Randomized, Open-label Clinical Trial of Extended-Release vs. Oral Naltrexone for Alcohol Treatment in Primary Care.
Phase: PHASE4
Conditions: Alcohol Dependence
Sponsor: NYU Langone Health

 
Title: 
EXtended-Release vs. Oral Naltrexone for Alcohol Dependence Treatment in Primary 
Care (X:ON) 
Protocol Version:  
7.0 
 
Date:  
 
14 February, 2017 
 
NYUMC Study #: 
S12-02263 
 
 
Principal Investigator: Joshua D Lee MD MSc 
 
Assistant Professor 
Department of Population Health 
Department of Medicine, Division of General Internal Medicine 
NYU School of Medicine 
Department of Medicine 
550 First Avenue, VZ30 712 
New York, NY   10016 
Telephone:  (212) 263-4242 
Fax:  (646) 201-5706 
Email:  joshua.lee@nyumc.org  
 
Funding: 
 
NIH, National Institute of Alcoholism and Alcohol Abuse (NIAAA) 
 
Notice of Grant Award:  1R01AA020836-01A1 (08/01/2013 – 04/30/2018) 
 
Sites:  
 
NYUMC 
Department of Population Health 
550 First Ave, VZ30 712 
NY NY 10016 
 
Bellevue Hospital Center 
 
 
 
460 First Ave 
 
 
 
NY NY 10016 
NCT #: 
 
NCT01893827 

Protocol v7.0                              X:ON, XR-NTX vs. Oral NTX for Alcohol Dependence 
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PROTOCOL OUTLINE 
1.0 
RATIONALE AND SCHEMA 
2.0 
STUDY TIMELINE 
3.0 
INTRODUCTION 
3.1 Significance and Innovation 
3.2 Optimizing Primary Care Alcohol Treatment 
3.3 Oral Naltrexone 
3.4 Extended-Release Naltrexone 
3.5 Cost-Effectiveness of Naltrexone 
3.6 Good Clinical Outcomes 
3.7 What outcomes matter most in primary care alcohol treatment? 
3.8 Preliminary Studies and Investigative Team 
3.9 Investigative Team Roles and Study Management 
4.0 
STUDY AIMS 
4.1 
Primary Aim 
4.2 
Secondary Aims 1 and 2 
5.0 
STUDY DESIGN 
6.0 
STUDY POPULATION 
6.1 
Inclusion Criteria 
6.2 
Exclusion Criteria 
7.0 
STUDY PROCEDURES 
7.1 
Recruitment and Pre-screening 
7.2 
Screening and Randomization 
7.3 
Study Interventions: Medical Management 
    
 
7.4  
Study Care vs. Usual Care 
7.5 
XR-NTX Plus MM 
7.6 
Oral NTX Plus MM 
7.7 
Research-only Visits 
7.8 
Rescue Strategies 
8.0 
ASSESSMENTS AND OUTCOME MEASURES 
8.1 
Primary Outcome Measure 
8.2 
Secondary Outcome Measures 
 
8.3  
Cost Effectiveness Outcomes 
9.0  
POWER AND SAMPLE SIZE 
10.0  STATISTICAL AND COST EFFECTIVENESS ANALYSIS 
 
 
10.1 Hypothesis 1: Primary Outcome: Treatment Effectiveness 
 
 
10.2 Hypothesis 2: Secondary Aim 1: Cost Effectiveness 
 
 
10.3 Secondary Aims 2  
11.0  DATA MANAGEMENT 
12.0 
PROTECTION OF HUMAN SUBJECTS 
 
 
12.1 Potential Risks 
 
 
12.2 Confidentiality 
 
 
12.3 Emotional Discomfort 
 
 
12.4 Risk/Benefit Ratio 
 
 
12.5 Resource and Data Sharing Plan 
12.6 Data and Safety Monitoring Plan 
 

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1.0 Rationale 
Though integration of alcohol pharmacotherapy into primary care settings is receiving increasing emphasis 
and support, rigorous data to inform clinicians’ treatment choice is lacking.  The most recently FDA-
approved alcohol treatment medication, an extended-release depot form of naltrexone (XR-NTX, Vivitrol®), 
could greatly simplify the medical home-centered alcohol treatment emphasized in the NIAAA Clinician’s 
Guide.1 Injected once a month, XR-NTX offers a long-acting and thus potentially more effective form of 
pharmacotherapy than oral naltrexone (O-NTX),2 which, despite the Combined Pharmacotherapies and 
Behavioral Interventions for Alcohol Dependence (COMBINE) trial and systematic reviews supporting some 
efficacy,3,4 has been characterized by low rates of overall prescribing, poor adherence,  suboptimal monthly 
refill and inadequate treatment retention.5,6,7,8 Yet while promising as an alternative to O-NTX, XR-NTX is 
substantially more expensive (~$1100 vs. ~$100 per month),9 and no head-to-head trials have compared 
the two forms of naltrexone.  A comparative effectiveness approach is required to systematically evaluate 
the following key questions:  In primary care settings, what is the relative clinical effectiveness of XR-NTX 
vs. O-NTX?  What are the benefits and costs of XR-NTX relative to O-NTX? And can patient and system 
characteristics be identified to inform treatment choice to maximize the probability of successful outcome?   
 
Primary Aim: Treatment Effectiveness.  To evaluate the effectiveness of XR-NTX vs. O-NTX in producing a 
primary good clinical outcome, defined as abstinence or moderate drinking (<2 drinks/day, men; 
<1drink/day, women; and <2 heavy drinking occasions/month), during the final 20 of 24 weeks of primary 
care-based Medical Management for alcohol dependence.   
Hypothesis: The rate of this good clinical outcome will be approximately twice as great among participants 
receiving XR-NTX compared with those receiving O-NTX.   
 
Secondary Aim 1:  Cost Effectiveness.  To estimate the incremental cost effectiveness of XR-NTX vs. O-
NTX, both in conjunction with primary care-based Medical Management.  
Hypothesis: XR-NTX treatment will be more cost effective than O-NTX.   
 
Secondary Aim 2:  Patient-Level Predictors of Effectiveness.  To identify patient-level characteristics 
associated with effectiveness in both arms.   
 
 
This proposed study is a pragmatic, randomized, open-label clinical trial of 24 weeks of XR-NTX vs. O-NTX 
using a COMBINE-adapted Medical Management primary care treatment model.  234 adults >18yo with 
alcohol dependence will be recruited from the community into treatment at a major New York City primary 
care site (Bellevue Hospital Center’s Adult Primary Care Clinic).  The primary outcome which powers this 
study is a dichotomous good clinical outcome defined by abstinence or moderate drinking, and as 
measured by the Timeline Followback and analyzed using an intention-to-treat approach among all 
randomized participants.  Secondary outcomes include the incremental cost effectiveness of the two arms, 
differences between arms by continuous measures of alcohol intake (drinks/day, % days abstinent, time to 
first heavy drinking day, biomarkers), and the exploratory analysis of factors possibly associated with 
effectiveness, including gender, pre-treatment abstinence, and mu opioid receptor (OPRM1) genotypes.   

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Study Schema 
 
 

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2.0 Study Timeline: This NIAAA notice of grant award was issued on July 18, 2013, award number: 
1R01AA020836-01A1.  We expect a 3-month start up phase during which we will complete the protocol 
approval process, hire study personnel, assemble study supplies and complete local SOPs.  Recruitment of 
234 enrolled and randomized participants will take place over 3 years, or approximately 6-7 persons 
randomized monthly, based on our pilot study.  The final 6 months of Year 5 will be devoted to the tail end 
of study visits, data cleaning and analysis, study close out, preparation of initial manuscripts, and 
dissemination and national presentations of results. 
 
 
 
 
3.0 Introduction 
3.1 Significance and Innovation 
  
The projected impact of this proposal has not changed since the original proposal: despite several 
years of experience, the comparative effectiveness of XR-NTX compared to older alcohol medications 
remains uncertain, particularly in a mainstream, primary care treatment model that is generalizable and 
broadly accessible.  Newer, novel, expensive medications for addiction disorders are historically greatly 
underutilized by primary care physicians.  This study is innovative both as a ‘head-to-head’ evaluation of 
XR- vs. O-NTX in primary care, and because expected participants will be primarily Medicaid-covered or 
uninsured persons who will not be excluded based on medical and psychiatric co-morbidities that often 
preclude participation in efficacy studies.  If health insurance expansion, parity reforms, medical homes and 
accountable care organizations are to define primary care as a core alcohol treatment setting in the coming 
decade, exactly this type of study is required to guide treatment protocols and resource allocation. 
Ultimately, more widespread adoption of cost-effective alcohol pharmacotherapies will result in longer, 
healthier lives and lower costs. 
 
