected visits related to side effects and adverse events will 
be accommodated (in the ED or clinic), and the PI will be available by phone for emergency consultation 
at any time. 
 
 
1.6.2 Other Risks of Study Participation 
Confidentiality: Risks to subjects include possible loss of confidentiality/privacy pertaining to their 
protected health information.  Subjects will be asked to provide sensitive information, including alcohol 
and drug use.  
 
The PI has completed requisite IRB Human Subjects and HIPAA trainings. Any future staff will have 
completed requisite IRB Human Subjects and HIPAA trainings. The PI will provide any future staff with 
training in their responsibilities for maintaining subject confidentiality.  
 


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The PI has obtained a Federal Certificate of Confidentiality to encompass protocol activity and subject 
data and ensure against the release of confidential information.   
Research records will be distinct from the medical record and enrollment in the study will not be stated in 
the medical record to help ensure the protections of the Certificate of Confidentiality.  Rather, we will state 
that the patient (subject) is being followed in the CPI Program (Compassion, Protection, Intervention 
Program- a collaborative initiative led by the PI to improve care for ED patients identified to be vulnerable. 
Currently, this program focuses on patients with alcohol use disorders, also known as Chronic Public 
Inebriates.) 
 
The diagnosis of an alcohol use disorder will already exist in the medical record of each eligible subject 
prior to enrollment; this is, in part, how subjects are identified for potential eligibility (i.e. we will not be 
adding a new diagnosis). Including treatment for this medical condition with naltrexone and care 
management in the medical record should not have additional ramifications (i.e. legal, stigma), particularly 
since naltrexone does not have abuse potential or mind altering effects. Therefore, the receipt of XR-NTX 
will be noted in the patient’s/subject’s medical record. Study assessments (e.g. questionnaires related to 
alcohol and drug use, legal and social problems, healthcare utilization, quality of life, consequences of 
alcohol use) will only be entered into the research record (using a unique identifier). There will be no 
mention of these research assessments or inclusion of the data resulting from them in the medical record.  
Any authorizations for release of information to partnering institutions that are included in the medical 
record to facilitate care management (e.g. Department of Homeless Services for housing facilitation) will 
also not include the study title (also to ensure that the protections provided by the Certificate of 
Confidentiality are not jeopardized).  
 
All research data will be entered into NYU-internal REDcap surveys administered on iPad tablet PCs 
using Bellevue’s secure network for any data containing subject protected health information. The iPad 
devices have security protections that are HIPAA compliant. Data will be stored on secure servers and/or 
in locked filing cabinets in my locked research office with access only to authorized study personnel as 
identified by the principal investigator and project manager for this study. Unique identifiers will be used to 
identify subjects in the password- protected database. Study findings will utilize only aggregate data and 
no publication or presentation will involve any use of individual information.  
 
All safeguards for storage of information on password-protected servers with HIPAA compliant firewall will 
be in place to ensure data are secure. There is a risk that if the iPad tablet PC is lost, it will compromise 
study information. To prevent this, the iPad tablet PC devices used in this research will have security 
features that are designed to protect the device and data while enforcing strict network and platform 
security including strong passwords, remote and local wipe, network security, and certificate based 
authentication. The extensive precautions available to iPad tablet PCs will minimize the risk involved with 
maintaining research databases on portable devices.  
  
Emotional Discomfort: There is a small chance that subjects may become upset during assessments that 
include their history of alcohol problems, psychosocial, and other potentially sensitive topics. These risks 
are not beyond usual clinical procedures in alcohol treatment. We will discontinue administration of 
research instruments if a subject shows great discomfort or asks to terminate an interview.  
 
Venipuncture: Subjects will have their blood drawn at the time of enrollment and during subsequent 
research visits to test for biomarkers genes that may predispose individuals to alcohol use disorders 
and/or alter the effectiveness of naltrexone. Potential risks associated with drawing blood include slight 
discomfort and/or bruising. Though highly unlikely, there is also the possibility of local infection, excess 
bleeding, clotting or fainting occurring. 
 
Protection Against Overall Risks:   
 
This trial will be conducted in compliance with the current version of the protocol, current Good Clinical 
Practice (GCP), the principles of the Declaration of Helsinki, and all other applicable regulatory 
requirements. We will obtain written approval of the study protocol, consent form, other supporting 
documents, and any advertising for subject recruitment from the NYUMC IRB. Any amendments to the 


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protocol or consent materials must be approved before they are implemented. Annual progress reports 
and local Serious Adverse Event (SAE) reports will be submitted to each IRB, according to its usual 
procedures. 
 
This study offers patients randomization to FDA-approved naltrexone treatment for alcohol dependence 
vs. standard care. As such, the potential risks of study participation are chiefly that of data collection (time 
and effort, confidentiality), and otherwise consistent with the usual care and use of these medications in 
everyday primary care practice.  
 
Risks from data collections and rating scales are not beyond usual clinical procedures in alcohol 
treatment. All appropriate actions will be taken by staff members in order to minimize the risks associated 
with loss of confidentiality (see above). To minimize any discomfort associated with reporting on sensitive 
behaviors, subjects will be informed that they may refuse to answer questions that they are not 
comfortable answering. Questions related to eligibility determination and monitoring of safety and 
treatment response are not optional. If a person declines to answer these questions, the PI will advise 
him/her that he/she will not be able to participate and will make a referral to other treatment if interested. 
As described above, the PI has obtained a Federal Certificate of Confidentiality from NIAAA/NIH to 
encompass protocol activity and subject data and ensure against the release of confidential information. 
The PI and any future staff will have completed requisite IRB Human Subjects and HIPAA trainings. The 
PI will provide any future staff with training in their responsibilities for maintaining subject confidentiality; 
we will use unique identifiers to identify subjects in the database; all data will be kept in locked filing 
cabinets in my locked research office or on our secure server to which only the investigators and project 
manager will have access. Study findings will utilize only aggregate data and no publication or 
presentation will involve any use of individual information. 
1.6.3 Potential benefits 
The benefits outweigh the risk of participation in this study. All subjects will have the opportunity to 
altruistically help to advance healthcare quality for others through their participation, which has been 
shown to be a strong motivating factor for study participation. Subjects will receive substance use 
treatment resources and an expedited referral to Bellevue (or other) ambulatory care for alcohol treatment 
and medical management. Subjects in the intervention arm will also benefit from their participation by 
obtaining FDA-approved treatment for alcohol dependence without the cost of medication. The individuals 
to be recruited traditionally receive their medical care in the ED and do not access primary or specialty 
ambulatory care. Thus, they are otherwise unlikely to receive and benefit from efficacious treatment for 
alcohol dependence. Subjects will receive care management that will include coordination with homeless 
outreach teams and other community peer supports and social service providers as needed. Several 
studies using similar interventions, including the PI’s prior pilot-clinical trial, have demonstrated a range of 
promising outcomes that have included decreased ED use, hospitalizations, accessing benefits and 
housing, entry into primary care, and improved quality of life. Most of the risks described are well defined 
side effects of XR-NTX or of on-going alcohol dependence. The additional risks of XR-NTX treatment are 
small compared to the expected benefit of discontinuing alcohol use.  
 
Importance of knowledge gained:  This study will assist us in evaluating the effects of initiating treatment 
for alcohol dependence in the ED with XR-NTX for patients with frequent ED use and alcohol 
dependence. Individuals with alcohol dependence often receive their care exclusively in EDs, where 
referrals for substance use are rarely initiated, resulting in significant healthcare costs and diminished 
access to treatment of this and other chronic conditions.7,24-29,32-36,92-97  A critical need exists to refine and 
test the use of medications to treatment alcohol dependent individuals in clinical settings where they 
frequently present such as the ED. Knowledge gained from this study will be invaluable towards 
decreasing individual illness and injury as well as societal costs of dependence. This information is 
important in order to develop and submit a full-scale research project looking at XR-NTX in ED patients, 
including assessment of cost-effectiveness, which ultimately would be of great benefit to society. By 
examining methods to improve the feasibility and acceptability of alcohol research and treatment in the 
ED, this study will help improve the access to quality treatment for alcohol dependence. It also has 
implications for the quality and safety of research involving alcohol, vulnerable populations, and the ED 


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setting. The study will examine of methods to assess and enhance decisional capacity, including the use 
of instruments previously validated in other populations. It will also provide information on the practical 
use in this population and setting of previously validated instruments commonly used in research. 
Informed consent procedures should provide adequate subject protection without placing unnecessary 
restriction on scientific advances. Investigators have an ethical responsibility to disclose information to 
potential subjects and to ensure that the subject has the capacity to reach a decision on the basis of the 
information provided. The process by which this is done is often vague; a more rigorous method will be 
developed in this study to help elevate the standards. Given the anticipated benefits to subjects and to 
society, the low risks to subjects are reasonable.  
 
2 Study Objectives 
 
Our primary aim is to assess the feasibility of initiating treatment in the ED with XR-NTX+CM (vs. 
standard care) and continuing care in cooperation with clinic providers as well as how best to assess 
outcomes. Secondarily, we will explore its effect on various health outcomes (healthcare utilization and 
engagement, expenditures, drinking and consequences, quality of life) as well as the association of 
patient-level characteristics (e.g. sex, race, baseline drinking, health and psychosocial factors, mu opioid 
receptor genotype) with effectiveness. Determining both how to implement XR-NTX+CM and rigorously 
test its effects in the ED (phase 1) is essential before planning a large-scale effectiveness trial (phase 2). 
 
Aim #1: To conduct a feasibility and acceptability study of XR-NTX+CM treatment in alcohol 
dependent patients with frequent ED use.  
Hypothesis: Enrollment of a limited number of subjects will allow identification of optimal processes for a 
definitive trial. 
 
Aim #2: To conduct an analysis of the effect of this intervention on healthcare utilization and 
engagement, drinking outcomes, quality of life, and consequences of drinking (initial analysis will 
be exploratory).   
Hypothesis: Measuring changes in healthcare utilization, drinking metrics, and indicators of quality of life 
and consequences will provide preliminary data on intervention effect size on various outcomes of 
interest to inform the second phase, definitive trial. 
 
Aim #3: To identify patient-level characteristics associated with effectiveness.  
Hypothesis: Exploratory analysis of patient and system-level characteristics possibly associated with 
effectiveness will inform treatment choice to maximize the probability of successful outcome. Factors 
assessed will include data collected in ongoing investigations of pharmacotherapy for alcohol 
dependence, including mu opioid receptor (OPRM1) genotypes, to facilitate comparison across study 
populations and settings. 
 
XR-NTX+CM is a potentially powerful treatment for this population that suffers poor health and 
psychosocial outcomes and has a disproportionate impact on public resource utilization. We will identify 
methods to enhance the feasibility and acceptability of its implementation in the ED as well as to ensure 
that future study can be carried out efficiently and rigorously. We anticipate using this data to support a 
future R01 application to test the intervention’s effectiveness as well as other health services research 
that uses the ED to extend the reach of AUD treatment. This data is essential to influence policy and 
practices regarding evidence-based treatment for AUDs and to ensure this necessary care is provided in 
an integrated health system, particularly for those who only present to EDs under gravely compromised 
circumstances. 


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3 Study Design 
3.1 General Design 
This a phase IV, randomized, open-label, non-placebo-controlled, single-center study of the feasibility, 
acceptability, and effect of initiating treatment in the ED with extended-release naltrexone 380mg 
intramuscular injection compared to standard care in subjects with severe alcohol use disorders (i.e. 
alcohol dependence) and frequent emergency department use. In the first two years, we will finalize study 
preparations, recruit and randomize 50 subjects for the pilot phase of this study.  The duration of each 
subject’s participation will be 12 months. Thereafter, in the second phase of study, we will enroll an 
additional 250 subjects (for a total of 300 subjects) to address remaining feasibility and acceptability 
concerns and test effects. 
 
The study investigators (PI and RA) will collect process data, including barriers and facilitators 
encountered in the completion of all study procedures.  For the following study procedures, study 
investigators (the PI and RAs) will enter data directly into NYUMC-internal REDCap system for use on 
portable tablet computers. NYUMC internal REDCap is HIPAA compliant and data will be stored on 
secure servers with access only to authorized study personnel. 
 
Brief Synopsis of Study Procedures:  The following study procedures are described in greater 
detail elsewhere in this protocol.   
Patients will be prescreened for potential eligibility and added to an automated alert system linked to ED 
registration by Bellevue Care Managers as part of an ongoing quality improvement initiative. When a 
potentially eligible patient presents to the ED, an automated page and/or email will be delivered to the 
study PI and Bellevue ED social work and care management staff, prompting consultation and potential 
referral of the patient to study investigators (PI/RA) for recruitment (See 4.3 Subject Recruitment and 
Screening). ED medical providers (inclusive of ED physicians, nurses, social workers, and care 
managers) may also refer patients by notifying study investigators (PI/RA) when potentially eligible 
patients are present in the ED. The medical provider will introduce the PI/RA to clinically sober and 
medically stable patients who have given their permission to be approached.  The PI/RA will describe the 
study, confirm capacity to consent using the University of California San Diego Brief Assessment of 
Capacity to Consent to Research (UBACC), and obtain written informed consent. The PI/RA will confirm 
eligibility by performing a chart and laboratory review (liver enzymes, pregnancy, urine drug screen), 
history and examination, and diagnostic interview to confirm alcohol dependence and assess for opioid 
use and chronic pain. The PI/RA will conduct research intake assessments and interview and collect 
blood for biomarker (17mL) and genetic (17mL) analyses.  The PI/RA will randomize subjects to 
intervention (XR-NTX+CM) or Standard Care using a random number generator with randomly permuted 
blocks embedded and performed within the secure REDCap software electronically. 
 
1. For subjects randomized to the Intervention Arm, the PI/RA will confirm the drug screen is 
negative for opioids prior to administering XR-NTX 380mg as an intramuscular gluteal injection.  
The PI/RA will facilitate a person-centered, harm-reduction-based motivational interview, and 
psychosocial assessment/interview to inform subjects’ care-management plans.  Subjects will 
receive a one-week referral to Bellevue ambulatory care and/or another suitable substance use 
treatment program for for initial Alcohol-Medical Management (MM) and will also be scheduled 
every 4 weeks (after most recent XR-NTX injection) for MM and XR-NTX injections. When 
possible, subjects who miss MM-injection visits will be navigated to clinic upon their next ED 
presentation and/or may receive MM and XR-NTX in the ED. XR-NTX will be administered by the 
PI or a provider (physician, physician assistant, or registered nurse) who is trained in the 
administration of XR-NTX. The schedule for MM-Injection visits is weeks 4, 8, 12, 16, 20, and 24.  
Subjects may be offered to continue XR-NTX treatment through this study for as many as 12 
injections in total as we explore the feasibility, acceptability and potential benefits of extending 
treatment duration to 12 months. The schedule for potential additional MM-Injection visits is 
weeks 28, 32, 36, 40, and 44.   The schedule for research assessment visits is weeks 12, 24, and 
48; the time-window during which these research assessments may be conducted will be 
extremely liberal. If a scheduled date has passed, we will perform a research assessment at the 


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next available opportunity (up to 6 months after the 48 week visit). During research visits, the 
PI/RA will repeat the assessments that were conducted at the initial enrollment visit plus adverse 
events and subject satisfaction and we will collect a 17mL blood sample to examine alcohol 
consumption biomarkers. Subject participation ends after the week-48 research visit. 
 
