Clinical trial NCT02330419
Conditions: Binge Drinking HIV
Keywords: Naltrexone
Sponsor: University of California, San Francisco
Start date: 2015-04-01; Completion date: 2021-01-01
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, placebo-controlled trial of 120 binge-drinking MSM to 12 weeks of naltrexone 50mg, to be taken in anticipation of heavy drinking. Ethnically and racially diverse participants will be recruited using Respondent Driven Sampling as well as active field recruitment. MSM will be seen weekly for alcohol-metabolite urine testing, study drug dispensing, and brief counseling for alcohol use. Safety assessments and behavioral surveys will be completed monthly.

Detailed description:
This is a double-blinded, placebo controlled trial of 120 binge-drinking MSM to 12 weeks of naltrexone 50mg, to be taken in anticipation of heavy drinking. Ethically and racially diverse participants will be recruited using venue based recruitment and social network bsed recruitment strategies. Participants will be seen weekly for alcohol metabolite urine testing, study drug dispensing and brief counseling for alcohol use. Safety assessments and behavioral surveys will be completed monthly. Efficacy on alcohol consumption and alcohol-associated sexual risk behavior (Aims 1-3) will be assessed using weekly timeline follow-back, screening for ethyl glucuronide (EtG) positive urines, and computer administered monthly interventions. Tolerability and acceptability (Aim 4) will be assessed through tracking of adverse events and medication adherence. Generalized estimating equation (GEE) models will be fitted to estimate treatment effects on repeated study outcomes.

Arms: arm 1: Placebo 50mg, as needed arm 2: Naltrexone 50mg, as needed
Interventions: intervention 1: Placebo intervention 2: Naltrexone intervention 3: Medical Management (MM) counseling for alcohol use: intervention 4: Urinalysis for novel alcohol biochemical markers: intervention 5: Behavioral survey measurements: intervention 6: Dried Blood Spot (DSB) Testing for Phosphatidylethanol intervention 7: Ecological Momentary Assessment
Intervention descriptions: intervention 1: Placebo capsules will contain microcrystalline cellulose (Medisca). Placebo and active medication will be provided in capsules that are an exact match in color, so as to make the placebo and active medication indistinguishable from each other. intervention 2: REVIA is a white, crystalline compound. The hydrochloride salt is soluble in water to the extent of about 100 mg/mL. REVIA is available in scored film-coated tablets containing 50 mg of naltrexone hydrochloride. intervention 3: MM is a low-intensity supportive program designed to increase problem recognition and enhance motivation to change maladaptive alcohol use patterns. Participants will receive individual 20 minute MM sessions weekly from trained staff supervised by a clinical psychologist intervention 4: Urine samples will be collected weekly and tested for ethyl glucuronide (EtG) to determine recent alcohol consumption. EtG is a relatively novel, highly sensitive indicator for recent alcohol consumption; this alcohol biomarker is detectable in urine for approximately 72 hours). intervention 5: Standardized and validated behavioral measure that will be assessed using audio computer administered surveys (ACASI) to minimize underreporting of risk activities and standardize data collection intervention 6: Phosphatidylethanol (PEth)-a phospholipid formed only in the presence of alcohol-is a novel, direct biochemical marker of alcohol that has shown high (\>95%) sensitivity and specificity to detect heavy drinking over a period of 2-3 weeks in several studies of dependent patients and abstainers. DSB samples will be collected at enrollment, weeks 3, 6, 9, 12, and post-treatment visits at month 1, 3, and 6. intervention 7: Ecological Momentary Assessments are SMS texts to collect data on alcohol consumption, number of drinks on drinking days, and targeted medication administration prior to anticipated drinking sessions. Messages will use short-hand notations to maintain participant confidentiality

Protocol documents:
Prot_SAP_000.pdf: 
PI: Santos, Glenn-Milo 
Confidential 
 
1 
 
University of California, San Francisco 
Clinical Research Protocol 
The Better THAN Study: Targeting Heavy Alcohol use  
with Naltrexone among MSM 
NCT02330419 
Protocol Number: 
14-14481 
Version Date: 
1/5/2020 
Investigational Product: 
Naltrexone 
IND Number: 
Exempt 
Development Phase: 
Phase IV 
Sponsor: 
Glenn-Milo Santos, PhD, MPH 
University of California at San Francisco 
Department of Community Health Systems 
School of Nursing 
2 Koret Way, N505 
San Francisco, California 94143-0608 
Funding Organization: 
National Institutes of Health, Office of the Director  
Principal Investigator: 
Name: Glenn-Milo Santos, PhD, MPH 
Telephone:  628-217-6231 
 