3.2 Optimizing Primary Care Alcohol Treatment 
  
This study addresses the comparative effectiveness of alcohol pharmacotherapies and associated 
treatments, a high priority area at NIH/NIAAA as evidenced by PAS-10-273, ‘Clinically Relevant 
Comparative Effectiveness of Alcoholism Treatments.’  This proposal is in keeping with NIAAA’s FY09-14 
priorities of expanding effective alcohol treatments in primary care and patient-centered medical home 
settings through the increased use of emerging pharmacotherapies, while further disseminating the 
treatment principles endorsed by the NIAAA Clinicians Guide.10,1 Stronger evidence of the clinical benefit 
and ease-of-use of medications like XR-NTX in a Medical Management primary care model should further 
activate the generalist workforce to screen and treat alcohol dependence. 
  
Alcohol disorders are common, costly, and undertreated: Unhealthy alcohol use exacts a 
tremendous toll in morbidity, mortality, suffering and cost.11 An estimated 23% of U.S. persons aged 12 or 
older reported binge drinking (5 or more drinks on any once occasion) at least once in the last 30 days, and 
an additional 7% reported “heavy use” (binge drinking on 5 or more of the last 30 days) in the 2008 National 

Protocol v7.0                              X:ON, XR-NTX vs. Oral NTX for Alcohol Dependence 
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Survey on Drug Use and Health.12 An estimated 4% of U.S. adults aged 18 or older met DSM-IV criteria for 
alcohol dependence in the most recent published NESARC data; 5% met criteria for abuse.13 The vast 
majority of persons with alcohol use disorders never attempt or succeed in accessing specialty treatment.14 
Though they do present frequently to emergency rooms, primary care clinics, mental health clinics, and 
other general care settings,15 alcohol pharmacotherapy is rarely offered in such settings.  Data 
demonstrating the practicality and effectiveness of pharmacotherapy for alcohol dependence in routine 
primary care would offer a powerful boost to efforts to expand the impact of evidence-based alcohol 
treatment.16 
 
3.3 Oral naltrexone pharmacotherapy is under-prescribed and plagued by poor ‘real-world’ adherence, yet 
O-NTX plus Medical Management was superior in the recent COMBINE trial  
 
Despite efficacy data, pharmacotherapies for alcohol disorders are not widely prescribed by either 
generalists or addiction specialists.17  Daily oral medications including disulfiram, oral naltrexone, and 
acamprosate remain in limited use, reflecting a paucity of specialty treatment centers or generalists 
prescribing these medications.5 The 2001 publication of the large Veterans Administration (VA) RCT of O-
NTX showed daily naltrexone adherence of 44% and 43%, respectively, in participants randomized to 12 
and 3 months of O-NTX.18 Commercial HMO prescription data has shown <15% rates of persistent O-NTX 
refills through 6 months, 6,19 while one analysis of New England VA pharmacy data reported <25% of O-NTX 
prescriptions persisting through this same timeframe.7 
The recent COMBINE study has renewed interest in combining naltrexone prescribing with Medical 
Management (MM), a physician-, nurse-, or other ancillary staff-led counseling approach that focuses on 
support for drinking abstinence and medication adherence, and that does not explicitly incorporate ancillary 
treatment or formal therapeutic approaches (i.e., 12-step facilitation, motivational interviewing, or cognitive 
behavioral therapy).20  Naltrexone, a full µ opioid receptor antagonist, reduces alcohol related euphoria, and 
craving and relapse among abstinent drinkers, in particular reducing heavy drinking episodes as opposed to 
slips.21,22,23  In COMBINE, oral naltrexone-treated alcohol dependent participants demonstrated a greater 
percent of days abstinent, fewer heavy drinking days, and a higher proportion of patients achieving a 
composite good clinical outcome (abstinence/moderate drinking) vs. placebo or acamprosate arms, and oral 
naltrexone with MM was more effective than other combinations of pharmacotherapy and behavioral 
treatment.  This data echoed earlier, smaller trials which also supported an O-NTX plus primary care MM 
approach.24,25 
Mean adherence to oral naltrexone in COMBINE was initially reported as high (85% of prescribed 
drug was not returned and assumed to have been taken), though these results are somewhat difficult to 
interpret as a large proportion of participants assigned to 16 weeks of naltrexone at some point discontinued 
the medication (96 of 154 participants assigned to naltrexone + MM discontinued the medication).  A 
subsequent secondary analysis of COMBINE medication adherence data reported 72% total daily 
adherence among MM patients receiving active naltrexone and placebo acamprosate, with better 
adherence to both naltrexone and placebo associated with favorable drinking outcomes.26  This highlights 
an important tension in the oral naltrexone literature: randomized trials of select alcohol dependent patients 
(typically excluding those with co-morbid substance use and psychiatric disorders, as was the case in 
COMBINE) report relatively high levels of medication adherence and moderate effect sizes, while 
commercial pharmacy data and naturalistic observational studies demonstrate quite low levels of oral 
naltrexone adherence and little real-world effectiveness.   
 
Importantly, the COMBINE trial’s Medical Management protocols standardized (and certified) the 
MM physicians, nurses, and pharmacists providers in a recovery support and medication adherence 
enhancement counseling approach delivered in an initial 45 min. session, and then in 20 min. follow-up 
visits, totaling 8 visits in 16 weeks (Weeks 1, 2, 4, 6, 8, 10, 12, and 16).   This basic approach to counseling 
strategies and follow-up visit frequency is summarized by the NIAAA Clinician’s Guide, which forms the 
basis of the physician-led Medical Management platform used as this study’s active psychosocial treatment. 
 
3.4 Extended-Release Naltrexone: Effective and Cost-Effective? 
  
Efforts to expand alcohol treatment options and improve adherence to naltrexone treatment 
contributed to the development of a long-acting, polylactideco-glycolide-based (PLG) naltrexone formulation 

Protocol v7.0                              X:ON, XR-NTX vs. Oral NTX for Alcohol Dependence 
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(XR-NTX, Vivitrol®, Alkermes, Inc).  Shown to be efficacious vs. placebo at reducing heavy drinking days in 
a dose-dependent fashion over 6 months (with 64% of all participants receiving 6 of 6 monthly injections),27 
XR-NTX gained FDA approval for alcohol dependence in 2006 (a separate opioid dependence indication 
was approved in 2010).  Despite its promise in eliminating daily adherence concerns, only one additional 
study has further estimated the efficacy of XR-NTX in general adult populations,28 and none have compared 
its effectiveness advantages vs. oral naltrexone.29  Our own pilot of XR-NTX in primary care is discussed 
below (Approach, 3.2 Preliminary Studies and Investigative Team) and demonstrated high rates of retention 
and significant decreases in daily and heavy drinking.2   
 
 
3.5 Cost-Effectiveness of Naltrexone 
Overviews of economic evaluation methods and empirical economic studies of addiction treatment 
provide compelling evidence of societal benefits from broadening the reach of effective alcohol 
treatment.30,31,32  Health system and societal cost-effectiveness estimates for specific alcohol 
pharmacotherapies including oral and XR-NTX are scant, however, with none based on a prospective 
randomized pharmacotherapy trial until the COMBINE study.33,34,35 Analysis from COMBINE ranked MM 
plus naltrexone as the more cost effective of the active intervention arms, including other pharmacotherapy 
combinations, at achieving two of the study’s primary endpoints (no heavy drinking and a ‘good clinical 
outcome’).36,37,38 
  
There 
are 
no 
prospective, 
randomized data comparing the cost-
effectiveness of XR-NTX against O-NTX.  
Data from commercial managed care 
examined 
by 
Marks 
suggest 
an 
encouraging impact of XR-NTX on costs 
through 
lower 
rates 
of 
high-cost 
emergency 
services 
and 
alcohol 
detoxification (Fig. 1).39  Importantly, this 
recent analysis was commissioned by 
Alkermes, the manufacturer of XR-NTX.  
The proposed study aims to address 
these vital cost issues more rigorously in 
a 
randomized 
control 
clinical 
trial 
including a long-term drinking and cost 
assessment at week 48 following the 
initial 
24 
weeks 
of 
treatment.  
Prospective, independent verification of 
these 
projected 
cost 
savings 
is 
warranted.   
 
3.6 What predicts good clinical outcomes in XR-NTX vs. O-NTX treatment?  
  
Baseline and longitudinal predictors of interest in naltrexone alcohol treatment efficacy and 
effectiveness trials include gender, ethnicity and mu opioid receptor genotype, pre-treatment abstinence, 
and ancillary alcohol behavioral treatment involvement.  Female gender has been shown to be associated 
with increased nausea and diminished oral naltrexone adherence40 and less overall treatment effect, 
including sub-group results from the pivotal Garbutt XR-NTX efficacy trial, and gender remains a 
stratification variable at randomization.27 
  
Naltrexone’s relative ineffectiveness in African American clinical trial sub-populations, including in 
the COMBINE trial,41 is possibly mediated by low rates of the Asp40 OPRM1 functional allele in persons of 
African descent, who are primarily Asn40 homozygous.42  This Asp40 (A118G, ‘G’ allele) OPRM1 functional 
single nucleotide polymorphism (SNP) has been shown to be associated with successful treatment with 
naltrexone.43,44  We will be able to determine prospectively whether this allele is associated with retention 
and treatment effectiveness in both arms, potentially representing one of the first studies to assess the 
impact of Asp40 on XR-NTX treatment outcomes, which we feel adds to this proposals significance and 
Figure 1. Charges for Detoxification Days Per 1,000 Patients 
(*** = comparison of other meds against XR-NTX)
$0
$200,000
$400,000
$600,000
$800,000
$1,000,000
$1,200,000
$1,400,000
$1,600,000
XR-NALTREXONE
ORAL
NALTREXONE
DISULFIRAM
ACAMPROSATE
*   P< 0.1
** P< 0.05
***P < 0.01
***
***
*

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innovative potential.  This will be in partnership with Charles O’Brien (consultant) and Dr. Wade Berrettini’s 
lab at the University of Pennsylvania, which will perform the genotyping in this proposal. 
  