2. For subjects randomized to the Standard care arm, the PI/RA will provide referral to Bellevue 
ambulatory care and/or another suitable substance use treatment program for MM.  Facilitating 
this referral (and offering another referral at the close of the study) is the extent of intervention for 
this arm. The schedule for research assessment visits is weeks 12, 24, and 48; the time-window 
during which these research assessments may be conducted will be extremely liberal. If a 
scheduled date has passed, we will perform a research assessment at the next available 
opportunity (up to 6 months after the 48 week visit).  During research visits, the PI/RA will repeat 
the assessments that were conducted at the initial enrollment visit plus adverse events and 
subject satisfaction and we will collect a 17mL blood sample to examine alcohol consumption 
biomarkers. Subject participation ends after the week-48 research visit. 
 
 
Schematic Diagram of Trial 
 
Figure 1: Schematic Diagram of Trial 
 
 
 
 


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Timeline of Study Procedures:   
 
Week 
0 
1 
4 
8 
12 16 20 24 28 32 36 40 44 48 
Enrollment (ED)  
Consent, Capacity Assessment (UBACC), DSM 
Diagnostic Interview (Alcohol Use), History & 
Physical Exam, Demographics, Below 
Assessments, Labs (AST, ALT, GGT, hCG, Drug 
Screen, genetics, CDT,), 
XR-NTX Arm*: Psychosocial Assessment, 
Interview, Care Management intake, XR-NTX 
injection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Visits   (ED, ED Office Space) 
• Broad Range of Assessments:  Alcohol and 
Substance Use, Health Status, Psychosocial 
(Housing, Legal, etc.), Quality of Life, Craving, 
Self-efficacy, Healthcare and Services 
Utilization, Adverse Events 
• Qualitative Assessments/Interview 
• Laboratory: Biomarker to Quantitate Drinking  
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Clinical Visits   (Clinic or ED) 
Adverse Event Form 
Medical Management Note 
 
X 
X* X* X* X* X* X 
X^ X^ X^  X^ X^  
Pre-Injection Labs (as needed): AST,ALT,GGT, 
hCG, Drug Screen 
X*  
X* X* X* X* X* X^ X^ X^ X^ X^ X^  
XR-NTX 380mg injection 
X*  
X* X* X* X* X* X^ X^ X^ X^ X^ X^  
Subject Compensation 
40 10 25* 25* 40 25* 25* 40 25^ 25^ 25^ 25^ 25^ 40 
Table 2: It is expected, particularly in this challenging cohort, that subjects will not be present for 
all clinical (and research) visits. The pragmatic study design allows considerable flexibility—
allowing delayed and missed visits. Similarly, the timing of certain clinical services (e.g. 
psychosocial assessments and care management intakes) will vary because they depend on the 
availability of existing clinical staff. The window for subjects to receive XR-NTX injections will not 
close until the 48th week after subject enrollment.  Key: [Green] is both arms; *[Turquois Blue] is 
intervention arm; ^[Grey-Blue] is intervention arm subjects that extend XR-NTX treatment. 
 
 
 
 
 
 
 
 
 
 
 


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Anticipated Study Timeline 
 
 
Figure 2: Anticipated Study Timeline:  Initial phase of study – to assess feasibility and 
acceptability and to explore effect of XR-NTX will inform the subsequent definitive trial. 
 
3.2 Primary Study Endpoints 
To conduct a feasibility and acceptability study of XR-NTX+CM treatment in alcohol dependent patients 
with frequent ED use. Data will be collected to determine optimal processes for enrollment, medication 
administration and treatment duration, navigation to ambulatory care, and refinement of the CM model for 
acceptance and continuing treatment engagement.  
Amongst the most pressing questions to answer in this study are the following: 
1. Screening and Recruitment: We will determine which potential subjects are willing and able to provide 
informed consent for study participation and how to improve enrollment, including through brief 
remediation and placing patients in an ED observation unit. 
2. XR-NTX: We will identify practical steps to maximize safety, acceptability, and adherence, and will 
explore extending treatment duration beyond 6 months. 
3. Continuity of Care: We will explore practical measures to engage subjects in their personal healthcare 
and improve continuity of care, including care coordination between hospital departments and 
community agencies (housing case workers), scheduling flexibility, and overnight placements in ED 
observation with direct entry into clinics. 
4. Quality Improvement: We seek to sustain and expand partnerships to improve the performance of 
services, tracking, and data sharing. We will explore adding components, such as emerging 
technologies for brief customizable interventions and tracking, and health record alerts.  
5. Outcomes Analysis: We will explore various sources of data to determine the most pragmatic, 
rigorous approaches to analyzing outcomes in this and future studies. We will assess the 
performance of biomarkers as objective measures of alcohol consumption. We will continue to 
explore which methods of assessing patient-level characteristics are most practical in this population 
and comparable to measures being collected by potential collaborators.   
 
3.3 Secondary Study Endpoints 
To conduct an exploratory analysis of the effect of this intervention on healthcare utilization and 
engagement, drinking outcomes, and quality of life. We will also explore patient-level predictors of 
effectiveness. 
 
We will explore the relative efficacy of XR-NTX+CM to standard care on decreasing acute healthcare use 
(ED, inpatient, Emergency Medical Services), associated expenditures, and cost-effectiveness. 
Secondarily, we will explore effects on healthcare engagement (clinic use, medication adherence, 
motivation to change), alcohol quantity/frequency, alcohol-related problems, and quality of life measures. 


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See Attachment #2.  We will evaluate and compare the performance of CDT and the combination of CDT-
GGT as an objective measure of alcohol consumption and its correlation to self-report.  We will also 
conduct an exploratory analysis of patient and system characteristics possibly associated with 
effectiveness.  These data will be used to inform the individualization of treatment choice to maximize the 
probability of successful outcome. Factors assessed will include data collected in ongoing investigations 
of pharmacotherapy for alcohol dependence to facilitate comparison across study populations and 
settings. This specifically includes the analyses modeled on those performed in an ongoing study directed 
by Dr. Joshua Lee (R01AA020836; S12-02263) at NYU.  All data analyzed will be de-identified and linked 
by a unique identification number.  
  
3.4 Primary Safety Endpoints 
XR-NTX is already FDA approved for the indication of alcohol dependence for which it will be used in this 
study.  We will repeat laboratory analyses (liver enzymes (AST, ALT, GGT), pregnancy, urine drug 
screen) as specified and maintain an adverse-effect profile and drug accountability log. Clinical 
assessments completed at week 1 and at Medical Management-Injection visits will include progress notes 
and Adverse Event Forms.  We will use vital statistics to track mortality in the event of drop-out.   
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for study enrollment: 
1) English or Spanish speaking* 
*Non-English Spanish speaking patients will not be enrolled initially until study documents have 
been translated, back translated, and approved by the IRB.  This will be done through a 
subsequent amendment. 
2) Emergency Department patient 
3) Aged 18-80 
4) Have had 6 or more emergency department visits in the last 24 months, with at least 3 visits in 
the last 12 months. Period of time can be extended by up to 6 months if incarcerated or 
institutionalized for ≥ 6 months. 
5) Meet DSM-IV criteria for alcohol dependence or & DSM-V criteria for alcohol use disorder, 
moderate or severe.  
6) Have ≥2 days/week of heavy drinking (>4 drinks/day)  
7) Capable of giving informed consent. 
4.2 Exclusion Criteria 
Subjects who meet any of the following criteria will be ineligible for study enrollment: 
1) Current physiologic dependence to opioids 
2) Acute or chronic pain requiring opioid treatment 
3) Acute liver injury (liver aminotransferase concentrations >5 times the upper limit of normal) 
4) Health condition considered unsafe for inclusion (at discretion of PI and/or attending physician)  
5) Lack of capacity or willingness to consent  
6) Currently prescribed pharmacotherapy for alcohol dependence (not including treatment of acute 
alcohol withdrawal syndrome)  
7) Currently enrolled in research in which the intervention includes treatment for alcohol or 
substance use disorders, pharmacotherapy, or that may otherwise interfere with the study or 
patient safety. 
8) Previous significant adverse reaction to naltrexone or diluent  
9) Pregnant, nursing, or not using effective methods of birth control 
10) Prisoners (as defined by Office of Human Research Protection) at the time of enrollment ARE 
NOT ELIGIBLE for study entry. 
• 
However, subjects who become prisoners after being enrolled will be included and not be 
withdrawn from the study 


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• 
Patients on parole or probation are eligible for enrollment.  
4.3 
Subject Recruitment and Screening 
All research will be performed on the NYU School of Medicine campus and Bellevue Hospital Center by 
study investigators. Recruitment will take place in the Bellevue ED (inclusive of Department of Emergency 
Medicine clinical and nonclinical space to ensure privacy and to minimize disruption of ongoing ED care). 
Follow up visits will occur in the Bellevue ED, Bellevue ambulatory care clinic, or the Clinical and 
Translational Science Institute Clinical Research Center. If it is only possible for subjects to conduct 
research assessments off site (e.g. due to mobility, health, or legal reasons), investigators may follow up 
with subjects off site.  
4.3.1 Prescreen:  
Potentially eligible patients will be identified in part through an administrative database search of Bellevue 
Hospital billing records. The data received includes a list of patients (name, date of birth, medical record 
number, number of visits) who had 6 or more ED visits within a 24-month period, with at least 3 visits in 
the past 12 months, and who were assigned an alcohol-related diagnosis; we will receive two years of 
data at a given time. Patients who have met this threshold are considered high-risk and added to an 
automated alert system to facilitate potential intervention. This alert system was first developed as part of 
a Medicaid High Cost Care Initiative demonstration project (PI: Raven, R# 06-336 and 06-412).73 It 
remains in use for various quality improvement initiatives, including for the population being studied- 
frequent ED users with alcohol dependence. Dr. McCormack remains involved in the process of 
identifying high-risk patients with substance abuse diagnoses via his role as a member of Bellevue 
Hospital care management committees.   
 
The high-risk patients added to the alert system are “Prescreened” as potentially eligible for study 
inclusion because, by definition, all will meet the visit threshold and were previously assigned an alcohol-
related diagnostic code.  They will be added to the briefly, aforementioned alert system.  Upon 
registration of potentially eligible patients in the ED, an automated alert will be delivered by secure email 
to the ED social worker, care manager, and the study PI (Dr. McCormack).  This alert triggers 
consultation by the social worker or care manager (as part of the quality improvement initiative) and alerts 
Dr. McCormack of a potential candidate for study inclusion. This system also ensures patients are 
identified promptly to facilitate for enrollment and for follow-up assessments.   
 
ED staff/providers (inclusive of ED physicians, nurse practitioners, nurses, social workers, health 
coaches, and care managers) also may notify study investigators (PI/RA) of potentially eligible ED 
patients, who may not have been identified through the alert system (e.g. due to miscoded diagnoses, 
outdated patient lists, and/or the alert system being unavailable for maintenance, etc.). These patients 
may be added to the alert system (if appropriate).  Staff referrals to the study do not necessarily need to 
originate from the alert system, as long as eligibility criteria are met. Research staff will remind ED clinical 
staff about the study and its eligibility criteria to help ensure appropriate referrals. 
 
4.3.2 Screen (in Bellevue ED):   
Recruitment will be triggered primarily by the aforementioned alert system or ED staff referral. Screening 
will be performed via convenience sample, dependent on the availability of the study investigators 
(PI/RA).  Recruitment during days, nights, and weekends will be scheduled to capture a representative 
sample. A limited number of patients may be held overnight in ED observation, providing additional 
opportunities for enrollment. We may oversample women and minorities to reach enrollment targets.  
 
Prior to approaching a patient for potential enrollment, the PI/RA will speak with ED staff/provider caring 
for the patient to ensure that the patient is appropriate and willing to be approached.  The provider will 
introduce the PI/RA to clinically sober and medically stable patients who have given their permission to be 
approached. The PI/RA will describe the study to the patient. 
 


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4.3.3 Capacity Assessment, Informed Consent, and Enrollment 
The PI and RA will obtain subjects’ written informed consent only after assessing their capacity to consent 
using the following stringent procedures.  The recruitment process will specifically address the likelihood 
that the subjects may have a compromised capacity to consent.  Subjects will not be enrolled until 
clinically sober and medically stable.  Subjects may be (re)assessed multiple times during their ED visit(s) 
as needed—and therefore will have multiple opportunities to be enrolled. We will use techniques shown 
to improve comprehension in informed consent procedures such as using a lower reading level, using 
larger typeface, quizzing and having multiple individuals providing the information. The PI will provide 
sensitivity training of investigators/RAs regarding difficult behaviors and limited comprehension and 
assessment of subject capacity to consent. 
 
The PI/RA will assess subject’s understanding of the study and capacity to consent to it using the 
University of California San Diego Brief Assessment of Capacity to Consent to Research (UBACC) 
(Attachment #2). The UBACC 10-item questionnaire is a 5-minute, easy-to-use, and validated tool, which 
we have studied in this population.43,98 It rates the basic elements of capacity (understanding, 
appreciation, reasoning, and ability to express a choice) to identify subjects with questionable capacity to 
consent to a specified research project. The UBACC assessment occurs after informing potential subjects 
about the study. Thus, first the RA/PI will review each page of the informed consent document with the 
patient, pausing to reassess comprehension throughout the process. Then, the RA/PI will administer the 
UBACC. Once the RA/PI confirms the subject’s comprehension (with the UBACC), the RA/PI will request 
the patient’s signature and provide the patient with a copy of the signed consent document. If, at any 
point during the consent process, the RA/PI does not believe the subject comprehends the study 
procedures the patient will not be enrolled at that time, but he or she may be eligible in the future. 
Patients who are not able to successfully complete (“pass”) the UBACC may be further assessed by 
psychiatry consultation. 
 
In addition, the PI/RA will ask the subject to consent to being audio recorded (for qualitative interviews, 
counseling sessions, and quality assurance monitoring). If the patient declines to provide their written 
informed consent to be recorded, the subject may still participate in the study (i.e. audio recording is 
optional).   
 