E-mail:  glenn-milo.santos@ucsf.edu 
Medical Monitor: 
Name: Phillip Coffin,  
 
Telephone:  : (510) 407-2603  
 
 
E-mail:  Phillip.coffin@sfdph.org 
 
Coordinating Center: 
San Francisco Department of Public Health 
Population Health Division 
25 Van Ness Avenue, Suite 500 
San Francisco, California 94102 
 
Approval: 
 
 
1/5/2020 
Glenn-Milo Santos, Ph.D, MPH 
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   


PI: Santos, Glenn-Milo 
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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision, as 
outlined in the protocol.  It is understood that all information pertaining to the study will 
be held strictly confidential and that this confidentiality requirement applies to all study 
staff at this site. Furthermore, on behalf of the study staff and myself, I agree to maintain 
the procedures required to carry out the study in accordance with accepted GCP principles 
and to abide by the terms of this protocol. 
 
Protocol Number:  14-14481 
 
Protocol Title:  The Better THAN Study: Targeting Heavy Alcohol use with Naltrexone 
among MSM 
 
Protocol Date:  1/5/2020 
 
 
 
1/5/2020 
Investigator Signature  
 
Date 
Glenn-Milo Santos, Ph.D., MPH 
Print Name and Title 
Site # 
1 
 
Site Name 
San Francisco Department of Public Health 
Address 
25 Van Ness Ave., Suite #500 
 
San Francisco, CA.  94102 
 
 
 
 
Phone Number 
628-217-6231 


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TABLE OF CONTENTS 
 
1 
BACKGROUND ................................................................................................................. 10 
1.1 
Overview of Clinical Studies ...................................................................................... 10 
2 
STUDY RATIONALE ........................................................................................................ 12 
2.1 
Risk / Benefit Assessment ........................................................................................... 12 
3 
STUDY OBJECTIVES ....................................................................................................... 13 
3.1 
Primary Objective ....................................................................................................... 13 
3.2 
Secondary Objectives .................................................................................................. 14 
4 
STUDY DESIGN ................................................................................................................. 14 
4.1 
Study Overview ........................................................................................................... 14 
5 
CRITERIA FOR EVALUATION
 
ERROR! BOOKMARK NOT DEFINED. 
5.1 
Primary Efficacy Endpoint .......................................................................................... 14 
5.2 
Secondary Efficacy Endpoints .................................................................................... 14 
5.3 
Safety Evaluations ....................................................................................................... 15 
6 
SUBJECT SELECTION .................................................................................................... 15 
6.1 
Study Population ......................................................................................................... 15 
6.2 
Inclusion Criteria ......................................................................................................... 15 
6.3 
Exclusion Criteria ....................................................................................................... 15 
7 
CONCURRENT MEDICATIONS .................................................................................... 16 
7.1 
Allowed ....................................................................................................................... 16 
7.2 
Prohibited .................................................................................................................... 16 
8 
STUDY TREATMENTS .................................................................................................... 16 
8.1 
Method of Assigning Subjects to Treatment Groups .................................................. 16 
8.2 
Blinding ....................................................................................................................... 16 
8.3 
Test and Control Formulation ..................................................................................... 17 
8.4 
Supply of Study Medication at the Site
 
Error! Bookmark not defined. 
8.5 
Study Medication Accountability ............................................................................... 19 
8.6 
Measures of Treatment Compliance ........................................................................... 19 
9 
STUDY PROCEDURES AND GUIDELINES ................................................................. 20 
9.1 
Clinical Assessments ................................................................................................... 20 
9.2 
Other Clinical Assessments ......................................................................................... 22 
9.3 
Clinical Laboratory Measurements ............................................................................. 21 
10 EVALUATIONS BY VISIT ............................................................................................... 22 
10.1 Visit 1 (Screening Visit – Week 1 ) ............................................................................ 23 
10.2 Visit 2 (Screening Visit – Week 2) ............................................................................. 23 
10.3 Visit 3 (Enrollment Visit)............................................................................................ 23 
10.4 Visit 4 (Weekly Visits)................................................................................................ 23 
10.5 Visit 5 (Monthly Visits) .............................................................................................. 24 