Lead-in drinking abstinence (3 days prior to initiating medications) will be analyzed a priori as a 
predictor of effectiveness in both medication arms.  A participant’s ability to abstain from drinking prior to an 
initial XR-NTX injection may predict treatment response and is highly relevant to the initiation of naltrexone 
treatment in monitored detox settings,45 though we did not observe this same association in our smaller XR-
NTX primary care pilot, which is described below and included few patients with pre-treatment abstinence or 
recently discharged from a detox unit.2 Our pilot 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.  We will be able to carefully track prior detox admissions, pre-treatment 
abstinence, and concurrent 12-step and specialty alcohol treatment involvement in the proposed trial in 
order to estimate associations with treatment effectiveness.  Likewise, while we will recruit only participants 
willing to try either form of naltrexone, participants will be queried at baseline for a strong preference of oral 
vs. XR. 
 
3.7 What outcomes matter most in primary care alcohol treatment? 
We clearly feel a dichotomous ‘good clinical outcome’ best defines a patient’s progress to ‘goal’ in a 
primary care comparative effectiveness trial, and represents innovation.  Our choice of a moderate-drinking-
only good clinical outcome reflects: a) the use of this same outcome in the COMBINE trial,3 b) its ability to 
capture both abstinence and reduced heavy drinking, and, c) a preference for a dichotomous 
success/failure primary outcome, which neatly deals with drop-outs and missing data as ‘failures.’  A 
dichotomous, success/failure primary outcome is in keeping with other recent and important comparative 
effectiveness trials.46,47,48,49,50  Further, this study will track and report all drinking rates over time based on 
TLFB, facilitating easy comparisons to other alcohol trials, and also analyze XR-NTX’s impact on 
biomarkers, including carbohydrate-deficient transferrin (CDT).  CDT is highly specific to heavy drinking and 
compliments well the primary good clinical outcome.  CDT has not been tracked in an XR-NTX clinical trial, 
a secondary outcome we feel adds substantially to this proposal’s innovative potential. 
Few studies have examined smoking cessation among heavy drinking smokers, or during naltrexone 
therapy for alcohol use disorders. Smoking continues to be an enormous health crisis within the United 
States. Those with alcohol use disorder are more likely to smoke than the general population and account 
for more than 6 million people in the United States.51,52 Additionally, smokers with concurrent alcohol use 
disorder are more likely to have a higher degree of tobacco addiction, smoke more heavily, and have 
significant morbidity and mortality from tobacco related diseases.53,54,55,56 Most studies investigating smoking 
cessation exclude people with current alcohol use disorder bringing into question their generalizability to this 
population.57 Of the studies that include current alcohol use, smoking cessation rates were much lower than 
the general population.58 These studies tended to have small sample sizes, failed to show long-term results, 
and have rarely investigated combination therapies.59 Given the prevalence, the burden of disease, and the 
limited success in treating heavy drinking smokers, further research is needed to discover effective 
therapeutic options. Our study will explore rates of quitting and reduced smoking in all active and new 
patients during NTX + MM alcohol treatment. 
A history of trauma and current post-traumatic stress symptoms and disorders are believed to be 
overly prevalent among addiction disorder patients and alcohol use disorder patient samples. A survey 
conducted on a nationally representative sample of the United States population showed that approximately 
46.4% of individuals in the United States with PTSD have a comorbid alcohol or drug use disorder.60 PTSD 
and substance use disorder comorbidity is associated with a poor prognosis in both disorders (increased 
psychiatric comorbidity, exacerbated PTSD symptoms, and greater risk of relapse during or after substance 

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use treatment.)61,62,63 There is a growing need in treatment interventions of co-occuring PTSD and AUD but 
the current literature provides inconclusive and contradictary results of various phamacologic 
treatments.64,65 The interaction of PTSD symptoms with active naltrexone alcohol treatment is one that is not 
well known or studied.66 We will pilot in all remaining new patients and existing active patients validated 
brief screeners for trauma history and PTSD symptoms for estimations of prevalence and changes over 
time during active NTX treatment of alcohol use disorders. 
 
3.8 Preliminary Studies and the Investigative Team: Alcohol and XR-NTX Research at NYUMC 
The foundation for our proposal was a single-arm evaluation of XR-NTX in monthly primary care 
medical management of alcohol dependence, led by Drs. Lee, Gourevitch, and Rotrosen (Co-Is). 
XR-NTX plus Medical Management in Primary Care: This recent pilot showed evidence of the 
feasibility, acceptability and likely effectiveness of a 3-month course of XR-NTX plus MM for treatment of 
alcohol dependence among 72 community-recruited adults using an open-label, single-arm, proof-of-
concept design.2  Rates of uptake, retention and adherence with monthly XR-NTX were robust within the 
same two clinical settings we now propose and among a study population which was 15% African 
American, 22% Latino, and 60% Medicaid/Medicare or uninsured.  Baseline drinking in this cohort (57%, % 
heavy drinking days) was similar to that of the COMBINE (63%) and Garbutt (64%) trials.  Most eligible, 
consented patients initiated (90%) and completed (62% of those initiating injections, 56% of N=72 patients) 
three months of treatment not involving monetary or other incentives, excepting a single $20 payment at the 
last visit, and medications and medical care at no cost (Table 1).  The 3-month adherence rate we observed 
was only slightly lower than in the relatively intensive Garbutt efficacy trial of XR-NTX (74%).26 These rates 
of adherence and treatment retention were also similar to uptake and adherence rates expected in primary 
care patients initiating pharmacotherapy for common chronic conditions, such as hypertension or high 
cholesterol.67,68,69  Finally, reductions in self-reported drinking reductions, including significantly fewer heavy 
drinking days, were significant and sustained among persons retained in treatment (Table 1). Thus, in this 
single-arm observational pilot, treating alcohol dependence in primary care settings with XR-NTX and 
monthly physician medical management appeared a feasible and possibly effective model of alcohol 
treatment. 
 
 
Table 1. XR-NTX + MM in Primary Care2  
Baseline 
Month 1 
Month 2 
Month 3 
% retained in treatment (received monthly injection) 
N=72 
90% 
68% 
56%* 
% heavy drinking days, last 30 days (median), if retained  
57% 
2% 
3% 
7% 
*62% of participants initiating XR-NTX injections completed 3 of 3 injections 
 
Additional research by Dr. Lee in collaboration with Drs. Gourevitch and Rotrosen has also involved 
addiction pharmacotherapies in primary care settings.  Related work includes primary care MM plus 
pharmacotherapy for opioid dependence, including, 1) piloting ‘at-home’ buprenorphine induction;70 2) 
buprenorphine/MM following release from jail;71 3) XR-NTX plus MM for opioid relapse prevention among 
criminal justice-involved participants;72 and, 4) participation as one of 12 sites in the NIDA CTN 0030 
Prescription Opioid Addiction Treatment Study, a comparative effectiveness and cost effectiveness trial of 
buprenorphine/MM plus intensive individual counseling vs. buprenorphine/MM.  Additionally, Dr. Rotrosen’s 
team at NYU and the Manhattan VA was a site in Garbutt’s XR-NTX pivotal trial.26   
Dr. Scott Braithwaite (Co-I, Cost Effectiveness), Chief of NYU’s Section of Value and Comparative 
Effectiveness, is an accomplished decision scientist with an strong record of NIAAA funding, including his 
current R01-AA017385, “Computer Simulation of the HIV Epidemic in sub-Saharan Africa.” Incremental cost 
effectiveness models and simulations for this proposal will draw on this team’s experience creating, 
validating, and using other computer simulations assessing the impact of alcohol interventions specifically 
on long-term costs and benefits.73,74,75 Dr. Laska (Co-I, Biostatistician) will provide core statistical advice as 
the study’s biostatistician and in keeping with his expertise and successful role as such in recent mental 
health and addiction trials;76,77,78,79 James Robinson will head data management, while two consultants, Dr. 
Charles O’Brien and Dr. Raymond F. Anton, will lend decades of expertise in naltrexone and alcohol 

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treatment effectiveness research to the design and interpretation of the study, including COMBINE MM 
adaptation (Anton), and assisting with measurements of baseline OPRM1 genotypes (O’Brien) and CDT 
analysis (Anton).   
 