Subjects may be required to sign separate authorization forms for release of their personal health 
information to and from entities involved in their care, including care managers, case workers, housing 
facilitators, health providers, and government agencies/institutions. These data will be used to help 
coordinate and facilitate health and social needs and track outcomes. The purpose of this will be primarily 
clinical, rather than research.  Each institution will ensure protection of PHI.  All institutions, with the 
exception of the NYC Department of Homeless Services, are HIPAA covered entities.  All Institutions will 
consult their respective IRBs; the NYC Fire Department Emergency Medical Services will use the IRB of 
the NYC Department of Health and Mental Hygiene.  
4.3.4 Additional Post-Consent Eligibility Assessment 
After obtaining informed consent, we will confirm eligibility by performing a chart and laboratory review 
(liver enzymes, pregnancy, urine drug screen), history and examination, diagnostic interview to confirm 
alcohol dependence, and assessment of opioid use and chronic pain.99  See also Sections 4.1 and 4.2 for 
Inclusion and Exclusion Criteria. 
4.3.5 Subject Randomization 
Subjects will be randomly assigned to one of two arms: Intervention or Standard Care.  The 
randomization will be completed using a random number generator with randomly permuted blocks in 
blocks of 2, 4, and 6 subjects.  Randomization is embedded and performed within the secure REDCap 
software electronically.  After subjects have provided their informed consent to participate in the study, 
are determined to be eligible for it, and have completed all baseline assessments, the RA or PI will click 
on the randomization button in REDCap for the treatment assignment.  


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4.3.6 Expected Human Subjects Characteristics 
Based on preliminary studies, this population will have a mean age 50 ± 10, and be predominantly male, 
ethnically diverse, be without other usual source of care, and be precariously housed or homeless. 
Approximately forty-five percent of Bellevue patients are of Hispanic/Latino ethnicity (representing many 
countries), 40% are African American (including Caribbean and African immigrants), 10% are Asian 
American. Overwhelmingly, the major payers are Medicaid, Bad Debt and Charity Pools from state and 
federal programs. Based on studies of this population, including our own, comorbidities are expected to 
include concurrent mental illness, nicotine and other substance use, and untreated chronic conditions, 
often related to chronic alcohol dependence. In a recent dataset of 129 individuals with frequent Bellevue 
ED use an assigned alcohol-related diagnosis, 124 were male and 5 were female. This marked disparity 
among frequent ED users with AUDs has been consistently observed at Bellevue and internationally.34,100-
103 There will be no special outreach programs to recruit females or minorities since subjects will be drawn 
from patients receiving care at the Bellevue Hospital Emergency Department and must meet study 
inclusion criteria. We will purposefully recruit females by using a lower threshold of baseline visits for their 
addition to the alert system used in the recruitment procedure (but all subjects will meet inclusion criteria 
as defined). This same procedure will be performed, as needed to ensure ethnic diversity that is 
representative of the overall Bellevue population.  
  
Prisoners (at the time of enrollment), pregnant females, persons under the age of 18 or over the age of 
80, and persons who lack decisional capacity, or do not consent to the study will not be included.  
Additional exclusionary criteria exist for those recruited for the clinical intervention trial, including active 
opioid dependence, acute or chronic pain requiring opioid treatment, acute liver injury/failure (liver 
aminotransferase concentrations >5 times the upper limit of normal), any medical condition considered by 
the PI to be incompatible with or unsafe for study inclusion (e.g. expectation of future opioid needs), 
previous significant adverse reaction to naltrexone, body habitus that precludes safe injection, or 
individuals currently being prescribed outpatient addiction pharmacotherapy. If a woman becomes 
pregnant during the study she will be removed from the study and appropriately referred. We have 
chosen to include an age range to 18 to 80 to reduce confounding influences. To our knowledge, XR-NTX 
has not been studied in persons over the age of 80 or under the age of 18; persons of this age will not be 
included in this pilot study. All Federal rules regarding vulnerable subjects will be incorporated into the 
study protocol, and reviewed by the NYU IRB.  
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
• 
Subjects will be withdrawn from the study who: withdraw consent, become pregnant, develop a health 
condition in which XR-NTX is contraindicated (including need for opioid pain control).  Abrupt 
termination of study treatment should not affect subject safety beyond its disease mitigating effects on 
alcohol dependence.  Appropriate referral will be made for ongoing and/or alternative addictions 
treatment for all subjects withdrawn from the study. 
• 
Subjects who are not adherent to the research protocol treatment schedule will not be withdrawn.  
XR-NTX administration will be allowed to resume after missed visits/injections, which is expected in 
this patient population due to subject-level factors such as psychosocial challenges, potential 
incarceration or transient medical conditions that may prevent or delay safe injection (e.g. elevation in 
aminotransferase elevation >5 times the upper limit of normal). The window for subjects to receive 
XR-NTX injections will not close until the 12th month after subject enrollment. Contraindications to 
treatment re-initiation (opioid dependence) will be reassessed. 
• 
To help minimize attrition and departure from protocol, we will provide incentives for subject visits, 
use previously piloted care coordination and subject tracking measures, and allow considerable 
flexibility through the pragmatic design of the study.  


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4.4.2 Data Collection and Follow-up for Withdrawn Subjects or Lost to Follow-Up 
Subjects 
If a subject withdraws consent to participate in the study, we will attempt to obtain permission to record at 
least survival data up to the protocol-described end of subject follow-up period. We will also seek 
permission to record the full data set on such subjects to fully support the analysis.  At the time the 
subject consents to participating in the study, we will obtain their permission to contact additional sources 
as described below in the event we are unable to collect survival data from the subject.  Methods to 
contact subjects will include, if possible, several phone calls on different days of the week and time of 
day, calls to next of kin, communication with community peer supports (case-worker, case manager, 
housing outreach personnel, etc.), electronic messaging, and certified letters. We will also use locator 
information available in health records, (e.g. Bellevue Hospital Medical Record, New York City 
Department of Homeless Services outreach data, New York City Fire Department and Emergency 
Medical Services transport data). We will track mortality data through vital statistics for subjects who are 
lost to follow up. 
5 Study Drug  
5.1 Description 
Extended-release naltrexone (XR-NTX) 380mg (4 mL) will be administered as an intramuscular gluteal 
injection. Naltrexone is an opioid antagonist with little, if any, opioid agonist activity. This study will use an 
extended-release depot form of naltrexone (XR-NTX, Vivitrol®) that is FDA-approved treatment for 
alcohol dependence. XR-NTX is supplied as a microsphere formulation of naltrexone for suspension, to 
be administered by intramuscular injection. The microspheres consist of a sterile, off-white to light tan 
powder that is available in a dosage strength of 380 mg naltrexone per vial. The microspheres will be 
suspended in a clear, colorless diluent (polylactide-co-glycolide) prior to injection.  
 
Pharmacodynamics/Kinetics 
Duration:  I.M.: 4 weeks 
Distribution: Vd: ~1350 L; widely throughout the body but considerable inter-individual variation exists 
Metabolism: Extensively metabolized via noncytochrome-mediated dehydrogenase conversion to 6-
beta-naltrexol (primary metabolite) and related minor metabolites; glucuronide conjugates are 
also formed from naltrexone and its metabolites 
Protein binding: 21% 
Half-life elimination: I.M.: naltrexone and 6-beta-naltrexol: 5-10 days  
Time to peak, I.M.: Biphasic: ~2 hours (first peak), ~2-3 days (second peak) 
Excretion: Primarily urine (as metabolites and small amounts of unchanged drug) 
5.2 Treatment Regimen 
Extended-release naltrexone (XR-NTX) dose at 380mg (4 mL) will be administered as an intramuscular 
gluteal injection every 3 to 4 weeks for a total of as many as 12 doses. XR-NTX administration will be 
planned to occur every 28 days, but XR-NTX may be given as early as every 21 days depending on 
subject’s clinical response and scheduling needs, which is consistent with usual clinical care. We will plan 
for each subject to receive 6 months of medication and will explore continuing treatment for up to 12 
months of XR-NTX. 
The duration of XR-NTX has not been established. We expect this population having a severe form of 
AUD may benefit from a longer duration of treatment.  
5.3 Method for Assigning Subjects to Treatment Groups 
Subjects will be randomized to intervention or standard care using a random number generator with 
randomly permuted blocks, in blocks of 2, 4, and 6 subjects. Randomization is embedded and performed 
within the secure REDCap software electronically.  After subjects have provided their informed consent to 


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participate in the study, are determined to be eligible for it, and have completed all baseline assessments, 
the RA or PI will click on the randomization button in REDCap for the treatment assignment.  
5.4 Preparation and Administration of Study Drug 
 
Extended-release naltrexone (XR-NTX, VIVITROL) dose at 380mg (4 mL) will be administered as an 
intramuscular gluteal injection.  XR-NTX (VIVITROL) will be prepared and administered by a healthcare 
professional (trained physician, physician assistant, or registered nurse) using aseptic technique at the 
FDA approved dosage using recommended administration techniques detailed below.  
 
The PI has been carefully trained on the proper techniques of medication administration, 
including in his role as medical clinician for the National Institute on Drug Abuse Clinical Trials 
Network #0048 CURB study (August 2011).  Any provider administering XR-NTX to study 
subjects will receive training as well. The PI will providing training personally and has access to 
supplemental webinar training resources as part of his membership in the National Institute on 
Drug Abuse Clinical Trials Network. Providers administering XR-NTX may include physicians, 
physician assistants, and registered nurses.   
 
The entire carton should be stored in the refrigerator (2-8 °C, 36-46 °F). Unrefrigerated, XR-NTX 
(VIVITROL) Microspheres can be stored at temperatures not exceeding 25 °C (77 °F) for no more than 7 
days prior to administration. Do not expose unrefrigerated product to temperatures above 25 °C (77 °F). 
XR-NTX (VIVITROL) should not be frozen. 
Parenteral products should be visually inspected for particulate matter and discoloration prior to 
administration. 
 
1. Remove the carton from refrigeration. Prior to preparation, allow drug to reach room temperature 
(approximately 45 minutes). 
2. To ease mixing, firmly tap the XR-NTX (VIVITROL) Microspheres vial on a hard surface, ensuring the 
powder moves freely. 
3. Remove flip-off caps from both vials. DO NOT USE IF FLIP-OFF CAPS ARE BROKEN OR MISSING. 
4. Wipe the vial tops with an alcohol swab. 
5. Place the 1 inch preparation needle on the syringe and withdraw 3.4 mL of the diluent from the diluent 
vial. Some diluent will remain in the diluent vial. 
6. Inject the 3.4 mL of diluent into the XR-NTX (VIVITROL) Microsphere vial. 
7. Mix the powder and diluent by vigorously shaking the vial for approximately 1 minute. Ensure that the 
dose is thoroughly suspended. A PROPERLY MIXED SUSPENSION WILL BE MILKY WHITE, WILL 
NOT CONTAIN CLUMPS, AND WILL MOVE FREELY DOWN THE WALLS OF THE VIAL. 
8. Immediately after suspension, withdraw 4.2 mL of the suspension into the syringe using the same 
preparation needle 
1. Select the appropriate needle for an intramuscular injection based on subject's body habitus: 
a. 1.5 inch TERUMO® Needle 
b. 2 inch NEEDLE-PRO® Needle 
2. Remove the preparation needle and replace with appropriately selected administration needle for 
immediate use. 
3. Peel the blister pouch of the selected administration needle open halfway. Grasp sheath using the 
plastic pouch. Attach the luer connection to the syringe with an easy clockwise twisting motion.  
4. Seat the needle firmly on the needle protection device with a push and clockwise twist. 
5. Pull the sheath away from the needle - do not twist the sheath because it could result in loosening the 
needle. 
6. Prior to injecting, tap the syringe to release any air bubbles, then push gently on the plunger until 4 
mL of the suspension remains in the syringe. THE SUSPENSION IS NOW READY FOR IMMEDIATE 
ADMINISTRATION.  
7. Administer the suspension by deep intramuscular (IM) injection into a gluteal muscle, alternating 
buttocks per monthly injection. Remember to aspirate for blood before injection.  


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8. If blood aspirates or the needle clogs, do not inject. Change to the spare needle provided in the 
carton and administer into an adjacent site in the same gluteal region, again aspirating for blood 
before injection. 
9. Inject the suspension in a smooth and continuous motion.  XR-NTX (VIVITROL) must NOT be given 
intravenously or subcutaneously. 
10. After the injection is administered, cover the needle by pressing the needle protection device against 
a flat surface using a one-handed motion away from self and others. Visually confirm needle is fully 
engaged into the needle protection device. DISPOSE OF USED AND UNUSED ITEMS IN PROPER 
WASTE CONTAINERS. 
5.5 Subject Compliance Monitoring 
We know this is a challenging population to work with, and anticipate that part of the feasibility study will 
be to address expected difficulties specific to this population for enrollment, initiating pharmacotherapy, 
coordinating aftercare, and collecting outcomes data necessitates additional feasibility and exploratory 
work. We will make substantial efforts to maximize participation and adherence and minimize attrition by 
incorporating strategies used successfully by our research team and network of collaborators.57,65,104-106 
We expect our flexible, patient-centered approach, achieved through robust collaboration, feedback, and 
technology, will significantly help achieving these goals. Measures to facilitate success are informed by 
our qualitative interviews and our pilot study; measures will include simplifying navigation to health and 
social services by intervening directly through pre-formulated care plans at all hours and days – 
contemporaneous with subjects’ ED visits- and building trust by addressing basic needs (food, hygiene, 
shelter, transportation). Our approach incorporates the fundamental principles of addiction treatment and 
emphasizes improving access to effective treatment tailored to address the unique needs of each 
individual.76,107 Methods to ensure subject contact subjects will include, if possible, reminder phone calls 
on different days of the week and time of day, calls to next of kin, communication with community peer 
supports (case-worker, case manager, housing outreach personnel, etc.), electronic messaging, and 
letters. We may also use locator information available in health records, (e.g. Bellevue Hospital Medical 
Record, New York City Department of Homeless Services outreach data, New York City Fire Department 
and Emergency Medical Services transport data).   
 
If a subject misses a dose, he/she should be instructed to receive the next dose as soon as possible. 
There are no data to specifically address re-initiation of treatment. Subjects reinitiating treatment with XR-
NTX need to be opioid-free at the time of dose administration. 
5.6 Prior and Concomitant Therapy 
As per eligibility criteria, patients actively being treated with pharmacotherapy for opioid or alcohol 
dependence (not including treatment of alcohol withdrawal syndrome) will not be eligible for study 
inclusion.  Otherwise, subjects may receive any concomitant medical therapy.   
5.7 Packaging 
Dosage Form: XR-NTX (VIVITROL) is an injectable suspension for single use. VIVITROL contains 380 
mg of naltrexone in a microsphere formulation per vial (337 mg of naltrexone per gram of microspheres) 
and 4 mL diluent. 
XR-NTX (VIVITROL) is supplied in single use cartons. Each carton contains one 380 mg vial of XR-NTX 
(VIVITROL) microspheres, one vial containing 4 mL (to deliver 3.4 mL) diluent for the suspension of 
VIVITROL , one 5-mL prepackaged syringe, one 1-inch 20-gauge needle, two 1.5-inch 20-gauge needles 
and two 2-inch 20-gauge needles with needle protection devices: NDC 65757-300-01. 
 