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10.6 Early Withdrawal Visit ............................................................................................... 24 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................ 24 
11.1 Adverse Events ........................................................................................................... 24 
11.2 Serious Adverse Experiences (SAE) ........................................................................... 26 
11.3 Medical Monitoring .................................................................................................... 26 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS................................... 27 
12.1 Withdrawal of Subjects ............................................................................................... 27 
12.2 Replacement of Subjects ............................................................................................. 27 
13 PROTOCOL VIOLATIONS ............................................................................................. 28 
14 DATA SAFETY MONITORING ...................................................................................... 28 
15 STATISTICAL METHODS AND CONSIDERATIONS ............................................... 30 
15.1 Data Sets Analyzed ..................................................................................................... 30 
15.2 Demographic and Baseline Characteristics ................................................................. 30 
15.3 Analysis of Primary Endpoint ..................................................................................... 30 
15.4 Analysis of Secondary Endpoints ............................................................................... 31 
15.5 Interim Analysis .......................................................................................................... 31 
15.6 Sample Size and Randomization ................................................................................. 31 
16 DATA COLLECTION, RETENTION AND MONITORING ....................................... 31 
16.1 Data Collection Instruments ........................................................................................ 31 
16.2 Data Management Procedures ..................................................................................... 32 
16.3 Data Quality Control and Reporting ........................................................................... 32 
16.4 Archival of Data .......................................................................................................... 32 
16.5 Availability and Retention of Investigational Records ............................................... 32 
16.6 Monitoring .................................................................................................................. 32 
16.7 Subject Confidentiality................................................................................................ 33 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................. 33 
17.1 Protocol Amendments ................................................................................................. 33 
17.2 Institutional Review Boards and Independent Ethics Committees ............................. 33 
17.3 Informed Consent Form .............................................................................................. 34 
17.4 Publications ................................................................................................................. 34 
17.5 Investigator Responsibilities ....................................................................................... 34 
18  APPENDIX ......................................................................................................................... 35 
18.1 Study Procedures ......................................................................................................... 36 
18.2 References ................................................................................................................... 36 
 


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LIST OF ABBREVIATIONS 
ACASI 
Audio Computer Assisted Survey Instrument 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
Complete blood count 
CBO 
Community based organization  
CCG 
Community Consulting Group 
CFR 
Code of Federal Regulations 
CRF 
case report form 
CPHR 
Center for public health research 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
DSM-IV 
Diagnostic and Statistical Manual for Mental disorders 
EtG 
ethylglucuronide test 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equations 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human Immunodeficiency Virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MM 
Medical Management counseling 
MSM 
Men who have sex with men 
NIAAA 
National Institute on Alcohol Abuse and Alcoholism  
PEth 
phosphatidylethanol 
PrEP 
pre-exposure prophylaxis 
PI 
Principal Investigator 
SAE 
serious adverse experience 
SAMHSA 
Substance Abuse and Mental Health Services Administration 
SCID 
Structural clinical interview for DSM disorders 
SFDPH 
San Francisco Department of Public Health 
SMS 
Text message 
TLFB 
Timeline follow-back 


PI: Santos, Glenn-Milo 
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PROTOCOL SYNOPSIS 
TITLE 
The Better THAN Study: Targeting Heavy Alcohol use with 
Naltrexone among MSM 
SPONSOR 
Glenn-Milo Santos 
FUNDING 
ORGANIZATION 
National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
NUMBER OF SITES 
1 site 
RATIONALE 
Oral naltrexone, FDA approved agent, was chosen because we believe it will 
be more acceptable to non-treatment seeking, non-alcohol dependent binge 
drinking men who have sex with men (MSM). Intermittent dosing makes 
sense for most binge-drinking MSM because data indicate that they do not 
binge drink daily.    
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled phase 2 study.  
PRIMARY 
OBJECTIVE 
To determine the efficacy of targeted naltrexone versus placebo in reducing 
binge drinking among non-dependent MSM, as determined by number of 
binge drinking days in timeline follow-back (TLFB), over the three-month 
treatment period. 
SECONDARY 
OBJECTIVES 
To determine the efficacy of targeted naltrexone versus placebo in reducing 
alcohol consumption among non-dependent MSM, as determined by the 
proportion of ethyl glucuronide (EtG) positive urines, over the three-month 
treatment period. 
NUMBER OF 
SUBJECTS 
120 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: (1) Male gender (2) self-reported anal sex with men in 
the prior three months while under the influence of alcohol (3) at least one 
binge drinking (five or more drinks on a single occasion) session per week 
in the prior three months; (4) interested in reducing binge alcohol 
consumption; (5) HIV-negative by rapid antibody test or medical record 
documentation of HIV infection (HIV positive participants);  (6) no current 
acute illnesses requiring prolonged medical care; (7) no chronic illnesses 
that are likely to progress clinically during trial participation; (8) able and 
willing to provide informed consent and adhere to visit schedule; (9) age 18-
70 years; (10) baseline CBC, total protein, albumin, glucose, alkaline 
phosphatase, creatinine, BUN, and electrolytes without clinically significant 
abnormalities as determined by study clinician in conjunction with 
symptoms, physical exam, and medical history. 
Exclusion Criteria: (1) Any psychiatric (e.g. depression with suicidal 
ideation) or medical condition that would preclude safe participation in the 
study; (2) known allergy/previous adverse reaction to naltrexone; (3) current 
use of/ dependence on any opioids or a known medical condition which 
currently requires/may likely require opioid analgesics; (4) opioid-positive 
urine at  enrollment; (5) current CD4 count < 200 cells/mm3 (6) 
moderate/severe liver disease (AST, ALT > 3 times upper limit of normal); 