3.9 Investigative Team Roles and Study Management 
 
Dr. Lee as PI will oversee all aspects of the study. As detailed in the Budget Justification, each Key 
Personnel will perform specific and distinct roles.  Our economic analysis team will plan and analyze the 
cost-effectiveness components.  Dr. Lee along with our study statistician will conduct the analyses of the 
primary and secondary effectiveness outcomes, based on the dataset collected and managed by our data 
managers.  Our team will also include co-investigators who will serve as study physicians and assist in all 
aspects of study conduct.  Dr. Rotrosen, a senior mentor to Dr. Lee and Director of the NIDA CTN NY 
Node, will serve as a co-investigator and assist with all aspects of the study in a senior advisory role.  Dr. 
Anton and Dr. O’Brien, consultants, will assist with CDT analysis, COMBINE MM implementation and 
OPRMI genomic analysis.  
Dr. Lee will be in daily contact with the Program Manager, Project Manager, Research Coordinators, 
and study clinicians.  Weekly meetings will bring together core staff to trouble-shoot study implementation 
and daily management.  Monthly conference calls will bring together all of the key personnel and, as 
needed, the two consultants, to discuss study conduct and eventual analysis and manuscript preparation.  
Separately, Dr. Lee will meet monthly or more frequently, depending on the study phase, with the study 
statistician and data manager regarding data management and analysis. 
 
4.0 Study Aims 
 
4.1 Primary Aim:  Treatment Effectiveness.  To evaluate the effectiveness of XR-NTX vs. O-NTX in 
producing a primary good clinical outcome, defined as abstinence or moderate drinking (<2 drinks/day, 
men; <1drink/day, women; and <2 heavy drinking occasions/month), during the final 20 of 24 weeks of 
primary care-based Medical Management for alcohol dependence.   
Hypothesis: The rate of this good clinical outcome will be approximately twice as great among participants 
receiving XR-NTX compared with those receiving O-NTX.   
 
4.2 Secondary Aim 1:  Cost Effectiveness.  To estimate the incremental cost effectiveness of XR-NTX vs. 
O-NTX both in conjunction with primary care-based Medical Management.  
Hypothesis: XR-NTX treatment will be more cost effective than O-NTX.   
 
Secondary Aim 2:  Patient-Level Predictors of Effectiveness.  To identify patient-level characteristics 
associated with effectiveness in both arms.   
 
5.0 Study Design: A Randomized Comparative Effectiveness Trial to Evaluate XR-NTX vs. O-NTX for 
Alcohol Dependence in Primary Care 
We propose a pragmatic randomized controlled trial to compare the effectiveness and incremental cost-
effectiveness of XR-NTX vs. O-NTX as a component of primary care-based Medical Management of alcohol 
dependence among 234 adults.  The 24 week treatment trial will assess monthly treatment retention, self-
reported drinking outcomes, biomarkers, and costs.  The primary effectiveness outcome is a moderate 
drinking good clinical outcome, defined as abstinence or moderate drinking (<2 drinks/day, men; <1 
drink/day, women, and <2 heavy drinking occasions/month), during weeks 5-24.  A long-term follow-up 
assessment at week 48 will gather further drinking and cost data.  The MM visit schedule and research 
assessment visits will occur as follows over 48 weeks (Table 2): 
 
 
Table 2. Visit Frequency (weeks) 
0 
1+ 
3 
5+ 
7 
9+ 
13+ 
17+ 
21+ 
25 
26 
48 
XR-NTX vs. O-NTX + MM visits 
x# 
x# 
x 
x 
x 
x 
x 
x 
x 
x 
x* 
 
Research-only assessment visits 
 
 
 
 
 
 
x# 
 
 
x# 
 
x# 

Protocol v7.0                              X:ON, XR-NTX vs. Oral NTX for Alcohol Dependence 
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*Safety documentation research visit 
# Compensation provided 
+ Medication Dispensed 
 
 
6.0 Study Population 
This study will attempt to recruit a general adult population of alcohol dependence, with few strict exclusion 
criteria in keeping with a ‘real-world’ comparative effectiveness design.   
 
6.1 Inclusion Criteria 
1. Adults (age >18 y.o.)  
2. Spanish- or English-speaking and able to understand study procedure and provide informed consent 
3. Current (within the last year) DSM-V diagnosis of alcohol use disorder as determined by the study 
physician and standard DSM-V checklist.   
4. Endorses goal of alcohol abstinence, and is able to achieve alcohol abstinence without inpatient 
detoxification, per study physician.   
 
6.2 Exclusion Criteria   
1. Current opioid dependence and/or positive urine toxicology for extended opioids. 
2. Pregnancy or female and planning conception. 
3. Allergy to naltrexone or the PGL XR-NTX formulation or diluent. 
4. Severe liver disease, liver failure, or liver function test levels greater than three times normal. 
5. Other severe, untreated or uncontrolled medical illness (e.g., severe heart failure or dementia). 
6. Untreated psychiatric disorder that might make participation hazardous (e.g. untreated psychosis, bipolar 
disorder with mania, significant suicide risk).  
 
 
7.0 Study Procedures 
7.1 Recruitment and Pre-screening 
Recruitment will consist of both in-clinic referrals of existing primary care patients, as well as community 
recruitment of patients new to primary care.  Recruitment will rely on the successful blend of ‘in-reach’ 
(meetings with clinicians, detailing, systematic communication) and local area outreach (ads, external 
detailing) that we employed during our pilot study to prescreen 116 persons, consent 76, and enroll 72 
eligible persons over a 13-month period (a rate of 5.5 persons enrolled per month, similar to that of the 
current study).  Routine screening for alcohol use is not presently standard practice at the study site.  
However, if routine alcohol screening launches during the course of the study (SBIRT implementation 
efforts are on-going within the HHC system), eligible persons identified through SBIRT efforts could be 
referred to the study.  Persons interested in study enrollment will call an intake number, or consult with a 
research coordinator in-person.  A brief eligibility pre-screen will determine probable eligibility, after which 
patients will be scheduled for a baseline screening visit.  Recruitment will be patient- or provider-initiated 
rather than initiated by the research team. Potential subjects will not be approached at random by research 
staff at Bellevue clinic or in any other setting unless patient-initiated.  Most referrals will come from in-clinic 
referrals by physicians or by local outreach recruitment ads. Potential participants will call the research team 
phone number advertised or received from referring physician. Research coordinators will complete a pre-
screening on the phone with potential subjects to do an initial assessment of eligibility. If potential 
participants are deemed initially eligible (based on phone-screen) by study staff and the PI, research 
coordinators will schedule the initial Screening Visit with subject at Bellevue Hospital. All documents 
containing PHI on pre-screen interviews of potential subjects pre-screened on telephone and found to be 
ineligible or not interested in study will be destroyed. The only information that will be retained from 
ineligible pre-screens will be gender and age. Participants will also be recruited through word of mouth 
referrals. Participants can earn a $50 referral bonus for each eligible person referred and successfully 

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randomized into this study. All participants will be provided travel reimbursements in the form of MetroCards 
at the end of every study visit. 
 
7.2 Screening and Randomization 
At the baseline visit, informed consent will be obtained and eligibility confirmed by the research coordinator 
and study physician.  A subsequent randomization/treatment visit will then be scheduled within a 2 week 
time period.  Several factors may be associated with naltrexone treatment success/failure.  We will stratify 
urn randomization by gender and recruitment status (in-clinic vs. community referrals).  Stratifying further, 
however, yields increasingly smaller cells, given 117 per arm; AA ethnicity, medication preference (monthly 
injectable vs. daily oral), and lead-in (3-day) abstinence will be analyzed as a priori predictors of 
effectiveness.  Randomization is the starting point of the study (day 1, week 1).   
 
7.3 Study Interventions: Medical Management plus XR-NTX vs. O-NTX 
Existing primary care physicians, all board-certified in internal medicine, physician assistants, and 
registered nurses at an adult primary care clinic, Bellevue Hospital, will be recruited to participate in this trial 
as MM clinicians.  As in our previous studies with XR-NTX and buprenorphine in these sites, study 
participants may see different individual providers over the course of 24 weeks, thus optimizing visit 
flexibility as well as enhancing generalizability to multi-provider practice settings.  The same study clinicians 
will provide both XR- and O-NTX treatment.  The study site relies primarily on physician visits as the core 
modality for primary care encounters, and it is expected study visits will be primarily with physicians. Study 
clinicians will provide all XR-NTX injections in clinic (Ambulatory Care, 2nd floor, Rm. #2111) each month for 
each participant randomized to the XR-NTX arm. O-NTX, which is a daily oral pill formulation of naltrexone, 
will be self-administered on a daily basis by O-NTX participants. 
 