For additional information, visit www.vivitrol.com or call 1-800-848-4876 
Manufactured and marketed by: Alkermes, Inc. 852 Winter Street Waltham, MA 02451-1420. Revised: 
October 2010. 
5.8 Blinding of Study Drug 
There will be no blinding in this open-label study. 


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5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
Drug will be provided at no cost to the subject.  Alkermes (manufacturer) will provide 225 VIVITROL kits 
(XR-NTX doses) free of charge.  If additional kits are required, we will approach Alkermes to request 
donation of additional kits or we will purchase the kits. Drugs will be obtained from Alkermes and shipped 
to the PI, Dr. McCormack, via Fisher through a site called Cenduit, and stored in non-Article 28 Space 
within a locked refrigerator (purchased specifically for use in this study) within secure administrative office 
space in the NYU Department of Emergency Medicine within Bellevue Hospital Center.   
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug receipt 
log filled out and signed by the person accepting the shipment.  It is important that the designated study 
staff counts and verifies that the shipment contains all the items noted in the shipment inventory.  Any 
damaged or unusable study drug in a given shipment (active drug or comparator) will be documented in 
the study files.  The investigator must notify study sponsor of any damaged or unusable study treatments 
that were supplied to the investigator’s site. We will maintain a drug accountability binder, which includes 
temperature logs, medication inventory logs, a standard operating procedure document, drug destruction 
forms/logs, manuals for study-drug and refrigerator management, package inserts, shipping receipts, and 
original prescriptions (as requested by the CTSI pharmacy). This binder is stored in a locked cabinet in 
the PI’s office. 
5.9.2 Storage 
Study medication will be stored in non-Article 28 Space within a locked refrigerator (purchased 
specifically for use in this study) within secure administrative office space in the NYU Department of 
Emergency Medicine within Bellevue Hospital Center.  The entire dose pack should be stored in the 
refrigerator (2 - 8°C, 36 - 46°F). Unrefrigerated, XR-NTX (VIVITROL) can be stored at temperatures not 
exceeding 25°C (77°F) for no more than 7 days prior to administration. Do not expose the product to 
temperatures above 25°C (77°F). VIVITROL should not be frozen. A temperature log will be maintained. 
 
Parenteral products should be visually inspected for particulate matter and discoloration prior to 
administration whenever solution and container permit. A properly mixed suspension will be milky white, 
will not contain clumps, and will move freely down the wall of the vial.  
 
For additional information, visit www.vivitrol.com or call 1-800-848-4876. 
5.9.3 Dispensing of Study Drug 
Study medication, XR-NTX, will be obtained by study investigators from the locked study refrigerator. XR-
NTX will be administered directly to each subject by a trained physician, physician assistant, or registered 
nurse. Regular study drug reconciliation will be performed to document drug assigned, drug consumed, 
and drug remaining.  This reconciliation will be logged on the drug reconciliation form, and signed and 
dated by the study team. 
5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and 
drug remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of 
unused study drug.  Drug destroyed on site or shipped back to Alkermes will be documented in the study 
files.  (Alkermes, Inc. 852 Winter Street Waltham, MA 02451-1420) 
6 Study Procedures 
See also:  
Section 3:  Study Design (also contains study overview and Attachments #4-6) 
Section 4.3: Subject Recruitment and Screening.     


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Attachment 4: Schematic Diagram of Trial  (also in Section 3.1) 
Attachment 5: Timeline of Study Procedures (also in Section 3.1) 
Attachment 6: Anticipated Study Timeline (also in Section 3.1) 
 
It is expected, in this challenging cohort, that subjects will not be present for all clinical (and research) 
visits. The pragmatic study design allows considerable flexibility—allowing delayed and missed visits. The 
window for subjects to receive XR-NTX injections will close 52 weeks after enrollment.  The schedule for 
research assessment visits is weeks 12, 24, and 48; the time-window during which these research 
assessments may be conducted will be extremely liberal. If a scheduled date has passed, we will perform 
a research assessment at the next available opportunity (up to 6 months after the 48 week visit).  
Research visits may be conducted up to 28 days prior to- or 90 days after- date in which research visits 
are due. The below described procedures are the “ideal” conditions that are not expected in this “real 
world” study. Non-completion of all procedures and deviation from intended schedule is expected and will 
not be considered protocol violations.  
 
For the following study procedures, study investigators (PI/RA) will enter data directly into NYUMC-
internal REDCap system for use on portable tablets or computers. NYUMC internal REDCap is HIPAA 
compliant and data will be stored on secure servers with access only to authorized study personnel. Any 
paper forms containing protected health information will be stored in a locked filing cabinet within the 
locked office of the PI. Data will be linked to the subjects using a unique identifier.   
 
Study Setting:  Research will be performed on the NYU School of Medicine campus and Bellevue 
Hospital Center by study investigators. Recruitment will take place in the Bellevue ED (inclusive of 
Department of Emergency Medicine clinical and nonclinical space to ensure privacy and to minimize 
disruption of ongoing ED care). Follow up visits will occur in the Bellevue ED, Bellevue ambulatory care 
clinic, or the Clinical and Translational Science Institute Clinical Research Center. If it is only possible for 
subjects to conduct research assessments off site (e.g. due to mobility or health), investigators may follow 
up with subjects off site.  
 
Study Personnel:  The PI will be responsible for all aspects of the study. The study investigators (PI, Co-
Investigators, and RAs) will collect process data, including barriers and facilitators encountered in the 
completion of all study procedures. The PI and RA will conduct study procedures related to screening, the 
enrollment visit (week 0), and the research visits at weeks 12, 24, and 48.  Biologic samples (blood/urine) 
will be collected by the PI, study clinicians, or clinical staff on duty.  Providers administering XR-NTX may 
include physicians, physician assistants, and registered nurses. Medical Management and subsequent 
XR-NTX injections will be performed by trained Bellevue ambulatory care or ED providers.  Care 
Management will be facilitated by Bellevue staff and/or community support staff. 
 
Subject Compensation: Subjects will be compensated $40 at enrollment and upon completion of 
research visits at months 3, 6, and 12.  Subjects in both arms will also be compensated $10 after the first 
(week 1) medical management visit.  Subjects in the intervention arm will receive $25 for each XR-NTX 
injection/clinical visit. In the event that the subject has a research visit and injection visit on the same day, 
the subject will only be compensated for the research visit.  Certain costs associated with arranging 
transportation of subjects, study personnel, and/or other staff will be reimbursed for paid by covered by 
the study when necessary.  Subjects will also receive food and small gifts in an effort to build trust. 
 
Laboratory Procedures 
Whenever possible, blood specimens to be collected for the purposes of this study will be collected at the 
same time as blood that is being collected for the clinical management of the patient (i.e. to avoid repeat 
venipuncture).  In some instances, this venipuncture will occur before the patient (potential subject) has 
provided his or her written informed consent to participate in the study.  The specimen(s) will not be 
processed and will be destroyed if the patient does not consent to the study. The rationale for this is to 
minimize study-related risks; it has been discussed with and recommended by the Data and Safety 
Monitors. 
1. It is possible to eliminate the risks of venipuncture for the study by collecting the research 
specimens with venipuncture that is planned already for clinical purposes. Potential risks 


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associated with drawing blood include slight discomfort and/or bruising. Though highly unlikely, 
there is also the possibility of local infection, excess bleeding, clotting or fainting occurring.   
2. The quantity of blood being obtained for research purposes, 34mL (2.3 tablespoons) is negligible 
and loss of this volume of blood poses no added harm.  
3. Because of the nature of the ED setting and need to address acute problems rapidly, delaying 
initial venipuncture may disrupt or delay clinical care and/or negatively impact ED staff 
productivity.  Thus, delaying venipuncture in order to first complete the lengthy informed consent 
process would be potentially harmful. 
 
Clinical Laboratory Analysis 
Laboratory studies that are necessary to assess subjects’ eligibility to receive XR-NTX will be performed 
as part of their clinical care and performed through the Bellevue laboratory.  These tests include serum 
liver function tests and urine hCG (pregnancy test). We may elect to use urine pregnancy tests purchased 
with study funds (at no cost to subjects) to expedite procedures. As an added safety measure, we will 
purchase and use urine drug screens that are capable of detecting opioids, like methadone and 
buprenorphine, that may not be detected using the earlier generation drug screens.  This will be 
performed at no cost to subjects.  
 
Serum Collection and Processing for Biomarker Analyses 
Carbohydrate-deficient transferrin (CDT), and gamma-glutamyl transpeptidase (GGT). will be used to 
quantitate heavy drinking.79,80,82,83,108,109 Co-investigator Joshua Lee, MD, will serve as advisor in this 
aspect of the study.  
 
Biomarker analyses will be conducted for research purposes primarily at 4 time points per subject 
(enrollment, months 3, 6, and 12). Each blood sample will be labeled with a unique subject ID number 
and the visit number obtained. No identifiable information will be included on the specimen tubes and only 
the PI and RA will have access to the list linking subjects to their ID Number assignment. Upon collection, 
the blood specimens will be delivered to the NYULMC Center for Biospecimen Research and 
Development (CBRD) where they will be stored until processed. The serum will be divided and aliquoted 
into multiple vials.  Cryovial(s) containing at least at total of at least 400 microliters of serum will be 
shipped in batches to the Medical University of South Carolina Center (MUSC) laboratory for CDT 
analysis.  Serum specimens (cryovials) in excess of what is required by the MUSC laboratory to perform 
the CDT analysis will be retained in the NYULMC CBRD until the end of the study (or until processed). 
This procedure of retaining the “left-over” vials will help ensure that serum is available perform additional 
analyses, including in the event that a specimen is lost or damaged, and/or for further biomarker, protein, 
or genomic analyses.  GGT will be processed immediately as part of the liver enzyme analysis (see 
above, Clinical Laboratory Analysis); however, GGT may be processed with the specimens collected for 
CDT analyses (by MUSC or NYULMC) if not obtained clinically. The whole blood specimens (for genomic 
analyses) will be stored in the NYULMC CBRD for future processing. (Laboratory is to be determined.) 
Only study team members and CBRD/Clinical Laboratory staff will have access to the stored specimens.  
Samples will be destroyed once processed; all samples will be destroyed prior to the end of the study.  
• 
8.5mL of whole blood will be collected and will be stored in a -20C or -80C freezer.  
• 
8.5ml of blood will be collected in a serum separator vacuum tube. Centrifuge at 1500 X g for 10 
minutes until clot and serum are separated. Pipette serum into the appropriately labeled plastic 
cryovials, cap cryovial tightly. Place into small microaliquot freezer storage boxes (or similar) and 
place in -30 to -80 freezer for storage. Vial(s) containing at least at total of at least 400 microliters of 
serum will be sent to MUSC for analyses.  Remaining serum-containing vials will be stored at 
NYULMC CBRD as stated above. Samples will be destroyed once processed; all samples will be 
destroyed prior to the end of the study. 
 
Blood Collection and Processing for Genomic Analyses  
Of the patient-level characteristics analyses we will conduct (Aim 3), the OPRM1 genotypic analysis is of 
particular interest, because the Asp40 (A118G, ‘G’ allele) OPRM1 functional single nucleotide 
polymorphism (i.e. the mu opioid receptor genotype, where naltrexone acts) has been shown to be 
associated with successful treatment with naltrexone.89,90 The association this and other genomic 
polymorphisms, biomarkers, and protein level changes is an active area of research with new data and 


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laboratory techniques emerging constantly.  As such, the laboratory and exact procedures we will use to 
process the specimens is to be determined.  
 
Whole blood for genomic analyses will be obtained once; this will occur at enrollment typically, but may 
be obtained at a later visit. Genomic blood draws will not be performed on subjects who become 
prisoners.  As mentioned in the previous section, we will also store serum (the excess of what is drawn for 
biomarker analyses), which may be suitable for biomarker, protein, and genomic analyses.  Each blood 
sample will be labeled with a unique subject ID number and the visit number of the specimen obtainment. 
No identifiable information will be included on the specimen tubes and only the PI and RA will have 
access to the list linking subjects to their ID Number assignment. Upon collection, the blood specimens 
will be delivered to the NYULMC CBRD, where they will be stored for future processing. (Laboratory is to 
be determined.) Only study team members and CBRD staff will have access to the stored specimens.  
Samples will be destroyed once processed; all samples will be destroyed prior to the end of the study. 
Whole Blood Collection, Processing, Storage for DNA OPRM1 analysis Instructions: 
• 
17mL of whole blood will be collected for DNA processing. The sample will be stored in a -20C or -
80C freezer.  
 
 
6.1 Visit 1:  Day 0  
Enrollment; Bellevue ED (PI and RA perform) 
• 
Upon presentation of a potentially eligible patient to the ED, an automated page will be delivered to 
the Bellevue ED social worker, care manager, and study PI triggering enrollment procedures. 
Alternatively, ED staff may directly refer a patient to the study team (PI/RA) for potential enrollment. 
(See 4.3 Subject Recruitment and Screening) 
• 
The ED staff/provider will introduce the PI/RA to potentially eligible patients who have given their 
permission to be approached.   
• 
The PI/RA will obtain written informed consent for study after confirming capacity to consent using the 
UBACC (Described in Section 4.3), and obtain optional consent for audio recording. Subjects who 
decline to participate in audio recording may remain in the study.  
• 
The PI/RA will confirm eligibility by performing a chart and laboratory review (liver enzymes, 
pregnancy, and urine drug screen - if already completed), history and examination, and diagnostic 
interview to confirm alcohol dependence and assess for opioid use and chronic pain.   
• 
Draw blood for liver enzymes (AST, ALT, GGT) (8.5mL), biomarker/CDT (17 
• 
mL), and genomic (17mL) analyses as per instructions above (Section 6.0: Laboratory Procedures). 
As stated above, in cases when blood is being collected clinically, research specimens may be 
collected prior to a subject providing written informed consent- in order to prevent repeat 
venipuncture. 
• 
Conduct research intake assessments and interview.  
o 
Data collected will include demographic information and assessment of a broad range of 
subject characteristics using validated, reliable instruments and qualitative interviewing 
techniques that are widely-used. We will use questionnaires to assess heavy drinking days 
and other substance use (TLFB, Form 90),110-113 craving,114 and quality of life and health, 
consequences, psychosocial status, and utilization of services (SIP-2R, EuroQoL-5D (EQ-
5D), Form 90).114-118 Attachment #2 contains the full instruments from which selected 
questions and measures have been taken. Additional instruments are included that will serve 
as “back-up” instruments to replace measures that cannot be reliably completed by subjects 
(i.e. ongoing feasibility testing).  
• 
Randomization of subjects to intervention (XR-NTX+CM) or Standard Care using a random number 
generator with randomly permuted blocks with allocations embedded within REDCap software. 
• 
Collect process data on enrollment procedures.  
o 
We will collect data and reason for non-inclusion for all subjects approached but not enrolled 
and time and attempts required for enrollment (e.g. delayed enrollment due to inebriation, 
instability, capacity).  