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(7) impaired renal function (creatinine clearance < 50 ml/min); (8) currently 
participating in another intervention research study with potential overlap; 
(9) alcohol dependence as determined by SCID criteria (participants with 
non-dependent alcohol use disorders/symptoms of alcohol abuse [per DSM-
IV] are eligible) (10) any condition that, in the principal investigator and/or 
study clinician’s judgment interferes with safe study participation or 
adherence to study procedures; (11) not having a cell-phone that can send 
and receive text messages. 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Naltrexone HCL 50 mg (ReVia), oral administration as needed.  
 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Placebo 50 mg, oral administration as needed.   
 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 9 months 
Screening:  up to 30 days 
Treatment:  3 months 
Follow-up:  6 months 
The total duration of the study is expected to be nine months. One month for 
subject recruitment and nine months for final subject participation and 
follow-up. 
CONCOMMITANT 
MEDICATIONS 
Allowed:  standard therapy 
 
Prohibited:  current use of/ dependence on any opioid medication or 
current naltrexone treatments.  
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
• 
To detect 27% reductions in numbers of binge drinking occasions, as 
well as 10% reductions in the average numbers of drinks on drinking 
days among treatment arm compared to placebo arm.  
SECONDARY 
ENDPOINTS 
• 
To detect 15-23% reductions in the urine positivity rate in the treatment 
arm compared to the placebo arm.    
OTHER 
EVALUATIONS 
Potential biomarkers for alcohol:  EtG and PEth 
SAFETY 
EVALUATIONS 
Change in clinical safety labs from baseline to week 12 
Incidence of adverse events 
PLANNED INTERIM 
ANALYSES  
No planned interim analyses.  Serious adverse events will be monitored by 
the committee on an ongoing basis throughout the study. 