The content of the Medical Management component will be the same in both arms, and will be 
based on the initial and follow-up MM visits outlined in the COMBINE MM manual and adapted by the 
NIAAA Clinician’s Guide.20  MM emphasizes: a) education surrounding the alcohol dependence diagnosis, 
b) a recommendation and emphasis on drinking abstinence, c) support for 12-step involvement (referrals to 
specialty outpatient treatment will not be part of the MM strategy – patients interested in such will not be 
prohibited from self-referral, and specialty referrals will be made in cases of relapse/treatment failure), d) 
self-efficacy counseling surrounding medication adherence, e) education and trouble-shooting of medication 
side effects, f) feedback on the success of drinking reductions, g) and non-specific support and motivational 
enhancement to make further changes toward abstinence.   
MM clinician’s will be trained at start-up and through quarterly calls and booster session in an 
adaptive approach consistent with the NIAAA COMBINE trial (see NIAAA COMBINE manual) and in 
consultation with Dr. Anton.  Strict standardization and certification of MM clinicians, as was done in 
COMBINE, will not be pursued, as this would diverge from a pragmatic clinical trial attempting to reflect the 
adoption of, but not absolute fidelity to COMBINE MM.   
 
7.4 Study Care vs. Usual Care: Participants in both arms may schedule additional MM visits as needed to 
address medication side effects or unanticipated study-related events.  Any such additional visits required 
will be tracked carefully as service utilization.  Telephone support with research coordinators and study 
clinicians will be available at all times during the study and also tracked as utilization.  However, clinicians 
cannot provide or bill for other routine primary care services, such as blood pressure management or 
cancer screening, during MM visits.  This is a conundrum in any NIH-funded, patient-level clinical trial in 
primary care, which cannot budget for comprehensive care.  Patients can initiate or continue access to all 
primary care services through the same clinician and in the same clinics, it will simply occur as a non-study 
visit at either clinical site, both of which are public clinics providing access to all patients regardless of 
insurance status or ability to pay.   
 
7.5 XR-NTX Plus Medical Management 

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XR-NTX will be delivered at the point of care as a single, 380mg IM injection (4cc) to alternating 
upper, outer, gluteal (buttock) quadrants.  Injections occur every four weeks.  Between-injection MM visits 
will assess and manage adverse events, treatment effects, and support the goal of alcohol abstinence.   
 
7.6 Oral NTX Plus Medical Management 
O-NTX will be provided by the facility’s pharmacy following each monthly medication 
dispensing/injection MM visit, and in keeping with standard ambulatory prescribing practices of a 
recommended 50mg daily dose.80  Participants with means or adequate insurance coverage may instead 
present their written prescription to an outside commercial pharmacy if they prefer.   
 
7.7 Research-only Assessment Visits 
 
As in any large clinical trial of usual care, some participants in both arms will not be present for all 
scheduled treatment visits.  In an attempt to ‘de-link’ complete cost, utilization, and longitudinal drinking data 
collection from a naturalistic observation of these same usual care patterns, we will conduct 3 Research-
only Assessment visits at week 13, 25 and 48.  These visits will not hinge on a participant’s treatment 
retention status, will be heavily incentivized to encourage participation ($100 for time and travel), and will be 
conducted preferably in-person but alternatively by telephone if a participant is otherwise unwilling or unable 
to appear in clinic. These visits will be carefully scheduled apart from MM treatment visits, which are 
otherwise not incentivized beyond the provision of no-cost care and medication, so as to minimize the 
influence of extra assessments, attention, and the monetary research participation incentive on a 
participant’s willingness to continue with MM. Participants will be paid $20 for the initial screening visit after 
completion of all research assessments and $20 after completing the randomization visit.  
 
7.8 Rescue Strategies among Treatment Non-Responders 
Clearly many outcomes will occur among the 234 planned participants, beyond drinking reductions, 
and include: remaining in treatment and tolerating either medication but without beneficial changes to 
baseline alcohol intake levels; dropping out of all treatment but reporting diminished drinking; or wishing to 
remain in primary care treatment but unable to tolerate either form of naltrexone.  Regarding continued 
heavy alcohol use, MM already informs and encourages interested patients to access AA, and this 
recommendation would be particularly relevant to those not responding to pharmacotherapy and amenable 
to an external referral to more intensive treatment.  At any point in the trial, patients 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 detox and specialty treatment through Bellevue Hospital.  Detox and intensive outpatient alcohol 
specialty services are immediately available to all participants through the Bellevue Hospital Chemical 
Dependency programs, including same-day admissions to our detox unit, regardless of insurance status or 
ability to pay.  All enrolled participants, however, will be encouraged to remain in their assigned treatment 
protocols and continue follow-up in primary care for the entire 24 week treatment period, independent of 
medication side effects, on-going drinking, or intermittent detox or other alcohol-related inpatient treatment 
episodes.  There is little risk, in other words, at keeping participants engaged in primary care MM regardless 
of on-going, frequent heavy drinking, in which case they would qualify as a primary good clinical outcome 
failure, or the need for further, more intensive specialty treatment, access to which the MM clinician and 
study staff may be crucial in facilitating.  At the conclusion of the 24 week treatment trial, all patients will be 
offered further primary care follow-up within the same clinics and referrals to specialty alcohol treatment, if 
indicated, through these universally accessible addiction specialty services at Bellevue Hospital.   
 
 
8.0 Assessments and Outcome Measures (Table 2) 
 
Table 2. Visit Frequency (weeks) 
0 
1+ 
3 
5+ 
7 
9+ 
13+ 
17+ 
21+ 
25 
26 
48 
XR-NTX vs. O-NTX + MM visits 
x# 
x# 
x 
x 
x 
x 
x 
x 
x 
x 
x* 
 
Research-only assessment visits 
 
 
 
 
 
 
x# 
 
 
x# 
 
x# 

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*Safety documentation research visit 
# Compensation provided 
+ Medication Dispensed 
 
 
A comprehensive panel of measures is planned including standard measures of drug and alcohol use, 
medical status, and on-going treatment services utilization. The Timeline Follow Back (TLFB), Alcohol Use 
Disorders Identification Test (AUDIT), and Obsessive-Compulsive Drinking Scale (OCDS) are all validated 
measures used to identify alcohol and drug use along with regular urine toxicology and breathalyzer tests. 
The ASSIST will be used to assess for substance abuse or dependence and PHQ-9 for psychosocial 
diagnoses. The Seek, Test, Treat and Retain (STTR) assessment will collect various demographic 
information for each participant. The Economic Form 90, Cost Survey, and World Health Organization 
Quality of Life Survey (WHOQOL) will be used to assess treatment and criminal history as well as to 
ascertain economic data for cost-effectiveness outcome measures. The Morisky Medication Adherence 
Scale (MMAS-8) will be administered to the O-NTX arm only, providing information on adherence to self-
administered medications. Fagerström’s test for nicotine dependence and recall of cigarettes per day will be 
used to assess smoking cessation measures. Adaptations of the Stages of Change Questionnaire (SOC) 
and Responses to Stress Questionnaire (RTS) will look towards patient motivation, self-efficacy, and coping 
skills. The DSM-V criteria for PTSD, Generalized Anxiety Disorder 7-Item Scale (GAD-7), and Perceived 
Stress Scale (PSS) will be used to assess PTSD. Throughout the treatment phase, all adverse events (AEs) 
will be recorded on an AE form at all treatment visits. 
 
 
Screening Visit (week 0): Informed Consent Form, Consent Quiz, medication preference question, DSM-V 
diagnostic interview and checklist, demographics, ASSIST, PHQ-9, WHOQOL, Alcohol Use Disorders 
Identification Test (AUDIT), Obsessive-Compulsive Drinking Scale, Fagerström, SOC, RTS, Questionnaire, 
DSM-V checklist for PTSD, GAD-7, PSS, history and physical exam, vital signs, liver function (AST, ALT, 
GGT), urine toxicology, pregnancy test, blood alcohol breathalyzer.   
 
Randomization Visit (week 1): Medical Management initial visit progress note, baseline biomarkers (CDT, 
Asp40 OPRM1 genotyping), urine toxicology, and Economic Form 90. 
 
Treatment Visits (week 3-25): Timeline Followback (TLFB), recall of cigarettes per day, Morisky Medication 
Adherence Scale (MMAS-8, O-NTX arm only), Medical Management follow-up visit progress note, Adverse 
Event form, labs (weeks 13 and 25 only, AST, ALT, GGT, CDT). 
 
Research-only Assessments* (week 13, 25, 48): TLFB, Economic Form 90, AUDIT, OCDS, WHOQOL, 
Fagerström**, SOC**, RTS**, DSM-V checklist for PTSD**, GAD-7**, and PSS**. 
 