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o 
We will collect data on barriers and facilitators and other data related to completion of 
assessment measures (with some refinements made during pilot phase). 
 
 
 
Intervention Arm:  
1. PI will administer XR-NTX 380mg as an intramuscular gluteal injection (after urine drug 
screen is confirmed to be negative for opioids). 
2. PI/RA will facilitate a harm-reduction based motivational interview and psychosocial 
assessment with the social worker or care manager (if available) that focuses on harm 
reduction and identification of subjects’ goals and needs to inform ongoing care 
management plan. PI will train future staff. See therapy manual - Attachment #3. 
Subjects’ healthcare, housing, and social assistance will be coordinated through the CM 
model.31 
3. Notify homeless services outreach of subject if homeless. Subject will be assigned a 
homeless outreach case worker and be offered shelter if eligible. 
4. Provide referral to Bellevue Chemical Dependency clinic (or a suitable alternative) for 
ongoing alcohol-medical management. Subjects will be navigated directly to the clinic on 
their enrollment visit if possible.  Subjects will receive a one-week referral to Bellevue 
ambulatory care for initial Alcohol-Medical Management (MM) and will also be scheduled 
every 4 weeks (or after most recent XR-NTX injection) for MM and XR-NTX injections (for 
a total of up to 12 injections).  
5. Provide card containing the PI’s contact information, dates of XR-NTX administration, 
and relevant medication information for medical personnel.  
 
       Standard Care Arm:  
• 
Typical care consists of patients being discharged once clinically sober/stable with or 
without an unscheduled referral to primary care clinic. Patients may receive limited care 
management or counseling. In this changing healthcare environment, we expect standard 
care to evolve naturally and may include care management for this patient population. 
• 
We will provide expedited referral for follow up care and substance use resources. 
  
 
Subjects in both the intervention and standard care arms will be compensated $40 at the completion of 
the enrollment visit.  
 
6.2 Visit 2:  Week 1 
Both Arms, Clinical Visit - Medical Management (MM) Visit (Ambulatory Care or ED) 
• 
Subjects in both arms will be referred to Bellevue ambulatory care as scheduled for an 
initial visit for Alcohol-Medical Management (MM) to assess and manage adverse events, 
treatment effects, and support the goals of reducing the harms associated with alcohol use. 
• 
Data will be extracted from the clinical note, including adverse events or concerns.  
• 
Subjects in intervention arm who miss appointment will be contacted though methods 
described in Section 4.4.2. Follow up will be performed in the ED if subject cannot be 
navigated to ambulatory care. Subjects will be given a week 4 appointment. 
• 
Subjects in the Standard Care Arm have no further clinical intervention beyond the initial 
referral but will have research assessments at weeks 12, 24, and 48.  Any ongoing medical 
care will be left to the discretion of their (non-study) treating providers. 


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6.3 Visit 3: Week 4 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5ml of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2.  Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care. 
6.4 Visit 4: Week 8 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5ml of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2. Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care. 
 
6.5 Visit 5: Week 12 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) and Research Visit 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5mL of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2.  Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care.   
 
Both Arms: Research Visit (ED)  
o 
Repeat research assessments and interview that was conducted at the initial 
intake/enrollment visit (see above, Week 0) plus assessment of adverse events and 
subject satisfaction. 
o 
Draw 17mL of blood serum to test for biomarkers (CDT) and 8.5ml of serum for liver 
function tests (AST, ALT, and GGT). 
o 
If a scheduled research visit date has passed, we will perform a research assessment at 
the next available opportunity (up to 6 months after the 48 week visit). Those who miss 
appointment will be contacted though methods described in Section 4.4.2.  


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6.6 Visit 6: Week 16 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5mL of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those in intervention arm who miss appointment will be contacted though methods 
described in Section 4.4.2.  Follow up will be performed in the ED if subject cannot be 
navigated to ambulatory care.  
6.7 Visit 7: Week 20 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5mL of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2.  Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care.  
6.8 Visit 8: Week 24 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5mL of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2.  Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care.  
 
Both Arms: Research Visit (ED)  
o 
Repeat research assessments and interview that was conducted at the initial 
intake/enrollment visit (see above, Week 0) plus assessment of adverse events and 
subject satisfaction. 
o 
Draw 17mL of blood serum to test for biomarkers (CDT) and 8.55ml of serum for liver 
function tests (AST, ALT, and GGT). 
o 
If a scheduled research visit date has passed, we will perform a research assessment at 
the next available opportunity (up to 6 months after the 48 week visit). Those who miss 
appointment will be contacted though methods described in Section 4.4.2.  


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6.9 Visit 9: Week 28 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5mL of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2.  Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care.  
6.10  Visit 10: Week 32 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5mL of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2.  Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care.  
6.11 Visit 11: Week 36 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 5mL of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2.  Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care.  
6.12 Visit 12: Week 40 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5mL of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2.  Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care.  


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6.13 Visit 13: Week 44 
Intervention Arm Only: Clinical Visit- Medical Management and Injection Visit 
(Ambulatory Care or ED) 
o 
Assessment of adverse events, medical management note.  
o 
Repeat laboratory analysis according to XR-NTX prescribing guidelines, (urine pregnancy 
test if of childbearing potential; liver enzyme analysis if exhibiting signs or symptoms of 
liver injury). Approximately 8.5mL of blood will be drawn if applicable. 
o 
Administer XR-NTX 380mg as an intramuscular gluteal injection.  
o 
Those who miss appointment will be contacted though methods described in Section 
4.4.2.  Follow up will be performed in the ED if subject cannot be navigated to ambulatory 
care.  
6.14 Visit 14: Week 48 – Study closure 
Both Arms: Research Visit (ED)  
o 
Repeat research assessments and interview that was conducted at the initial 
intake/enrollment visit (see above, Week 0) plus assessment of adverse events and 
subject satisfaction. 
o 
Draw 17mL of blood serum to test for biomarkers (CDT) and 8.5ml of serum for liver 
function tests (AST, ALT, and GGT). 
o 
If a scheduled research visit date has passed, we will perform a research assessment at 
the next available opportunity (up to 6 months after the 48 week visit). Those who miss 
appointment will be contacted though methods described in Section 4.4.2. 
o 
We will also provide subjects in both arms a referral for follow up care and substance use 
resources (if needed). 
7 Statistical Plan 
7.1 Sample Size Determination 
Naltrexone has not demonstrated a robust treatment effect; however, most studies did not use the XR-
preparation, are limited by poor adherence, and did not include this higher-severity population or other 
intervention components. We do not know what the “ideal” population for XR-NTX is, but posit that it may 
have a greater effect size in this more severely affected population than amongst the higher 
socioeconomic status population historically targeted. A recent pilot of XR-NTX suggests a possible 
greater effect (and acceptability) in a population similar to ours.67 Our literature search yielded no studies 
of initiating pharmacotherapy for alcohol dependence in the ED. There are only limited data on XR-NTX 
effects on several long-term outcomes of interest, including healthcare use, treatment engagement, and 
quality of life measures. ED-based case management studies demonstrate promising healthcare 
utilization outcomes, but most were uncontrolled and overestimated effect because of regression to the 
mean. The heterogeneity in study designs, interventions, and cohort characteristics precludes meta-
analysis.21,31,33,34,44-46  
 
Determining sample size is challenged by limitations in the existing data and heterogeneity of 
populations.  Definitively testing the relative effects of intervention components may require additional 
arms with as many as 75 to 200 subjects in each.51,54,57,60,65,90,119,120 Thus, we chose to start with the 
strongest intervention and compare it to standard care to maximize the likelihood of seeing an effect and 
of exploring effect size on various outcomes. The 2-arm design will minimize the loss of power and allow 
us to focus on the primary goal of assessing feasibility.   
 
The first phase of study will be a feasibility and acceptability study, through which we will obtain 
preliminary data to inform the power analysis for the subsequent definitive trial. In the first phase, we plan 
to pilot the study in 50 subjects.  In the second phase of study, we project enrolling 125 subjects in each 
of the two arms to definitively test the intervention’s effect on multiple outcomes of interest. Thus, we 


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project enrolling a total of 300 subjects in both phases. These estimates are founded in the current 
literature and the analyses, hypotheses, and predictions of experts in the field.   
 
Joshua Lee, MD’s ongoing study (R01AA020836) comparing the effectiveness of oral naltrexone to XR-
NTX in alcohol dependent primary care patients has a targeted enrollment of n=117 in each of the two 
arms to detect a 20% absolute difference in primary clinical outcomes based in the Fisher’s exact test 
with a projected power of 90%.  Susan Collins, PhDs’ (R01 AA022309) four-arm RCT of alcohol 
dependent homeless individuals recruited from a community housing program (XR-NTX + Counseling, 
Placebo + Counseling, Counseling alone, Treatment as Usual) will enroll a total of 300 patients 
(N=75/arm).  This study population is similar to the one we will be studying.  
 
A sample of 125 subjects per arm would allow us to detect a moderate effect size (Cohen’s d of slightly 
less than 0.40) to provide power of 0.80 or greater at α <.05. Another consideration when determining 
sample size is to power the study to detect the reduction in ED visits that would entirely offset the cost of 
medication. The institutional costs of a dose of Vivitrol (XR-NTX) is comparable to the estimated 
institutional cost of a single ED visit to Bellevue Hospital (according to the New York State Institute Cost 
Review). To detect a difference of ≥ 6 ED visits (i.e. a 6 month course of Vivitrol) between study arms 
comprised of subjects having a mean of 22 ± 15 ED visits per year (per our pilot study data), would 
require 100 subjects per arm with α = 0.05; β = 0.20 or, more conservatively, 133 subjects per arm with α 
= 0.05 and β = 0.10.  
 
Sample Size - Performance of Biomarkers as an objective measure of Alcohol Consumption: 
Based on the literature, the correlation between the CDT level and self-reported alcohol consumption 
using validated, reliable methods among alcohol consumption in alcohol dependent patients ranges from 
approximately r= .35 to r=.60.79-85  However, the relationship between CDT levels and alcohol intake may 
be influenced by age, gender, BMI, cirrhosis, smoking status, flushing, and other factors, such that the 
correlation among these subgroups groups is less (although, typically not powered to reach statistical 
significance).81,84 Because of potential inter-individual variation, measuring the change in CDT from an 
individual’s baseline as a continuous variable appears to improve performance.  Recent studies have also 
suggested that the combination of CDT and gamma-glutamyl transpeptidase (GGT), via the equation 
[0.8*ln(GGT) + 1.3*ln(CDT)], has higher diagnostic sensitivity and stronger correlation with the actual 
amount of alcohol consumed than either of the parent compounds alone; in one study the correlation of 
CDT-GGT was  r=.76; p<.001.79,82,84,86  
 
We will determine the correlation between serum biomarker values and self-reported alcohol intake 
ascertained using the timeline followback method, which is reliable, validated, and widely used in 
addictions research. For our sample size calculation, the null hypothesis is there is no correlation 
between CDT value and reported consumption. The alternative hypothesis uses the values found in 
literature.  The sample size calculation for each of these studies uses a type I error of 0.05. The 
correlation between alcohol intake and CDT level with a sample size 49, a correlation coefficient 0.39 can 
be detected with power 0.8.  Correlation between change in CDT to change in drinking with a sample size 
61, a correlation coefficient 0.35 can be detected with power 0.8.  All sample size calculations are done 
by PASS (Power Analysis and Sample Size) 2008. See also Table 3. The first phase of study, N=50, has 
the approximate power required to test the primary hypotheses. We will also pool the results of Phase 1 
subjects with those enrolled in phase 2.   
 
Author 
Study Results 
N  
required 
r 
p 
Mikkelsen 
0.39 
0.006 
49 
Hietala 
0.59 
<.001 
20 
Anton (all)^ 
0.35 
<.05 
61 
Anton (outliers removed)^ 
0.54 
0.001 
24 
Kim (flushers only)# 
0.608 
<.01 
18 


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Kim (non-flushers only)# 
0.274 
<.01 
102 
Table 3: Sample size calculation results.  Ha: R0<>R1. The value “N required” shows the required 
sample size with power 0.8 and Type I Error 0.05. ^The correlation increased from r=.35 to r=.54 after 
removal of three outliers. #The Asian cohort was stratified into persons who do and do not flush upon 
alcohol consumption.   
 
7.2 Statistical Methods 
7.2.1  Data Collection and Variables: (Table 2) 
Study investigators/RAs will enter data directly into NYUMC-internal REDCap for use on iPad portable 
tablet computers.   
Feasibility: The PI/RA will collect process data, including barriers and facilitators encountered in the 
completion of all study procedures, including data and reason for non-inclusion for all subjects 
approached but not enrolled.   
Clinical Assessments: We will also extract data from assessments completed by clinical staff, which will 
include Medical Management and XT-NTX administration progress notes, Adverse Event Forms,121 and 
laboratory data (liver enzymes (AST, ALT, GGT), pregnancy, urine drug screen), which is consistent with 
prior and ongoing XR-NTX studies at our institution (PI: Joshua Lee).57,65   
Research Assessments (Aim 2): We will collect demographic information and assess a broad range of 
subject characteristics using validated, reliable questionnaires and other instruments that are widely-
used, including in ongoing XR-NTX studies, and for which trainings are available. Data collection at 
enrollment and months 3, 6, and 12 will include several outcome variables of interest that we have 
broadly classified as drinking metrics, healthcare utilization, and quality of life. The 30-day Timeline 
Follow-Back (TLFB) for heavy drinking days is the standard method for assessing self-reported alcohol 
consumption. 110,111 The Economic Form 90 notably was used in the COMBINE study and is currently in 
use by in ongoing alcohol research for assessment of a broad range of health and public sector services 
utilization (including medical, self-help, legal services) and cost-effectiveness analyses.112,113,119,120  The 
Short Index of Problems Related to Alcohol (SIP-2R),117 and EuroQol-5D (EQ-5D) will be used for quality 
of life assessments.115,116  We will also conduct a 30-minute semi-structured qualitative interview and 
assess craving (Penn Alcohol Craving Scale),114 Self-Efficacy (Alcohol Abstinence Self-Efficacy Scale 
(AASE)),122 and Patient Motivation and Satisfaction scales. We will collect blood levels of carbohydrate 
deficient transferrin and GGT, which are biomarkers used together to objectively quantitate heavy 
drinking.79,80,82,83,108,109  We will ascertain healthcare utilization by triangulating data from Bellevue/HHC 
hospitals databases, EMS ambulance transports to all NYC EDs, Medicaid claims data, and subject self-
report. 
 