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STATISTICS 
Primary Analysis Plan 
We will use generalized estimating equations (GEE) to estimate treatment 
effects on repeated study outcomes. Primary analyses will be by intention-
to-treat, without regard to adherence to treatment. In our prior trials, we had 
excellent retention and visit adherence. Nonetheless, in this high-risk 
population, missing data may be encountered.123, 124 We will conduct 
sensitivity analyses imputing all missing urine samples as positive, adjusting 
for baseline correlates of missingness, and using inverse probability of 
censoring weights.125  
Specific Aim 1: To determine the efficacy of targeted naltrexone versus 
placebo in reducing binge drinking among non-dependent MSM, as 
determined by number of binge drinking days in timeline follow-back 
(TLFB), by arm. GEE Poisson models with robust standard errors will be 
used to assess reductions on weekly drinking outcomes. Baseline TLFB 
results will be included in the analysis.   Minimum detectable effects 
(MDEs): In calculating minimum detectable effects, we hypothesized on 
pharmacologic grounds that oral naltrexone will reach full efficacy against 
alcohol use almost immediately; accordingly we expect treatment-control 
differences to be approximately constant over the 12 weeks of the trial. 
Based on the prior trial (93% retention), we estimate that 90% of 
participants will be retained at 12 weeks. Using estimates based on data 
from Project ECHO92 for the within-subject correlation and over-dispersion 
of the outcomes, as well as the mean frequency among controls, we estimate 
that the proposed study will have 80% power in 2-sided tests with a type-I 
error rate of 5% to detect 27% reductions in numbers of binge drinking 
occasions, as well as 10% reductions in the average numbers of drinks on 
drinking days.   Specific Aim 2: To determine the efficacy of targeted 
naltrexone versus placebo in reducing alcohol consumption among non-
dependent MSM, as determined by the proportion of ethyl glucuronide (EtG) 
positive urines, by arm.  GEE logistic models with robust standard errors 
will be used to assess reductions frequency of positive urine tests, 
accounting for within-subject correlation.   MDEs: Using the assumptions 
for loss to follow-up for Aim 1, as well as estimates based on biomarker data 
from Batki et al’s study on Topiramate for alcohol use disorders122 for the 
within-subject correlation and control group urine positivity rate, we 
estimate that the study will have 80% power in 2-sided tests with a type-I 
error rate of 5% to detect 15-23% reductions in the urine positivity rate in 
the treatment arm.   Specific Aim 3:  To determine the efficacy of targeted 
naltrexone versus placebo in reducing alcohol-associated sexual risk 
behaviors, we will use GEE Poisson models with robust standard errors for 
the four monthly ACASI assessments on numbers of male anal sex partners, 
HIV-serodiscordant unprotected anal sex partners, unprotected anal sex 
partners while intoxicated with alcohol, and unprotected anal sex events 
with serodiscordant partners, including the baseline value. In the event that 
these outcomes are severely over-dispersed, we will analyze indicators for 
any self-report of each behavior, using GEE logistic models.   MDEs: Based 
on estimates of within-subject correlation and control prevalence from our 
Project Echo trial, we estimate that the study will have 80% power to detect 
31% reductions in numbers of male anal sex partners, 57% reductions in 
SDUA partners, 46% reductions in UA partners while intoxicated with 
alcohol, and 56% reductions in UA events with serodiscordant partners. In 


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analyses using GEE logistic models, we will have 80% power to detect 
reductions of 14%, 38%, 39%, and 30% in any report of these four sexual 
risk behaviors, respectively.    
Rationale for Number 
of Subjects 
Given our estimate that there are 48,070 binge-drinking MSM in San 
Francisco19, 20 and our prior trial enrollment rates, we are confident that we 
will be able to recruit 120 eligible non-dependent, binge-drinking MSM for 
the proposed trial. 
 


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1 
BACKGROUND 
1.1 
Overview of Overview of Clinical Studies 
Binge drinking is a major health issue for men who have sex with men (MSM) at high-
risk for acquiring or transmitting HIV. In the National HIV Behavioral Surveillance (NHBS) 
survey, 84% of MSM consumed alcohol in the past 30 days, and 57% reported at least one 
occasion of binge drinking.3 The prevalence of binge drinking for MSM is 3.5 times the 
prevalence in the general US adult population.1 The high rates of alcohol use in MSM have 
been observed for decades and these rates will likely persist.15-17 In San Francisco, 72% and 
55% of MSM reported binge drinking in the past 12 months, and the past 30 days, respectively.18 
Binge drinking is by far the most prevalent exposure attributed to HIV infections among MSM 
and it is estimated that there are 48,070 binge-drinking MSM in San Francisco.19, 20 MSM are 
disproportionately impacted by HIV, accounting for 61% of new infections in 2009.21 For San 
Francisco MSM, HIV prevalence is estimated at 22.7% and HIV annual incidence is estimated at 
1.27% per year.22 It is imperative to develop more evidence-based HIV-prevention interventions 
that are not only efficacious, but also feasible and acceptable to MSM.   
 