**Only at weeks 13 and 25. 
 
 
Banked Genetic and Biomarker Testing: At randomization, participants will provide two separate blood 
draws (3 teaspoons blood for each) for genotyping and biomarker testing. Each of these blood samples will 
be labeled with the subject ID number and the date of blood draw only. No identifiable or private health 
information will be included on the labs prior to and when sent out for testing. Blood samples for a single 
biomarker (CDT) for heavy alcohol use will be drawn at randomization, weeks 13, and 25, and kept frozen 
at secure NYUMC facility freezer. At the conclusion of enrollment for study, samples will be sent in large 
batches to the Medical University of South Carolina (MUSC) and Dr. Raymond Anton’s, a consultant on this 
protocol, laboratory.  Results filed under the study ID only will be communicated and entered into the study 
database.  Whole blood samples for a single nucleotide polymorphism (SNP) at the mu opioid receptor, the 
A118G OPRM1 SNP, will likewise be frozen, banked, and shipped in batch fashion for analysis at MUSC by 

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Dr. Anton.  All samples will be destroyed following analysis and not preserved for future use.  Results from 
either CDT or OPRM1 will be for research purposes only, will not be considered in real-time or used for 
participant counseling, and will be analyzed at conclusion of the study as secondary biomarkers and genetic 
baseline predictors of treatment outcomes.   
 
8.1 Primary Outcome: The primary outcome measure of this study is a binary measure of success/failure 
consisting of a composite good clinical outcome (yes/no) through the final 20 weeks: abstinence or 
moderate drinking (<2 drinks/day, men; <1 drink/day, women; <2 heavy drinking episodes every 4 weeks 
[heavy drinking is >5 drinks/occasion, men; >4 drinks/occasion, women).  Abstinence, drinks/day, and 
heavy drinking days will be assessed by the TLFB calendar81 administered at each MM and Research-only 
visit.  As the final MM visit (week 25) does not involve medication prescribing or constitute active treatment, 
the week 26 research-only assessment visit TLFB will be used to capture complete heavy drinking data 
among participants missing the final week 25 MM visit.   
Rationale: Why a binary good clinical outcome of abstinence or moderate drinking only as the 
primary outcome, vs. % days abstinent or time to first heavy drinking day?  As stated earlier and in the 
original proposal, we are interested in all of these important alcohol treatment outcomes, and which we will 
track and report.  Our strong preference is to anchor the design of this comparative effectiveness trial on a 
pragmatic good clinical outcome that would have genuine face validity for both patients and treatment 
providers.  This analytic approach is consistent with pragmatic comparative effectiveness trial designs 
focusing on simple and important behavioral outcomes, such as post-intervention cancer screening, 
appropriate post-stroke smoking cessation treatment, or self-reported pain control over time.46,47,48,49,50 
 
8.2 Secondary Drinking, Adverse Events, and Measures: drinking measures will be evaluated at each 
monthly visit (TLFB), along with self-reported O-NTX adherence (MMAS-8) and adverse events.  Liver 
function tests (aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase 
(GGT) and carbohydrate-deficient transferrin (CDT) will be measured every three months (week 0/1, 13, 
and 25), with AST, ALT, and GGT results available in real-time to study physicians.  CDT, a validated 
biomarker for heavy drinking,82,83,84 is not in use or available at either facility, and will not be reported to 
participants or study physicians, but rather used as a secondary marker of baseline and in-treatment heavy 
drinking.  CDT represents a ‘cutting edge’ alcohol biomarker, and one not previously studied in the context 
of an XR-NTX treatment trial.  Analysis and interpretation of CDT results will be coordinated with Dr. Anton 
and his laboratory.  Likewise, baseline assessments of drinking severity and psychiatric function (OCDS,85 
MINI-SCID,86 Form 9087) and naltrexone mu receptor susceptibility (Asp40 OPRM1 genotyping) will be 
captured for research purposes only, and not integrated into the clinician’s MM strategies.   
 
8.3 Cost Effectiveness Outcomes: Economic data will be derived primarily from the Economic Form 90,88 
Non-Study Medical Service and HHC electronic medical records assessments, EQ-5D (functional status),89 
and a cost survey or standardized question querying patient reports of specific non-medical related costs 
(including lost/gained work, lost/gained dependent care, transportation costs, arrests, motor vehicle 
accidents) collected at baseline and at week 13, 25, and 48 assessments.  The week 48 assessment is 
included to gain longitudinal, post-treatment cost, drinking, and functional data at a small cost to the overall 
study budget.  Whenever possible, verification of productivity (paystubs) and medical costs (medical 
records) will be sought to corroborate self-report.   
 
 
 
9.0 Power and Sample Size 
As in the original proposal and based on our recent feasibility study of XR-NTX in primary care2 and 
the O-NTX treatment retention and adherence literature,6,7,19 including the single review by Roozen 
comparing the two medications, 28 we are powering this study on the assumption that XR-NTX is 
approximately twice as effective as O-NTX at achieving drinking reductions, including a good clinical 
outcome of abstinence or moderate-drinking-only during weeks 5-24, and also increased days abstinent 
and reduced rates of heavy drinking, drinks per drinking day, and drinks per day overall.  This is 

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hypothesized to be mediated by superior naltrexone adherence.  We predict based on our pilot data and the 
literature that 40-50% of patients will complete 24 weeks of treatment on XR-NTX, compared to <20% on O-
NTX, based on O-NTX clinical trial and commercial refill data.  We then estimate rates of the primary good 
clinical outcome of approximately 20% in O-NTX participants and 40% in the XR-NTX arm, roughly the 
same as adherence rates.  This is based on our pilot data, in which 36 of 40 persons completing 12 weeks 
of XR-NTX qualified for the moderate-drinking-only good clinical outcome, and COMBINE, in which 
adherent oral naltrexone/MM patients reported high rates of the same moderate-drinking-only good clinical 
outcome during the final 8 of 16 weeks of the study.  With 100 subjects per group, we anticipate power of 
0.84 to detect a 20% absolute difference in the primary outcome based on the Fisher's exact test.  These 
projected rates, however, are not well established, nor based on large datasets of heterogenous alcohol 
populations, and therefore we have increased the target screening n to 468, with a very conservative 
assumption of 2 subjects screened for every 1 enrolled, for a target sample of N=234 and n=117 per arm, 
which increases the projected power to 0.90. 
 
10.0 Statistical and Cost Effectiveness Analysis 
Preliminary analyses of balance: balance across the study on potentially prognostic baseline 
variables will be appraised using analyses of variance for continuous variables and log-linear models for 
discrete and ordinal responses.  Variables for which significant differences were observed will be included 
as covariates in later analyses.  Sometimes variables with strong clinical associations with the primary 
outcome are identified post hoc, and usually included in the analysis to reduce bias and improve efficiency 
(yielding smaller p-values and narrower CIs). Further, in mixed models there is always a possibility that an 
analysis will not converge. This danger is minimized by including in the model only essential covariates. 
Hence, before analyzing the primary outcome measure, the plan is to determine which predictive variables 
rise to a sufficient level of importance. 
 
10.1 Hypothesis 1: The rate of the primary good clinical outcome will be approximately twice as high among 
participants receiving XR-NTX compared with those receiving O-NTX. (Primary Aim, Treatment 
Effectiveness:  To evaluate the effectiveness of XR-NTX vs. O-NTX in producing a primary good clinical 
outcome defined as abstinence or moderate drinking (<2 drinks/day, men; <1drink/day, women; and <2 
heavy drinking occasions/month), during the final 20 of 24 weeks of primary care-based Medical 
Management for alcohol dependence)    
 
The primary outcome measure of this study is a binary measure of success defined by abstinence or 
moderate drinking only, as measured by the TLFB, with drop-outs from MM and research-only assessments 
assumed to have resumed baseline rates of heavy drinking, and therefore defined as good clinical outcome 
failures.  Our analytic approach will be an intention-to-treat comparison of all randomized participants 
(N=234). The analysis will utilize a logistic regression with an indicator variable for treatment and covariate 
terms for baseline potential prognostic indicators that are not stratified for at randomization, including AA 
ethnicity, lead-in abstinence, medication preferences, baseline drinking severity, in-trial specialty treatment 
involvement, clinical site, and OPRM1 genotype. If the coefficient of treatment is significant the null 
hypothesis of equal treatment effect is rejected. Odds ratios will be calculated to quantify the risk to 
treatment failure of significant predictors (Secondary Aim 2: Patient-Level Predictors of Effectiveness: To 
identify patient-level characteristics associated with effectiveness in both arms). To differentiate time to a 
good clinical outcome failure, we will use a "cure model." The form of a cure model is H(t) = 1- p + pS(t); 
where H(t) is the probability of failure at a time greater than t, p represents the probability of failure, and S(t) 
the distribution of time to failure, conditional on failure occurring. The parameters will be estimated based 
both on Kaplan Meier methods and parametrically. The equality of the values of p for the two treatment 
arms will be tested using a nonparametric likelihood ratio test. For the parametric test, a logistic will be used 
to model p and a Weibull survival distribution will be used to model time to failure, S(t). Both allow the use of 
covariates, which will complement the above logistic regression approach. 
 