Attachment #2 contains the full instruments from which selected questions and measures have been 
taken. Additional instruments are included that will serve as “back-up” instruments to replace measures 
that cannot be reliably completed by subjects (i.e. ongoing feasibility testing). Of note, we have included 
assessments and measures used by other investigator’s studying XR-NTX for alcohol dependence so 
that we may perform similar analyses and draw comparisons through potential future collaboration.  
These investigators (potential future collaborators) specifically include Drs. Joshua Lee at NYU and 
Susan Collins at University of Washington (R01AA020836; R01 AA022309). To clarify, we will not use 
data from their studies nor share any identifiable data with these investigators, but rather perform 
analyses similar to those employed in their investigations.  
 
 


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7.2.2  Statistical Analysis Plan 
 
Aim 1: Feasibility and Acceptability:  
Formal statistical analysis is not planned for this primary aim, in which we will a) further develop and pilot 
procedures and b) descriptively document feasibility and acceptability of XR-NTX for frequent ED users 
with severe AUDs. Process data collected will be used to determine optimal processes for enrollment, 
medication administration, navigation to ambulatory care, and conducting assessments. Proportions will 
be generated for potential subjects who (1) are able and willing to consent; (2) accept injections, (4) 
attend clinic appointments, (5) complete planned 3-, 6-, and 12-month assessments. Subjects’ 
acceptability will be assessed via interviews and questionnaires. We will extract qualitative themes from 
interview transcripts to inform the further development of intervention and improve acceptability.123  
 
Safety Monitoring: We will repeat laboratory analyses as specified and maintain an adverse-effect profile 
and drug accountability log.121 We will use vital statistics to track mortality in the event of drop-out.  
 
Aim 2:  Analysis of Effect:  
a. We will explore the relative efficacy of XR-NTX+CM to standard care on decreasing acute 
healthcare use (ED, inpatient, other (ambulance, detoxification)) and associated expenditures.  
b. Secondarily, we will explore effects on healthcare engagement (clinic use, medication adherence, 
self-efficacy, motivation to change), alcohol quantity/frequency, alcohol-related consequences, 
quality of life measures, and cost-effectiveness. 
c. We will triangulate data sources for outcome measures to explore their correlation and to address 
missing data. Of specific interest, we will assess the performance of biomarkers (CDTand GGT, 
combinations) as an objective measure of changes in heavy drinking, which will inform the design 
of the second phase of study (definitive trial). 
 
Although randomization would predict equal distribution of cofounders, we will examine their distribution 
and adjust accordingly. Interactions or confounding may occur between outcome domains (e.g. quality of 
life may have an effect on healthcare utilization); other cofounders may include age, race, sex, 
socioeconomic status, comorbidities, and social stability. See Figure 3. 
 
We will ascertain healthcare utilization by triangulating data from subject self-report (Form 90)112,113 and 
from various other sources (pending availability), including Bellevue Hospital and New York City Health 
and Hospitals Corporation databases, partnering hospital medical records, EMS database of ambulance 
transports to all NYC EDs, and Medicaid claims data.  We will report expenditures as reimbursement 
payments and/or using Medicaid payment rates as a cost proxy.  
 
We will use a mixed-methods approach with questionnaires and instruments (See 7.2.1) that are widely-
used as well as database analyses to assess heavy drinking days and other substance use (TLFB, Form 
90),110-113 craving (Penn Alcohol Craving Scale),114 self-efficacy (AASE),122 and quality of life (EQ-5D), 
consequences related to drinking (SIP-2R, Form 90),  health and psychosocial status and utilization of 
services (Form 90).114-118  Changes in heavy drinking will also be assessed (secondarily) via analysis of 
biomarkers (CDTand GGT combinations will be tested); described below in Aim 2c (below).112,113 Multiple 
endpoint variables will not be normally distributed. We will generate descriptive statistics to characterize 
subjects, describe the distribution of baseline health and functioning, and calculate changes in severity 
scores. We will adopt a mixed methods approach to identify relationships between these variables. We 
will use independent t-tests or Wilcoxon rank-sum tests to compare pre-treatment variables of the two 
groups, and paired t-tests or Wilcoxon signed-rank tests to test pre- to post-treatment changes within 
each group. We will conduct an intention-to-treat analysis of healthcare use and expenditures for the 6- 
and 12-month periods before and after intervention using differences-in-differences multivariate linear 
regression modeling and repeated measures analysis. Correlations between the triangulated outcome 
measures will be assessed and inform the second phase of study.  
 
Short-term estimates of costs and effectiveness will be obtained using a combination of pre-specified 
medical record and survey endpoints using methods described by Dr. Joshua Lee in his protocol # S12-


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02263.  Cost assessment will be conceptually similar to recently published analyses of the COMBINE 
interventions and will include medical and non-medical costs as well as payer and societal costs (Form 
90.112,113 Effectiveness assessment will include alcohol consumption measures, quality of life, 
consequences, and the EQ-5D. The EQ-5D is among the most commonly used quality-of-life measure for 
informing cost-effectiveness analyses because it has minimal respondent burden, is well validated, and it 
yields utilities (preference-based measures on a scale of 0 to 1), the desired input for cost-effectiveness 
models. Because costs are skewed, incremental costs will be assessed using ordinary least squares and 
median regression models with covariates for treatment intervention and other relevant factors, and 
conditional models may be used because of cost data that may include “zeros.” 
 
 
 
 
Figure 3: The Predictor variables (study arms) are shown on the left and four outcome domains on the right 
(Healthcare utilization, Drinking, Quality of Life, and Consequences) with the specific measures noted 
alongside each domain.  The outcomes may be mediated by the subjects’ development of engagement 
(assessed by AASE scale, motivation visual analogue scale, adherence to treatment arm, and participation in 
clinic). Several potential interactions are hypothesized, some of which may also act as confounders. 
Interactions or confounding may occur between outcome domains (e.g. quality of life may have an effect on 
healthcare utilization); other cofounders may include age, race, sex, socioeconomic status, comorbidities, 
and social stability. Randomization will be employed to help mitigate potential threats. 
 
 
Aim 2c:  Correlation of Biomarker and Self-Reported Alcohol Consumption: 


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For this substudy, data from subjects in both arms (N=50 in phase 1) will be pooled as a single cohort to 
assess the performance of %CDT and the %CDT-GGT combination as a marker of heavy alcohol use.  
We will determine the correlation between serum biomarker values and self-reported alcohol intake 
ascertained using the timeline follow-back (TLFB) method (within the Form 90), which is reliable, 
validated, and widely used in addictions research.111 Correlations between the measures will be assessed 
and inform the second phase of study.  
I. We will measure the correlation between biomarker levels and self-reported alcohol 
consumption using the Timeline Followback method of obtaining (a) 30-day average 
alcohol intake, and (b) 7-day alcohol intake. We hypothesize that biomarker levels will be 
correlated with alcohol intake for both periods of time. 
II. We will measure the correlation between changes in biomarker levels and changes in 
alcohol intake. We hypothesize that changes in alcohol intake will be correlated to the 
associated changes in biomarker levels.   
III. We will compare the performance of biomarkers in subjects for whom CDT has been 
shown to have higher diagnostic accuracy (males, low BMI, non-smoker, non-cirrhotic liver) 
to subjects having at least one characteristic previously found to lower the accuracy of CDT 
(women, high BMI, smokers, cirrhotic liver). 
 
We will calculate correlations using Pearson product-moment coefficients for continuous non-skewed 
parameters or the Spearman’s rank correlations for non-continuous variables, as required. To reduce the 
effect of baseline variation and to allow each subject to be evaluated in relationship to his own drinking 
status, and initial blood level, CDT and GGT will be expressed at each treatment week as a percentage of 
their baseline level.  Therefore, at each treatment evaluation, every individual’s levels would either 
decrease or increase.  A multivariate approach to repeated-measures ANOVA will be conducted for the 
biomarker levels using the percentage of baseline at the three treatment evaluations (Months 3, 6, and 
12) as the dependent units for analysis in comparing the outcome groups. Multiple sensitivity analyses 
will be conducted to address missing data.  
 
 
Aim 3: Patient-Level Predictors of Effectiveness:   
Baseline and longitudinal predictors of interest in naltrexone alcohol treatment efficacy and effectiveness 
trials include gender, ethnicity, mu opioid receptor genotype, and ancillary alcohol behavioral treatment 
involvement. Naltrexone’s relative ineffectiveness in African American clinical trial sub-populations, 
including in the COMBINE trial,124 is possibly mediated by low rates of the Asp40 OPRM1 functional allele 
in persons of African descent, who are primarily Asn40 homozygous.125 This Asp40 (A118G, ‘G’ allele) 
OPRM1 functional single nucleotide polymorphism has been shown to be associated with successful 
treatment with naltrexone.126,127 A pilot conducted by Dr. Lee at Bellevue did find a strong association 
between persons involved at baseline or who became involved during primary care XR-NTX treatment 
with specialty alcohol treatment and/or Alcoholics Anonymous.65 Thus, we hypothesize a priori that there 
will be less robust effectiveness among African Americans; voluntary specialty alcohol treatment and 
Alcoholics Anonymous involvement, and presence of the Asp40 OPRM1 SNP will be associated with 
treatment effectiveness.  We note, however, that these analyses will be exploratory, as the study is not 
powered to carefully test these secondary hypotheses. 
 
We will collect patient-level characteristics data to explore the association of patient-level characteristics 
(e.g. sex, race) with effectiveness. We will be able to carefully track prior detox admissions and 
concurrent 12-step and specialty alcohol treatment involvement in the proposed trial in order to estimate 
associations with treatment effectiveness. Multivariate models will be used to identify patient 
characteristics associated with treatment success. The analysis will utilize a logistic regression with an 
indicator variable for treatment and covariate terms for baseline potential prognostic indicators, including 
African American ethnicity, baseline drinking severity, and status of housing, social support, quality of life, 
and OPRM1 genotype.  Odds ratios will be calculated to quantify the risk to treatment failure of significant 
predictors. As originally proposed, naltrexone appears most effective at reducing heavy drinking, as 
opposed to producing complete abstinence.  A harm reductionist perspective delineating treatment 
success from failure is particularly important in this population having a greater severity of AUD and 
psychosocial dysfunction. All traditional alcohol treatment trial clinical endpoints, including continuous 


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drinking and heavy drinking variables, as well as the %CDT biomarker, the change in CDT, and the 
combined CDT-GGT equation, which are specific for heavy drinking, are of great interest, and will be 
reported.   
 
7.3 Subject Population(s) for Analysis 
 
For both the primary and secondary aims/outcomes, we will study an all-randomized population:  Any 
subject randomized into the study, regardless of whether they received study drug. 
 
We will also collect process data, including barriers and facilitators encountered in the completion of all 
study procedures. This data will include reason for non-inclusion for all subjects approached but not 
enrolled.   
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research). 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in inpatient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 


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All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. By definition, all subjects in this study population have the pre-existing condition of 
frequent use of acute medical services, including ambulance transports, emergency department visits, 
and inpatient and outpatient admissions for detoxification and other alcohol-related problems, injuries, 
and consequences.) 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the 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 any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study.  
The sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 


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8.2 Recording of Adverse Events 
At each contact with the subject, the investigator 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 module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should be 
recorded in the source document, though should be grouped under one diagnosis. 
 
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 determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
 
Investigators and the protocol sponsor will conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible.  Events that will be reported include, 
but are not limited to events that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 
For Narrative Reports of Safety Events 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study treatment 
8.3.1 Investigator reporting: notifying the study sponsor 
 
The following describes events that must be reported to the study sponsor in an expedited fashion. 
 
Initial Report: within 48 hours: 
The following events must be reported to the study sponsor within 48 hours of awareness of the event:  
• 
Unanticipated problems related to study participation,  
• 
Serious adverse events, regardless of whether they are unexpected.  
   
Study Sponsor: NIAAA Program Officer: Brett Hagman, 301-443-0638, Brett.Hagman@nih.gov 
 
Follow-up report: within 48 hours: 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated problem in the form of a written 
narrative.  This should include a copy of the completed Unanticipated Problem form, and any other 
diagnostic information that will assist the understanding of the event.  Significant new information on 
ongoing unanticipated adverse device effects shall be provided promptly to the study sponsor. 
 


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Other Reportable events: 
• 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval 
before they are initiated. Any protocol deviations initiated without Sponsor and the investigator’s 
IRB approval that may affect the scientific soundness of the study, or affect the rights, safety, or 
welfare of study subjects, must be reported to the Sponsor and to the investigator’s IRB as soon 
as a possible, but no later than 5 working days of the protocol deviation. 
 
• 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing 
IRB as soon as a possible, but no later than 5 working days of the IRB notification of withdrawal 
of approval. 
 
8.3.2 Investigator reporting: notifying the IRB 
 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, to 
which we will adhere.  
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the investigator becomes aware of the event: 
• 
Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be 
caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations 
from the IRB approved protocol) for any of the following situations:  
– one or more subjects were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• New Information indicating a change to the risks or potential benefits of the research, in 
terms of severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a 
more severe or frequent side effect; Other research finds arm of study has no therapeutic value; 
FDA labeling change or withdrawal from market) 
• Report of Changes or Amendments to the Protocol  


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All proposed changes/amendments to the protocol will be filed with the IRB. IRB approval of such 
amendments will be forwarded to the NIAAA project officer, and the original amendment 
approvals will be filed in the primary document manual. 
 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event Form” or 
as a written report of the event (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other 
study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
8.3.3 Sponsor reporting: Notifying the FDA 
N/A 
8.3.4 Sponsor reporting: Notifying participating investigators 
N/A 
8.4 Unblinding Procedures 
N/A. Study is not blinded. 
8.5 Stopping Rules  
During the review process, the DSMB will evaluate whether the study should continue unchanged, require 
modification/amendment, continue or close to enrollment. Either the principal investigator, DSMB, or the 
NYU IRB have the authority to stop or suspend the study or require modifications.  
 