Binge and other heavy drinking patterns are associated with HIV risk behaviors. 
NHBS data show that alcohol use before or during unprotected sex was common for MSM—41% 
and 43% of alcohol drinkers surveyed reported unprotected insertive and unprotected receptive 
anal sex while intoxicated on alcohol, respectively, during their most recent sexual episode.3 
Similarly, in Project Mix, one of the largest randomized controlled trials of MSM in the US, 40% 
of current drinkers reported having unprotected sex while intoxicated during their most recent anal 
sex episode.23 Interventions that can be utilized within the risk environment may be more 
efficacious at reducing HIV risk in this highly impacted population. Alcohol use is deeply 
entwined with social activities of MSM15 and although drinking, per se, does not always predict 
unprotected intercourse, certain risk contexts are more consistently associated with alcohol use.4, 24 
The acute effects of alcohol consumption (e.g., altered cognition, impaired judgment and increased 
sexual desire and confidence) may contribute to risk-taking behaviors.25-28 A myriad of 
psychosocial factors (e.g., cognitive escape, impulsivity, expectancies) are believed to mediate the 
association between alcohol and sexual risk behaviors.26, 29-34 Furthermore, bar and club venues 
frequented by MSM provide conducive environments for both meeting sexual partners and binge 
drinking.12-15 Notably, event-level analyses of alcohol use immediately before or during sexual 
episodes in two separate systematic reviews consistently found that binge drinking is 
independently associated with increased likelihood of having unprotected sex.4, 5 According to 
event-level analyses for 1,712 HIV-negative MSM, compared to non-binge drinkers, binge 
drinkers had three times the likelihood of having unprotected sex with non-primary partners.35 
These event-level assessments of alcohol use provide the most precise temporal link between these 
two behaviors and provide stronger evidence for causality.5, 24 Binge drinking and other patterns of 
heavy alcohol use are independently associated with a variety of high-risk behaviors in MSM, 
including unprotected anal sex, multiple partners, and having HIV-serodiscordant partners17, 35-44—
a link also observed among black, Native American, and older MSM.45-47 Binge-drinking and 
heavy alcohol consumption are major causes of incident HIV infections in MSM. Binge 
alcohol use was independently associated with a greater than three-fold increase in odds for new 
HIV diagnoses among MSM who had a previously (past 12 months) negative HIV-test in a case-
control study.48 In the Explore study of 4,295 HIV-negative MSM from six metropolitan areas, 
29% of HIV incidence was attributable to use of alcohol or other drugs before sex; 6.1% was 
attributable to heavy alcohol use.7 Similarly, in the Multicenter AIDS Cohort Study of 3725 HIV-
negative MSM, the hazard for seroconversion among heavy drinkers was 61% greater, compared 
to those who abstained from alcohol during the 24 year follow-up (1984-2008).49  


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Figure 1: Hypothesized mechanism of action for naltrexone
 
Behavioral interventions to address binge drinking to date have failed to reach 
MSM. Novel interventions are needed for MSM who binge drink.8 Because excessive alcohol use 
is nearly ubiquitous among MSM and is commonly associated with high-risk sexual behavior and 
HIV infection, interventions that reduce alcohol consumption are likely to have an impact on the 
transmission of HIV. The primary prevention approaches to binge drinking for MSM are therapy 
and alcohol treatment programs. Individual50 and couples51 behavioral therapy approaches have 
been shown to reduce heavy alcohol use among MSM. However, only 20% of MSM who use 
alcohol or non-injection drugs have ever participated in alcohol or drug treatment programs.3 In 
San Francisco, only 16% of binge-drinking MSM have sought alcohol treatment, underscoring the 
need for novel alcohol interventions.18 MSM may be less likely to completely abstain from alcohol 
than heterosexual men,52 emphasizing the need to consider alternative treatment outcomes 
including reductions in drinking. Despite the link between binge drinking and HIV risk, the 
use of pharmacologic interventions to reduce alcohol-intake or alcohol-related sexual risk 
among MSM is almost entirely unexplored. The absence of published studies on efficacious 
interventions to reduce alcohol-related sexual risk behaviors among MSM who have no desire to 
abstain from alcohol presents a major gap in the field of alcohol research and HIV 
prevention. Pharmacotherapy trials for methamphetamine dependence and cocaine dependence in 
MSM have shown that reductions in substance use can result in parallel reductions in HIV-sexual 
risk behaviors among MSM not seeking treatment.53, 54 A pharmacologic intervention for binge 
drinking may lead to an analogous parallel reduction in alcohol-related sexual risks. A critical 
challenge for HIV prevention interventions with MSM is the lack of interventions that reach 
MSM and effectively address HIV risk conferred through unprotected sex for MSM who 
binge drink. 
 