As originally proposed, naltrexone appears most effective at reducing heavy drinking, as opposed to 
producing complete abstinence, and all traditional alcohol treatment trial clinical endpoints, including 
continuous drinking and heavy drinking variables, as well as the CDT biomarker, which is specific for heavy 
drinking, are of great interest, and will be reported in the primary publication from this trial.  In addition, rates 

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of medication treatment adherence, and an alternative good clinical outcome, treatment retention AND no 
heavy drinking, will be reported.  Treatment differences in % days abstinent, overall % heavy drinking days, 
time to first drink, and time to first heavy drinking day, will be compared using mixed model repeated 
measures (MMRM) analysis including terms for subject, treatment, and time by treatment interaction, and 
covariate terms for baseline variables. To examine differential treatment effects at each week, we will 
perform tests of simple main effects.  The MMRM will assume a means model, an unstructured covariance 
matrix and estimation will be based on restricted maximum likelihood. The baseline values will be adjusted 
by the overall mean. The assumptions relating to the mixed-effects model will be reviewed by examining 
residual scatter plots to examine deviations from normality and to assess lack-of-fit. In case of violation of 
assumptions, a randomization test will be performed based on the same MMRM. 
 
10.2 Hypothesis 2: XR-NTX treatment will be more cost effective than O-NTX.  (Secondary Aim 1:  Cost 
Effectiveness.  To estimate the incremental cost effectiveness of XR-NTX vs. O-NTX both in conjunction 
with primary care-based medical management of alcohol dependence). 
We will estimate the incremental cost-effectiveness of XR-NTX compared to O-NTX. In technical 
terms the incremental cost-effectiveness is the ratio of incremental costs to incremental benefits; in lay 
terms, the incremental cost-effectiveness indicates the ‘bang for the buck’ of XR-NTX compared to O-NTX.  
The incremental cost-effectiveness of XR-NTX treatment compared to O-NTX treatment is equal to (Cost of 
XR-NTX minus Cost of O-NTX) divided by (Effectiveness of XR-NTX minus Effectiveness of O-NTX). 
Cost-effectiveness analysis requires estimates of costs and estimates of effectiveness. 
Consequently, we will use primary data analyses from this study (Specific Aim 1 in the proposal) to inform 
costs and effectiveness estimates in the short-term, and we will synthesize these short-term estimates with 
published reports that allow us to estimate the longer-term, downstream costs and effects of the changes in 
alcohol consumption observed in Specific Aim 1. We will alternatively use societal and payer perspectives 
for assessing costs, and we will use the standard discount rate of 3% for costs and benefits.90 The discount 
rate reflects the time preference with regard to costs and benefits (i.e., a dollar today is worth more to most 
people than an inflation-adjusted dollar at some time in the future). All costs will be inflated to 2011 US $ 
using alternatively the consumer price index (CPI) for all goods and services and the CPI for Medical 
services (reflecting the ongoing debate over whether the Medical services CPI overestimates inflation 
because of the difficulty of discriminating the effect of service improvement from service inflation). 
 
Short-term estimates of costs and effectiveness of XR-NTX compared with O-NTX.  Short-term 
estimates of costs and effectiveness will be obtained from primary analysis of data from the trial proposed in 
Aim 1, using a combination of pre-specified medical record and survey endpoints. Cost assessment will be 
conceptually similar to recently published analyses of the COMBINE interventions, 36,37,38 and will include 
medical and non-medical costs as well as payer and societal costs. Effectiveness assessment will include 
alcohol consumption measures as described elsewhere in this proposal, as well as quality of life. Quality of 
life will be assessed using 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 (OLS) 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.”  
 
Longer-term estimates of costs and effectiveness.  To estimate the comparative effectiveness of XR-
NTX relative to O-NTX over longer time horizons than are reflected by our data, we will incorporate these 
short-term results within a state-transition (Markov) computer simulation of outcomes that enables a cohort 
of hypothetical alcohol-dependent patients to be followed over time until death, and to be exposed to 
alternative alcohol interventions for specified time durations beyond the week 24 assessment.  We will 
develop this simulation expressly for this proposal, drawing on our experience creating, validating, and 
using other computer simulations assessing the impact of alcohol interventions on long-term costs and 
benefits.91,92,93,94,95 The simulation will be able to aggregate the lifetime benefit of remitting alcohol 
dependence for designated periods of time using trial endpoints (e.g. frequency of heavy drinking days), 
and also can quantify benefits of the levels of improvement short of full remission (e.g. if alcohol 

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dependence remits but the patient still is an at-risk drinker). The simulation will estimate lifetime costs and 
benefits over a lifetime horizon, measured in both life-years and quality-adjusted life-years. (Quality-
adjusted life years is a preference-based, quality of life metric that considers quality of life simultaneously 
with quantity of life, and instantiates the notion that a typical person would trade away some quantity of life 
to get a greater quality of life.) In sensitivity analyses we will consider time horizons shorter than lifetime (10 
year and 20 year) because these horizons are sometimes preferred by decision makers, even though the 
longer, lifetime horizon is advocated by the Panel on Cost-Effectiveness in Health and Medicine.77 
 
Further considerations of the cost-effectiveness approach: The above simulation will assume that 
the costs and benefits observed in the trial have varying levels of persistence. In the most pessimistic 
scenario, any treatment effect observed in the trial would wane rapidly after the trial follow-up period, and 
therefore any benefits that accrue in the long-term would be attributable to the short-term effect, or, in the 
more optimistic scenario, any treatment effect observed would persist indefinitely, as long as the treatment 
is continued.  Therefore, the simulation would aggregate incremental benefits of magnitude observed in the 
trial that are assumed to persist as long as the treatment is continued. The most optimistic, albeit unrealistic, 
scenario is that the treatment effect will persist indefinitely after the trial concludes, and no additional 
treatment would be necessary. Because this scenario is unrealistic, we will only perform analyses along 
these lines as sensitivity analyses; however, we will analyze scenarios in which persistence of treatment 
effect requires select treatment “boosters” of variable duration and frequency. 
 
To aggregate the impact of remission of partial and/or complete alcohol dependence, the simulation 
will require estimates of the impact of alcohol dependence and other alcohol use disorders (e.g. at-risk 
consumption and harmful consumption) on quantity and quality of life, and on costs. These estimates will be 
based on published reports that have aggregated the impact of alcohol on the morbidity and mortality and 
costs of specific diseases with substantial risk attributable to alcohol (e.g., hypertensive heart disease, 
cirrhosis of liver, oral cancers, etc).96 In addition, simulation input will also draw on published reports that 
have aggregated the impact of alcohol on morbidity, mortality, and costs of non-medical sequelae of alcohol 
consumption (e.g., motor vehicle collision, arrests)97  As in our previously published simulation work, we 
develop the computer simulation for this proposal by incorporating the standard, stepwise procedure of 
specification (defining the structure and mathematical relationships of the variables in the model), 
verification (otherwise known as “debugging”; making sure the model performs consistently with 
expectations across a wide range of inputs, including “stress tests” when inputs may be deliberately set to 
extreme, clinically unrealistic values in an attempt to unmask flaws in the model), parameterization 
(inputting variable estimates based on relevant data or expert opinion), calibration (making sure model 
output is similar to observed clinical output in relevant circumstances), and validation (testing model 
performance in circumstances or clinical populations distinct from those used for model development).   
 
Uncertainty: we will estimate 95% confidence intervals around point estimates of incremental cost-
effectiveness using standard approaches in which vectors on the cost-effectiveness plane are identified 
corresponding to the 2.5th and 97.5th percentiles of incremental cost-effectiveness.  We will also create 
corresponding acceptability curves, which denote the probability that a particular program or programmatic 
decision is favorable given a particular willingness to pay for health benefits.  
 
If the trial is negative, what’s the purpose of Aim 2?  It might be observed that, if an intervention is 
not effective, it is meaningless to estimate its cost-effectiveness. Therefore, it might appear that the 
scientific validity of Aims 1 and 2 are inter-dependent. However, in the event that Aim 1 produces negative 
results, we will employ the computer simulation developed for Aim 2 for a slightly different purpose. Rather 
than using the simulation to estimate the cost-effectiveness of XR-NTX versus O-NTX, we will instead use 
the simulation to ask “what is the minimum level of incremental effectiveness required for an intervention to 
deliver sufficient value?” so that Aim 2 remains scientifically relevant and useful for decision makers. For 
example, even if XR-NTX does not deliver significant improvements in effectiveness compared to O-NTX, 
we would use the simulation to infer what levels of incremental effectiveness would be necessary to deliver 
sufficient value, given particular assumptions about incremental costs. For example, if a new intervention 
cost $100/month more than O-NTX, how many fewer heavy-drinking days would it need to reduce 
compared to O-NTX in order to deliver sufficient value (incremental cost-effectiveness ratio < 
$100,000/QALY)? That way, simulation results can inform future trial design. This approach is detailed in 
our recent publication,98 and is concordant with principles of value-of-information analysis.99 
 

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10.3 Secondary Aim 2:  Patient-Level Predictors of Effectiveness.  The multivariate models described for 
Aim 1, while testing the main and subsidiary hypotheses, will also be used to identify patient characteristics 
associated with treatment success.  We hypothesize a priori that there will be less robust effectiveness in 
both arms among women and African Americans, while pre-treatment abstinence, voluntary specialty 
alcohol treatment and Alcoholics Anonymous involvement (patients are not directly referred to ancillary 
treatment), and presence of the Asp40 OPRM1 SNP will be associated with treatment effectiveness.  We 
also hypothesize that these positive associations will be more pronounced within the XR-NTX arm due to 
the sustained medication adherence following each injection.  We note, however, that these analyses will be 
exploratory, as the study is not powered to carefully test these secondary hypotheses. 
 