DSM Plans typically include stopping rules that specify the outcome differences detected between groups 
during an interim analysis that can result in stopping the clinical trial. In general, stopping rules will reflect 
one of the following conditions: 1) there is clear evidence of harm or harmful side-effects of the treatment; 
2) there is not likelihood of demonstrating treatment benefit; 3) there is overwhelming evidence of the 
benefit of the treatment. The current trial is not blinded, so the DSMB would be able to compare the 
outcome of the two groups during each review without decoding the subject’s group and determine 
whether the study should have an early termination. However because we are comparing an alternative 
paradigm of delivering a medication that is already FDA-approved for the indication in question, and 
regarding which preliminary data do not suggest significant safety considerations, early stopping on the 
basis of clear benefit (yes/no) is not anticipated. 
8.6 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study. 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 9 
Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular assessment of the number 
and type of serious adverse events. 
8.6.1 Data Monitoring Committee 
Although the PI has assessed the proposed study as one of moderate risk (consistent with prior XR-NTX 
studies), the potential exists for anticipated and/or unanticipated adverse events, serious or otherwise, to 
occur since it is not possible to predict with certainty the absolute risk in any given individual or in 
advance of first-hand experience with the proposed study methods.  
 


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The PI will have overall responsibility for monitoring the data, assuring protocol compliance, and 
conducting the safety reviews at the specified frequency. 
   
A Data and Safety Monitoring Board (DSMB) will be established for ongoing protocol review, including 
data, protocol compliance, safety and efficacy data, in compliance with NIH and NIAAA guidelines. , The 
DSMB will be comprised of two individuals during phase 1 of study and 2-5 members during phase 2 of 
study, DSMB members will meet NIH requirements regarding background and experience, and none will 
have ethical conflicts, including financial interest related to study outcome. Individuals invited to serve on 
the board will disclose any potential conflicts in writing.  
 
For the initial phase of study, the DSMB will be composed of: 
 
1. Robert S. Hoffman, MD (Chair) 
Professor, Departments of Emergency Medicine and Medicine   
NYU School of Medicine 
455 First Ave, Room 123, New York, NY 10016 
Phone: 212-447-8153 
 
2. Scott E. Sherman, MD 
Associate Professor, Departments of Population Health, Medicine, and Psychiatry 
NYU School of Medicine 
227 East 30th St, Room 642, New York, NY 10010 
Phone: 212-686-7500, ext 7386 
 
The DSMB will conduct a review of the initial study protocol. It will make certain that the protocol captures 
the information necessary to evaluate the safety and efficacy of the study when it is ongoing and 
completed. The DSMB may provide recommendations to improve upon the protocol. The board will meet 
at least annually (unless more frequent meetings are deemed necessary).  
 
At these meetings, Dr. McCormack and other research personnel will report on the trial status, followed 
by a closed session under the direction of the DSMB chairperson, during which time the investigators and 
research team may be present. This will be followed by an executive session restricted to DSMB 
members. Issues discussed may include those related to subject safety and benefit, whether the primary 
study question is being answered, conflict of interest, confidentiality, and ongoing study review (including 
AEs, SAEs, and regulatory issues).  
 
All adverse events and unanticipated problems during follow-up will be reported to the IRB, DSMB, and 
NIAAA. Serious adverse events and unanticipated problems will be reported to the IRB and to the NIAAA 
project officer within 48 hours of it becoming known to the investigator, using the appropriate forms found 
on the website. The PI and DSMB will conduct a review of all adverse events upon completion of study 
subjects. The PI will evaluate the frequency and severity of the adverse events and determine if 
modifications to the protocol or consent form are required. 
 
During the review process, the DSMB will evaluate whether the study should continue unchanged, require 
modification/amendment, continue or close to enrollment. Either the principal investigator, DSMB, or the 
NYU IRB have the authority to stop or suspend the study or require modifications.  Following each DSMB 
meeting, recommendations will be made by the chairperson to Dr. McCormack and a final report (edited 
by all DSMB members) will be prepared and submitted to NIAAA, the NYUMC IRB, and (if required) the 
FDA.  
 
Stopping the trial due to safety concerns or interim analysis of the primary outcome are not anticipated; 
the study medication, XR-NTX, is FDA-approved, its use in this trial is consistent with its FDA labeling, 
and no significant safety issues have arisen in national post-marketing use. DSM Plans typically include 
stopping rules that specify the outcome differences detected between groups during an interim analysis 
that can result in stopping the clinical trial. In general, stopping rules will reflect one of the following 
conditions: 1) there is clear evidence of harm or harmful side-effects of the treatment; 2) there is not 


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likelihood of demonstrating treatment benefit; 3) there is overwhelming evidence of the benefit of the 
treatment. The current trial is not blinded, so the DSMB would be able to compare the outcome of the two 
groups during each review without decoding the subject’s group and determine whether the study should 
have an early termination. Again however, because we are comparing an alternative paradigm of 
delivering a medication that is already FDA-approved for the indication in question, and regarding which 
preliminary data do not suggest significant safety considerations, early stopping on the basis of clear 
benefit (yes/no) is not anticipated. 
 
Procedures in Place to Ensure the Validity and Integrity of the Data 
Study clinicians and research staff will undergo the same baseline training at the inception of the study. 
The PI will ensure the quality of the clinicians’ and the research assistants’ administration of study 
assessments and instruments and of integrity of the data recorded through regular reviews and on-going 
data monitoring. Integrity of collected data: The identification key linking the separate charts containing 
the Informed Consent document and subject identifiers (name, signature, DOB, address, phone numbers) 
and the assessment instruments and study dataset will be stored in a locked cabinet (paper copy) as well 
as on a password-protected file stored on a secure NYUMC server, accessible only to the study staff. The 
study dataset will be otherwise de-identified and securely stored as described below. Only authorized 
study staff will have access to the dataset. All reasonable requests for data-sharing will be 
accommodated after study close. 
 
Procedures to Guarantee the Accuracy and Completeness of the Data during Data Collection, Entry, 
Transmission, and Analysis 
Study data will be entered directly into NYU-internal REDcap surveys administered on iPad tablet PCs 
over a cloud using Bellevue’s secure Wi-Fi network for any data containing subject protected health 
information and the cellular network for de-identified data. The iPad devices have security protections that 
are HIPAA compliant. Data will be stored on secure servers and/or in locked filing cabinets in my locked 
research office with access only to authorized study personnel as identified by the principal investigator 
and project manager for this study Unique identifiers will be used to identify subjects in the password- 
protected database. Quality control is performed as the data are being entered, and then at further stages 
of the storage and management process. Study findings will utilize only aggregate data and no 
publication or presentation will involve any use of individual information.   
 
Reporting of Serious Adverse Events 
Death, disability, hospitalization (or prolongation hospitalization), congenital defects, and life threatening 
events including drug overdose will be deemed serious adverse events (SAEs) and immediately reported 
(orally and by fax) to the NYU School of Medicine Institutional Review Board (IRB), at the time they are 
identified by the investigators or research staff. In addition, a written report will be filed within 72 hours to 
the IRB and to the NIAAA program office (and FDA as indicated by applicable regulations). When 
additional clinical information becomes available, a follow-up and/or final SAE report will be filed with the 
IRB, NIAAA, and the FDA (if indicated). 
 
Reporting of IRB Actions to NIAAA 
The initial IRB approval will be forwarded to NIAAA for review, as will all subsequent approvals and any 
amendments to the protocol. All proposed protocol amendments will be presented to the IRB and 
communicated to the NIAAA project officer if approved. Documented IRB approval of amendments will be 
forwarded to the NIAAA project officer, and the original amendment approvals will be maintained in the 
regulatory file. 
 
Report of Changes or Amendments to the Protocol 
All proposed changes/amendments to the protocol will be filed with the IRB. IRB approval of such 
amendments will be forwarded to the NIAAA project officer, and the original amendment approvals will be 
filed in the primary document manual. 
 
In the present protocol, there are no plans for interim analysis of safety or effectiveness data (see above). 
However, the PI and Key Personnel will examine safety data on an ongoing basis. Adverse experience 


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and safety contrasts will be performed as indicated, in response to recommendations by the PI. If interim 
analysis of safety data is deemed advisable by NIAAA or our IRB, we will enact such a plan. 
 
Disclosure of Any Conflict of Interest 
The investigator, co-investigators, and consultants will report on an annual basis or more frequently if 
indicated any conflicts of interest or apparent conflicts of interest to the IRB as well as to NIAAA. On an 
annual basis, the above individuals will sign a disclosure statement. There are currently no declared 
conflicts of interest with the proposed study among all Key Personnel. 
 
 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
 
The PI has obtained a Federal Certificate of Confidentiality to encompass protocol activity and subject 
data and ensure against the release of confidential information. Any future staff will have completed 
requisite IRB Human Subjects and HIPAA trainings. The PI will provide any future staff with training in 
their responsibilities for maintaining subject confidentiality; unique identifiers will be used to identify 
subjects in the database; all data will be kept in locked filing cabinets in my locked research office or on 
our secure server to which only the investigators and project manager will have access. Study findings 
will utilize only aggregate data and no publication or presentation will involve any use of individual 
information.  
9.2 Confidentiality and HIPAA 
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 (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
9.3 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, 
dispensing records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-
technical departments involved in the clinical trial. 
9.4 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 


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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 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
9.5 Records Retention 
For non-FDA regulated studies, summarize the record retention plan applicable to the study (taking into 
account any applicable NYULMC Department, Division or Research Center requirements, or applicable 
funding sponsor requirements.) 
 
For FDA-regulated studies the following sample language is appropriate: 
 
The Principle Investigator will retain study essential documents for at least 2 years after the last approval 
of a marketing application in their country and until there are no pending or contemplated marketing 
applications in their country or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  These documents will be retained for a longer period if 
required by an agreement with the sponsor.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan in Attachment #8.  As described in Section 
8.6.1, a DSMB will be established for ongoing protocol review, including data, protocol compliance, safety 
and efficacy data, in compliance with NIH and NYU guidelines.  Dr. McCormack and other research 
personnel report on the trial status, followed by a closed session under the direction of the DSMB 
chairperson, during which time the investigators and research team may be present. This will be followed 
by an executive session restricted to DSMB members. Issues discussed may include those related to 
subject safety and benefit, whether the primary study question is being answered, conflict of interest, 
confidentiality, and ongoing study review (including AEs, SAEs, and regulatory issues). Following each 
DSMB meeting, recommendations will be made by the chairperson to Dr. McCormack and a final report 
(edited by all DSMB members) will be prepared and submitted to NIAAA, the NYUMC IRB, and (if 
required) the FDA. Stopping the trial due to safety concerns or interim analysis of the primary outcome 
are not anticipated; the medication is FDA-approved, its use in this trial is consistent with their FDA 
labeling, and no significant safety issues have arisen in national post-marketing use. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups 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 University compliance and quality assurance offices. 
11 Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board 
(IRB) or independent Ethics Committee (EC) in agreement with local legal prescriptions, for formal 


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approval of the study conduct.  The decision of the IRB/EC concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of IRB/EC members and their affiliate 
to the sponsor.  
 
The patient population being studied is at risk of transient and long-term cognitive impairment that may 
limit potential subjects’ ability to consent and benefit from this study. Individuals with AUDs often receive 
their care exclusively in EDs, where referrals for substance use are rarely initiated, resulting in significant 
healthcare costs and diminished access to treatment of this and other chronic conditions.7,24-29,32-36,92-97 
Research to develop and practically implement effective interventions is even less common, particularly in 
those with severe AUDs in whom attrition and exclusion is expected.42  Inclusion of this patient population 
in study is of great significance because it may provide efficacious treatment and social stability to a 
population that has a disproportionate impact on healthcare and societal costs, and one that traditionally 
does not seek or receive care in medical settings offering addiction treatment. It has the potential to 
transform revolving door ED visits into an effective point of public health intervention and to incorporate 
the ED and its unique populations into a more integrated healthcare system.  
 
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.  
See Attachment #9 for a copy of the Subject Informed Consent Form.  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 IRB-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject and the investigator-designated research 
professional obtaining the consent. The enrollment process will be documented in the study’s Subject 
Screening and Enrollment log. 
 
The study investigator will use a process of informed consent that will be structured to be conducive to 
rational and thoughtful decision making by the subject. The PI and RA will obtain subjects’ written 
informed consent after assessing their capacity to consent using the stringent procedures described in 
Section 4.3.3 and restated here: 
 
The recruitment process will specifically address the likelihood that the subjects may have a 
compromised capacity to consent.  Subjects will not be enrolled until clinically sober and 
medically stable.  Subjects will be (re)assessed multiple times during their ED visit(s) as 
needed—and therefore will have multiple opportunities to be enrolled. We will use techniques 
shown to improve comprehension in informed consent procedures such as using a lower reading 
level, using larger typeface, quizzing and having multiple individuals providing the information. 
The PI will provide sensitivity training of investigators/RAs regarding difficult behaviors and limited 
comprehension and assessment of subject capacity to consent. 
 
The PI/RA will assess subject’s understanding of the study and capacity to consent to it using the 
University of California San Diego Brief Assessment of Capacity to Consent to Research 
(UBACC) (Attachment #2). The UBACC 10-item questionnaire is a 5-minute, easy-to-use, and 
validated tool, which we have studied in this population.43,98 It rates the basic elements of 
capacity (understanding, appreciation, reasoning, and ability to express a choice) to identify 
subjects with questionable capacity to consent to a specified research project. The UBACC 
assessment occurs after informing potential subjects about the study. Thus, first the RA/PI will 
review each page of the informed consent document with the patient, pausing to reassess 
comprehension throughout the process. Then, the RA/PI will administer the UBACC. Once the 
RA/PI confirms the subject’s comprehension (with the UBACC), the RA/PI will request the 
patient’s signature and provide the patient with a copy of the signed consent document. If, at any 
point during the consent process, the RA/PI does not believe the patient comprehends the study 
procedures the patient will not be enrolled at that time, but he or she may be eligible in the future. 
Patients who are not able to successfully complete (“pass”) the UBACC may be further assessed 
by psychiatry consultation. 
 


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In addition, the PI/RA will ask the subject to consent to being audio recorded (for qualitative interviews, 
counseling sessions, and quality assurance monitoring).  If the subject declines to provide their written 
informed consent to be recorded, the subject may still participate in the study (i.e. audio recording is 
optional).   
 
Subjects may be required to sign separate authorization forms for release of their personal health 
information to and from entities involved in their care, including care managers, case workers, housing 
facilitators, health providers, and government agencies/institutions. These data will be used to help 
coordinate and facilitate health and social needs and track outcomes. The purpose of this will be primarily 
clinical, rather than research. Each institution will ensure protection of PHI.  All institutions, with the 
exception of the NYC Department of Homeless Services, are HIPAA covered entities.  All Institutions will 
consult their respective IRBs; the NYC Fire Department Emergency Medical Services will use the IRB of 
the NYC Department of Health and Mental Hygiene.  
 