 
 
Naltrexone is an efficacious and 
effective pharmacologic treatment for 
alcohol dependence that blocks the 
reinforcing positive effects of alcohol 
use. Alcohol consumption results in the 
release of β-endorphins that bind and 
activate μ-opioid receptors.55 Naltrexone 
competitively blocks β-endorphins from 
activating μ-opioid receptors56 in the 
nucleus accumbens and ventral tegmental 
area, which mediate dopamine release 
(Figure 1, adapted from 57). Thus, the 
opioid antagonistic mechanism of action 
of naltrexone decreases the activity of the 
dopamine reward pathways,58, 59 tempering the positive neurobiological effects of alcohol.56, 60 
Naltrexone is effective in attenuating the positive subjective effects of alcohol intoxication—
including quality of “high”, craving, and euphoria, supporting its efficacy among current 
drinkers.61-65 A two-year longitudinal study of “heavy social drinkers” who habitually binge drink 
found that the positive subjective and stimulant effects of alcohol are strong predictors of 
sustained and increased binge drinking.66 Given naltrexone’s efficacy in reducing the positive 
effects of alcohol that have been linked to future binge drinking,66 naltrexone may be a 
promising option to reduce binge drinking. Naltrexone is well-tolerated by active alcohol 
drinkers and has no known significant drug interactions.56, 67-70 Naltrexone has few serious side 
effects, no known abuse potential, 68, 69, 71-74 and no known sexual side effects.71 
 
Naltrexone’s pharmacokinetic properties support targeted administration (i.e., use in 
anticipation of heavy alcohol use on an “as needed” basis). Naltrexone’s activity is believed to be 
due to both the parent and the 6-β-naltrexol metabolite.71 Naltrexone reaches peak plasma levels 


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within one hour of oral administration. The mean elimination half-life for naltrexone and 6-β-
naltrexol are four and 13 hours, respectively.71 Naltrexone also has high affinity to the μ-opioid 
receptor (Ki = 2.5 ± 0.21 nM) and a single 50 mg dose can block μ-opioid receptors for up to 72 
hours75 raising the possibility that dosing even 1-2 days prior to anticipated alcohol consumption 
may be effective. Targeted administration of naltrexone on an “as needed” basis has shown 
promise in reducing heavy drinking among heterosexuals. Targeted naltrexone dosing was 
feasible and acceptable in a small pilot study of heavy-drinking young adults not ready or willing 
to abstain from alcohol; the trial completion and targeted medication adherence rates were 93% 
and 83%, respectively.76 Other samples of non-dependent heavy drinkers have also been 
successfully recruited and retained in targeted dosing studies.11, 77-79 Targeted naltrexone 
administered after a period of daily dosing significantly reduced heavy-drinking relapse.80 
Similarly, in a trial conducted by Kranzler, et al., men assigned to targeted naltrexone showed 
significant reductions in mean drinks per day, and in number of drinks during drinking days, 
compared to those assigned to daily naltrexone administration, daily placebo, or targeted 
placebo.11 Intermittent dosing schedules for opioid antagonists like naltrexone show similar 
results: targeted nalmefene reduced heavy drinking days, “very heavy” drinking days, and number 
of drinks during drinking days in randomized controlled trials.81, 82 None of these studies have 
evaluated sexual risk behaviors or exclusively recruited binge drinking MSM at risk for acquiring 
or transmitting HIV. Questions about the efficacy of targeted naltrexone to reduce alcohol-
related sexual risk behavior remain unanswered; no efficacy trial has determined if targeted 
use of pharmacologic agents for binge drinking can reduce HIV risk behavior. 
2 
STUDY RATIONALE 
Oral naltrexone was chosen because we believe it will be more acceptable to non-treatment 
seeking, non-alcohol dependent binge drinking MSM. Intermittent dosing makes sense for most 
binge-drinking MSM because data indicate that they do not binge drink daily. Injectable 
naltrexone's opioid blockade can last a month or more and overcoming the opioid antagonism with 
high opioid doses requires close monitoring and expert personnel.75, 132 Injectable naltrexone is 
also associated with more adverse events than oral naltrexone.132, 133   Oral naltrexone was 
specifically chosen because of its mechanism of action, and safety profile. Dilsufiram is not ideal 
as it requires abstinence,134 which may not be acceptable in our target population. Acamposate has 
been shown to sustain abstinence, although not in intention-to-treat analyses in American 
studies134 and thrice-daily dosing limits its utility.134    
Much like other chemoprophylaxis strategies, intermittent targeted dosing of oral naltrexone will 
not be acceptable to everyone. However, the fact remains that for most MSM, bars, clubs and 
other venues that serve alcohol remain the dominant setting for social interactions with other 
MSM.12-15 For MSM who are interested in reducing binge drinking but do not wish to isolate 
themselves from these venues, targeted dosing of oral naltrexone may be an attractive alternative. 
Indeed, preliminary data from our ongoing pilot, the Project iN study, suggest that taking a 
medication to reduce alcohol consumption is feasible and acceptable among binge-drinking MSM. 
If targeted dosing is efficacious among binge-drinking MSM, it may ultimately expand strategies 
for MSM to reduce their alcohol consumption. 
2.1 
Risk / Benefit Assessment 
Adverse drug effects: A primary risk of participation in this study is the potential of AEs due to 
taking naltrexone. These risks are seen as reasonable, given the favorable side effect profile for 
this medication and the fact that we will exclude persons from the trial who are at higher risk for 
AEs. As part of the informed consent process, participants will be informed of the potential risks 
of taking naltrexone. 