 
11.0 Data Collection and Management 
Data recording and instruments will be collected by the RCs in real-time using web-based CRFs and 
the NYUMC data management platform.  The NYU/HHC CTSI and NYULMC Clinical Research Informatics 
and Data Management Unit (CRIDM), led by James Robinson, M.Ed., will provide clinical research 
informatics and data management support for the study.  Building on the a proprietary platform, CRIDM 
personnel will develop the additional required electronic case report forms (CRFs) to complete the data 
management system for this proposal, and work with study personnel to insure the completeness and 
integrity of all study data.  All data will be checked in real-time and stored in a centralized database; all data 
will be reviewed and monitored for completeness and accuracy, and a final data clean will be completed 
following the last subject visit, following which the study database will be locked. 
 
12.0 Protection of Human Subjects 
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 participant recruitment from the NYUMC IRB.  Any amendments to the 
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. 
 
12.1 Potential Risks 
This study offers patient randomization to two forms of FDA-approved naltrexone treatment for 
alcohol dependence.  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.   
All participants will receive 24 weeks of office-based naltrexone treatment. As with any patient 
starting naltrexone, participants in either arm may experience nausea, headache, and fatigue (‘naltrexone 
flu’), particularly during the initial first few days of dosing.  Nausea may be more likely with oral vs. injectable 
naltrexone. In most published naltrexone clinical trials, these side effects are well-tolerated by patients, 
though it is certainly possible some patients will discontinue the medications based on these common and 
expected naltrexone side effects, as a small percentage of patients did in our pilot, the COMBINE study, 
and the Garbutt XR-NTX efficacy studies.2,3,26  Theoretically both forms of naltrexone can cause transient 
liver inflammation, and liver function will be monitored throughout the trial.  In reality, few patients in recent 
clinical trials or usual care experience any naltrexone-related liver toxicity.   
Injectable XR-NTX carries a unique set of adverse event risks, including injection site soreness, 
usually well tolerated, and more severe injection site reactions, which may be prolonged and resemble a 
sterile abscess.  Nationally, a small number of injection site reactions have been recorded, with a very low 
percentage progressing to necrosis and requiring surgical debridement, according to a 2008 FDA Alert, 
Naltrexone Injection Site Reactions (www.fda.gov).  Our own pilot recorded one such severe injection site 
reaction (1 of 154 injections), in this case an older female with substantial hip adipose tissue.2  It is thought 
that mis-injection of the XR-NTX bolus into subcutaneous adipose tissue is the cause of injection site 
reactions, as opposed to proper intramuscular placement.  Study staff will be carefully trained on this issue 

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and take extra caution among participants with increased hip and buttocks adipose tissue.  We will not, 
however, exclude patients based on body habitus or BMI, as this is not a national recommendation and 
therefore not part of usual care.   
XR-NTX also introduces a prolonged mu opioid antagonist blockade, complicating the treatment of 
acute or chronic pain with opioid medications.  O-NTX also produces an antagonist blockade, but can 
simply be discontinued in the face of an unexpected painful event.  Persons randomized to XR-NTX will be 
provided a wallet card identifying them as an XR-NTX patient and containing the PI’s and study phone 
numbers.  XR-NTX blockade can be ‘overridden’ due to competitive mu receptor pharmacodynamics with 
increasing doses of full mu agonists, which should provided only in a monitored medical setting such as an 
Emergency or Recovery Room.  There were no such unanticipated painful events in our pilot study, and 
persons with chronic pain conditions requiring opioid medications are excluded from enrollment. 
All participants will be given information concerning all of these potential risks prior to giving 
informed consent.  The informed consent document and informed consent quiz will in simple and plain 
language detail all of the above medication-related risks.  The Medical Management visit schedule may be 
altered to accommodate unexpected visits related to side effects and adverse events, and study staff will be 
available by phone for emergency consultation at any time (all patients will be given the PI’s direct mobile 
number).   
 
Otherwise this is a study of treatment for alcohol dependence, and there is no guarantee patients 
will benefit from either intervention, and thus remain chronic, heavy drinkers, with all of the daily and long-
term risks and hazards alcohol dependence entails.  Both arms of the study represent evidence-based, 
FDA-approved interventions designed to treat alcohol dependence and minimize these risks, and we expect 
most patients to derive some minimal benefit from treatment.  However, at any point in the trial, patients 
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 detox and specialty treatment through Bellevue Hospital.  Detox and intensive 
outpatient alcohol specialty services are immediately available to all participants through the Bellevue 
Hospital Chemical Dependency programs, including same-day admissions to our detox unit, regardless of 
insurance status or ability to pay.   
These ‘risks,’ inherent to identifying and initiating treatment in previously out-of-treatment alcohol 
dependent patients, are common to all alcohol intervention trials and usual care, and do not seem to 
complicate Medical Management protocols.  Our recent pilot of XR-NTX did not, for example, refer any of 
the 72 patients to detox services, and none reported severe withdrawal or seizures after the initiation of XR-
NTX treatment.  Most likely patients with severe physiologic alcohol dependence and at greatest risk for 
withdrawal seizures, phenomena which occur in a small minority of alcohol dependent patients and are not 
thought to be opioid receptor mediated, do not experience great benefit from naltrexone treatment and 
continue to drink heavily.   
 
12.2 Confidentiality 
Participants will be asked to provide information regarding a number of sensitive behaviors (e.g., alcohol 
and drug use, sexual history, and illicit activities). We will obtain a Federal Certificate of Confidentiality from 
DHS/NIH to encompass protocol activity and participant data and ensure against the release of confidential 
information. We will provide all 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 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.  Data sharing of de-identified data is discussed below. 
 
12.3 Emotional Discomfort 
There is a small chance that participants may become upset when discussing their history of alcohol 
problems, family conflict, prior trauma, or role failure, etc.  We will discontinue administration of research 
instruments if a subject shows great discomfort or asks to terminate an interview.  Such events were not 
observed in our pilot study.  

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12.4 Risk/Benefit Ratio 
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 compared to the expected benefit of 
discontinuing alcohol use. 
 
12.5 Resource and Data Sharing Plan 
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 patient 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. Lee 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 
participant, 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.   
 
12.6 Data and Safety Monitoring Plan (DSMP) 
12.6.1 Data Safety & Monitoring Board (DSMB) 
A safety monitoring board will be established for ongoing protocol review, including data, protocol 
compliance, safety and efficacy data, in compliance with NIH and NYU guidelines. Constition of the DSMB 
is pending and will be presented to the IRB when complete.  All board 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. The board will meet every six months (unless more frequent meetings are deemed necessary). Dr. 
Lee 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. Lee 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; both medications are FDA-approved, their use in this trial is consistent with their FDA labeling, 
and no significant safety issues have arisen in national post-marketing use; as a comparative and cost-
effectiveness trial comparing two efficacious treatments, full recruitment and maximal follow-up is warranted 
to ensure complete outcome data, nor would an emerging effectiveness advantage in favor of one of the 
medications present an ethical issue in terms of continuation.   
  
12.6.2 Procedures in Place to Ensure the Validity and Integrity of the Data 
Study clinicians and research staff will be undergo the same baseline training at the inception of the 
study. The Project Manager and Data Management staff 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 patient 
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 

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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 (see Resource and Data 
Sharing Plan). 
 
12.6.3 Procedures to Guarantee the Accuracy and Completeness of the Data during Data Collection, Entry, 
Transmission, and Analysis 
Accuracy and completeness of the data will be ensured by the NYU/HHC CTSI and NYULMC 
Clinical Research Informatics and Data Management Unit (CRIDM), led by James Robinson, M.Ed., and as 
described in the Research Strategy. Study data will be managed by two Data Managers using a proprietary 
web-based e-research platform. Data will be entered using laptops with wireless broadband internet cards 
connected to the NYUMC secure intranet, encrypted, and transmitted to CRIDM servers at NYUMC. All 
data analyses for the study will be performed by the biostatistician, Eugene Laska PhD, of the Dept. of 
Psychiatry of NYU School of Medicine. Quality control is performed as the data are being entered, and then 
at further stages of the storage and management process. 
 
12.6.4 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). 
 
12.6.5 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. 
 
12.6.6 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 NIDA project officer, and the original amendment approvals will be 
filed in the primary document manual. 
 
12.6.7 Trial Stopping Rules 
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 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. 
 
12.6.8 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. 

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