Individuals who are authorized to obtain consent must be listed on the protocol. If necessary to use 
‘Auditor/Witness’ and/or translator, these roles would be described in this section. During follow-up visits 
subjects capacity will be reassessed and subjects will be asked to provide assent to continue participating 
in the study.  
 
12 Mandatory Biomarker and Genetic Testing 
Whole blood (17mL) for genomic analyses will be obtained once; this will occur at enrollment typically, but 
may be obtained at a later visit. The 17mL of blood will be obtained from consenting subjects for genetic 
analysis to test predisposition to alcohol use disorders and naltrexone effect mediation (e.g. via OPRM1 
genomic analysis).79,112,113,129 During the initial enrollment visit and subsequent research visits (week 
0,12,24,48), 17mL of blood will be obtained for analysis of biomarkers associated with alcohol 
consumption and alcohol use disorders. Each blood sample will be labeled with a unique subject ID 
number and the visit number of the specimen obtainment. No identifiable information will be included on 
the specimen tubes and only the PI will have access to the list linking subjects to their ID Number 
assignment. Upon collection the blood specimens will be delivered to the NYULMC CBRD, where they 
will be stored until shipped in batches to the Medical University of South Carolina (MUSC) Laboratory for 
analysis. Only study team members and CBRD staff will have access to the stored specimens.  Samples 
will be destroyed after analysis. 
 
 
13 Inclusion of Prisoners 
 
“Prisoner” is defined to include any individual involuntarily confined in a penal institution. The term is 
intended to encompass individuals sentenced to such an institution under a criminal or civil statute, 
individuals detained in other facilities by virtue of statutes or commitment procedures which provide 
alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained 
pending arraignment, trial, or sentencing. Persons receiving care in a medical treatment setting, who are 
also “prisoners” as defined above, can be considered for enrollment in research only as permitted for 
other prisoners as subjects.  
 
This study involves research on conditions that particularly affect prisoners as a class. These conditions 
include alcoholism, unstable housing, and fragmented health and social services with frequent ED use 
and often without other usual source of care. There are considerable data, including our own studies, 
describing the pattern of frequent contacts this patient population typically has with both the hospital and 
the criminal justice system as well as the limited coordination of services between institutions.128,129 
Although medical, social services, criminal justice, and public health institutions are eager to assist this 
difficult, high cost and resource utilizing population, large institutions typically operate in silos, lacking the 


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coordination necessary to respond cohesively and effectively to the needs of the population.  These 
individuals are arrested typically for minor charges related to alcohol consumption (e.g. open contain, 
public intoxication) and unstable housing (e.g. loitering). The resulting brief periods of incarceration are 
unlikely to negatively impact study procedures or outcomes consequentially.  Further, recurrent episodes 
of incarceration can be disruptive to the delivery of healthcare (e.g. missed appointments) and social 
services (loss of housing); thus, it is critical to learn about these challenges that specifically affect 
prisoners as a class in order to develop strategies to intervene more effectively. 
 
As an extension of our preliminary work to develop and pilot a broadly defined care management 
intervention, this study will explore how to better address the inadequacies of current systems of care that 
affect prisoners. As is reflected in the primary study aim of assessing and enhancing feasibility, we will 
gain valuable insight into improving continuity and coordination of care of prisoners.  Specifically, we will 
establish linkages with the NYC Department of Health-Corrections and NYC Homeless Services and their 
contracted agencies to coordinate care among these high users of ED, criminal justice system, and 
homeless services. Each institution has caseworkers designated for high-risk, high-service utilizers; we 
are developing a mechanism for timely communication between these institutions to allow patient/client 
tracking and coordinated discharge planning. For example, selected individuals could potentially be 
released from jail into the care of their housing outreach case-worker and brought directly to a supportive 
housing facility and have medical aftercare plans established prior to release.  Even in the event that the 
study medication cannot be administered, which we do not anticipate being a problem (for the below 
reasons), continued study participation could benefit the subjects through enhanced continuity of care – 
including upon release from incarceration. 
 
This paragraph describes which prisoners will be eligible for enrollment and under what circumstances 
prisoners will be withdrawn from the study. Patients on parole or probation are eligible for enrollment.  
Patients who are prisoners at the time of potential enrollment will NOT eligible for study entry/inclusion. 
Enrolled subjects who become prisoners will remain in the study.  
 
Extensive provisions are incorporated in the study protocol to ensure adequate protections of the 
subjects, all of who are considered to be vulnerable. No persons who are prisoners will be eligible for 
enrollment.  In other words, all subjects will be entering the study as non-prisoners. Thus, there is no risk 
of coercion of prisoners to enroll/participate in the study.  All patients will have a rigorous assessment of 
their capacity to consent to research participation, as described in section 4.3.3. The risks involved in the 
research are commensurate with the risks that would be accepted by non-prisoner volunteers. There are 
no added safety risks should subjects become prisoners. No additional advantages accruing to a prisoner 
through his/her participation in the research are of such magnitude that his/her ability to weigh the risks 
and benefits of the research will be impaired.   
 
As medication (XR-NTX) is being administered in this study, it is important to explicitly state that there are 
no additional safety concerns for subjects in the arm receiving medications should they become 
prisoners. This FDA-approved medication is being administered in accordance with its safe prescribing 
guidelines. We do not anticipate that administration of XR-NTX will be disrupted as a result of 
incarceration; this is because Bellevue Hospital has an existing clinic dedicated to the care of prisoners 
(mostly from Rikers Jail).  Protocols for the transfer of prisoners from detention centers to Bellevue 
Hospital for clinical care have existed many years. Subjects who are prisoners will return to Bellevue 
Hospital for their medical management, which may include laboratory testing and XR-NTX administration.  
XR-NTX is not administered unless the requisite pre-administration laboratory testing is completed.  .  
Thus, if the subject is unable to return to our medical clinics for medical management and laboratory 
testing, then the subject will not receive the subsequent dosage of XR-NTX.  There are no adverse 
effects associated with disrupted treatment (other than the lack of benefit provided by the medication); 
XR-NTX may be discontinued at any time.  
 
Commensurate with non-incarcerated subjects, all Alcohol-MM clinical follow-up visits and Research 
Visits will be conducted at Bellevue Hospital Center when possible. Research assessments (Visits 5, 8, 
and 14) will be conducted at Bellevue when subjects return for their clinical appointments. For 
incarcerated subjects who will not be coming to Bellevue Hospital for an Alcohol-MM or other clinical 


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reasons, we will arrange through the jail administrators for the subjects to return to Bellevue for a 
Research Visit. When making arrangements with prison administrators and disclosing that the prisoner is 
a research subject, we will not disclose the title or purpose of the study – as we have done in the past to 
ensure the subjects’ privacy. For security reasons, subjects/prisoners will not be notified of the specific 
time of the visit, which will be coordinated through the jail.  
 
As mentioned above, there are existing systems in place for New York City prisoners to receive outpatient 
care in Bellevue clinics that are specifically designated for prisoners. Thus, a new workflow does not need 
to be established. While we know the procedures and regulations for Riker’s jail and New York City 
detention centers, it is possible that subjects will be incarcerated outside of New York City and/or in 
facilities that may not participate in bringing prisoners to Bellevue for care.  In the event that a subject is 
unable or unwilling to return for an Alcohol-MM visit, this will not pose additional medication safety risks 
because the subject cannot receive the medication (XR-NTX) without presenting to Bellevue.  If the 
subject is unable or unwilling to return to Bellevue for Research Visit(s), we will attempt to make 
arrangements with jail administrators for us to meet with the subjects at the jail or by phone to conduct the 
research assessments as we have done in other studies. If it is not possible to speak with a prisoner in 
private and without being recorded by the jail/prison, then we will remind the subject that he/she does not 
need to answer any questions that he/she does not wish to answer, and we will limit research 
assessments to include non-incriminating data only (e.g. no questions related to drug use or criminal 
behavior), such as healthcare utilization, medication side effects, and quality of life. This may result in not 
completing research assessments for some subjects. We will address how to handle the missing data 
with our DSMB.  Our justification for retaining prisoners in the case of data not being collected is that 
these are important feasibility data that should be captured in this study whose goals include assessing 
and enhancing feasibility. Plus, the subject/prisoner may be able to participate in a subsequent research 
assessment (if released during study timeframe). Further, we do not anticipate encountering these 
difficulties (because of the aforementioned arrangements with local jails), and are including their potential 
in the protocol now so that we can maximize the retention of subjects and quality of data without 
jeopardizing the safety, privacy, or confidentiality of the subjects.  
 
We will make sure the parole boards will not take into account a subject’s participation in the research in 
making decisions regarding parole. Again, we will not disclose the title or purpose of the study to jail 
administrators.  This anonymity also helps to ensure that research participation does not influence parole 
boards.  Subjects are also informed verbally and in the written informed consent document that we will 
not provide input on their behalf to parole boards. We have received a Certificate of Confidentiality so that 
we cannot be compelled to provide testimony if subpoenaed.  
 
If the subject is currently on parole, he or she must determine if their monitoring can include their 
scheduled follow-up visits to the Bellevue clinic. If these visits are not permitted, the subject will not be 
able to continue his or her participation in the study. As with all subjects enrolled in the study, all 
measures will be taken to ensure confidentiality is maintained. To protect the rights of this vulnerable 
patient population, study staff will only disclose the minimum amount of information required by prisoners. 
Study staff, for example, will never mention the title or content of the study or disclosure that a specific 
individual is participating in the study. Details of the nature of the research will not be shared with the staff 
at the jail/prison, and visits whether in person or by phone, will only be conducted if the subject’s 
confidentiality can be maintained and no audio-taping occurs . In the event the research staff would want 
to conduct visits via phone, they will submit a request to have the study phone number placed on the “Do 
Not Record” list”. 
 
Incarcerated subjects will receive the same financial incentives for participating in the study as non-
incarcerated subjects (as long as permitted by the prison, detention center, or other governing body within 
the criminal justice system). Depending on the prison/detention center’s policies, the stipend may be 
provided directly to the subject, provided to the prison to retain until the subject’s release, stored at the 
study site until the subject is released and can come retrieve it, debited to the prison commissary, paid to 
a relative, or mailed upon the subject’s release. At the completion of the study, subjects in both arms of 
the study will be provided with harm reduction counseling and health care resources, including referral for 
alcohol-MM. 


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14 Audio Recording 
After subjects sign the initial informed consent document, they will also be asked to sign a consent 
document for audio recording. If the subject does not consent for audio recording, he or she can still 
participate in the study. If the patient provides consent, the study’s RA may audio record subject 
interviews during the initial and follow up medical management and research visits. The sessions will be 
recorded for quality assurance and for training approved study personnel in qualitative interviewing. Data 
will also be collected from the recordings if any information was not captured during the in-person 
interview.  
 
Each recording will be labeled with a unique identifier, encrypted, and stored in a locked cabinet in the 
Principal Investigator’s office or electronically on a secure, HIPAA-compliant NYULMC server. If the 
subject verbally states their name, or any other identifying information, during the recording editing 
software will be used to expunge this information from the file, if possible. All recordings will be destroyed 
upon the study’s conclusion.  
15 Study Finances 
15.1 Funding Source 
The PI has received an award from the US National Institute of Health – National Institute on Alcohol 
Abuse and Alcoholism (NIAAA) to finance the initial phase of study, 1K23AA022989.   Alkermes, Inc.™ 
has approved the PI’s Investigator Initiated Trial application and will provide 225 Vivitrol ™ kits (each 
containing a single dosage) at no cost. The PI has been awarded funding through the New York 
University CTSI to cover certain CTSI-related expenses (CBRD, laboratory, pharmacy).  The NYU School 
of Medicine Department of Emergency Medicine will also provide study support. The PI will apply for 
additional funding to provide additional study support, including financing the second phase of study 
(definitive trial) and biomarker and genomic analyses.  
15.2 Conflict of Interest 
Currently no investigators have a conflict of interest with this study. 
Any investigator who has a conflict of interest with this study will have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the study sponsor prior to participation in this study.  All NYULMC 
investigators will follow the applicable University conflict of interest policies. 
 
Cost to Subjects 
Subjects will not incur any cost for the study medication.  The drug manufacturer, Alkermes, Inc will 
provide the medication free of cost.  Subjects and/or their insurance companies will be billed for medical 
management visits and associated laboratory tests per standard of care.  Subjects will not be charged for 
biomarker or genetic testing.   
 
15.3 Subject Stipends or Payments 
Subjects will be compensated $40 at the completion of the enrollment visit (Week 0) and the research 
visits at Weeks 12, 24, and 48.  Subjects will be compensated $10 after the first (week 1) medical 
management visit.  Subjects in the intervention arm will receive $25 for each Medical Management/XR-
NTX injection clinical visit. Compensation for incarcerated subjects will not exceed maximums allowed by 
penal institutions. 
16 Publication Plan 
 
The Principal Investigator has the primary responsibility for publication of the results of the study.  Neither 
the complete nor any part of the results of the study carried out under this protocol, nor any of the 


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information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study sponsor.  Any investigator involved with this study is 
obligated to provide the sponsor with complete test results and all data derived from the study.  
 
Our plan to share data and our management of intellectual property will be in accordance with NYUMC 
and NIH policies and guidelines. All investigators involved in this project will adhere to NIH’s Data Sharing 
Policy and Implementation Guidance of March 5, 2003 and NIH Grants Policy on Sharing of Unique 
Research Resources including the “Sharing of Biomedical Research Resources: Principles and 
Guidelines for Recipients of NIH Grants and Contracts” issued in December, 1999. The final research 
data will be available in acceptable formats commonly accepted for documenting and supporting research 
findings (i.e., .csv, .xls). The final research data will not contain any subject identifiers. Research data that 
documents, supports, and validates research findings will be available after the main findings from the 
final research data set are accepted for publication and/or presented at national meetings. Individual 
researchers, government, or other not-for-profit organizations petitioning Dr. McCormack for access to the 
data who document both a commitment to use the data for legitimate research purposes and not to 
identify an individual study subject, and a commitment to secure use of the de-identified data including 
not making unauthorized copies of the dataset available to others, will be provided the study dataset at no 
charge. 
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18 Attachments 
 
1. Selected diagnostic codes related to alcohol use 
2. Assessment Measures – Note: Sections and Questions from selected instruments will be used. 
3. Motivation Interview Therapy Manual 
4. Schematic Diagram of Trial 
5. Timeline of Study Procedures 
6. Anticipated Study Timeline 
7. MEDWATCH Form, FDA Form 3500A 


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8. Data and Safety Monitoring Plan 
9. Sample Consent 
10. Consent – A/V