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Naltrexone is well-tolerated and has no known significant drug interactions.54In 
randomized controlled trials, naltrexone has few serious side effects; it has no known abuse 
potential and dependence has not been reported.54, 66, 67, 69-72.  Naltrexone’s activity is believed to be 
due to both the parent compound and the 6-naltrexol metabolite.69 The mean elimination 
half-life of for naltrexone and 6-naltrexol are four and 13 hours, respectively.69 Initial trials 
evaluating the efficacy of naltrexone as treatment for alcohol dependence raised no safety 
concerns.65, 66. Naltrexone was also well-tolerated in subsequent studies in more clinically 
heterogeneous populations with co-morbid conditions.67, 112. Naltrexone has not been shown to 
cause significant increases in complaints in placebo-controlled trials in patients known to be free 
of opioids for more than 7 to 10 days.69. The largest safety study to date on clinical use of 
naltrexone as a pharmacotherapy for treatment of alcoholism was a multi-center safety trial 
involving 865 individuals (500 naltrexone-treated patients, 238 patients in an unmedicated 
control group).68. Results of this study demonstrated that the most commonly reported side effects 
were nausea (9.8%), headache (6.6%), dizziness (4.4%), nervousness (3.8%), and fatigue 
(3.6%); serious side effects were uncommon. 68.  Naltrexone was discontinued in 15% of the 
participants, with nausea being the most common reason for medication discontinuation. 68. Studies 
in alcoholic populations and healthy volunteers have suggested that a small number of patients 
may experience an opioid withdrawal-like symptom complex including tearfulness, mild nausea, 
abdominal cramps, restlessness, arthralgia, myalgia, and nasal symptoms.69Naltrexone has no 
known sexual side-effects69, supporting its potential acceptability for sexually-active MSM. 
Depression, suicidal ideation, and suicide attempts have been reported in both groups when 
comparing naltrexone and placebo for treatment for alcoholism. 69There is no indication that 
naltrexone treatment increases the risk of suicide.63 
 
A review of the literature concluded that in patients treated for heroin or alcohol dependence, 
naltrexone does not cause clinically significant liver disease or exacerbate pre-existing liver 
disease.71. However, naltrexone has the capacity to cause hepatocellular injury in excessive doses 
and is contraindicated in acute hepatitis and liver failure. 69. Patients with these conditions will be 
excluded from our trial. Naltrexone is also contraindicated in patients who are currently dependent 
on opioids or in acute opioid withdrawal. The team anticipates that few participants will be 
excluded by virtue of current opioid use; for example, in our recently published mirtazapine study, 
only 7% of MSM met criteria for opioid dependence. Although the opioid blockade produced by 
naltrexone is surmountable, this situation requires careful medical management by trained 
personnel in settings equipped for resuscitation. Attempts by patients to overcome naltrexone’s 
opioid antagonism may lead to an overdose. Naltrexone may also precipitate severe opiate 
withdrawal, including mental status change, nausea, vomiting, diarrhea, and dehydration in 
patients who are not opioid-free for a minimum of 7 to 10 days. 69. For this reason, urine opioid 
testing is needed to screen all potential participants for opioid use. Patients who have a foreseeable 
need for opioid pain management (e.g. potential elective surgery in the study period) will also be 
excluded. Additionally, all patients will be fully informed verbally and in the written consent form 
about the potential for overdose by attempting to overcome naltrexone’s opioid antagonism. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to determine the efficacy of targeted naltrexone versus placebo in 
reducing binge drinking among non-dependent MSM, as determined by number of binge drinking 
days in timeline follow-back (TLFB) over the three-month treatment period.  
 


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3.2     Secondary Objectives 
To secondary objectives include 1) to determine the efficacy of targeted naltrexone versus placebo 
in reducing alcohol consumption among non-dependent MSM, as determined by the proportion of 
ethyl glucuronide (EtG) positive urines, over the three-month treatment period; 2) to determine the 
efficacy of targeted naltrexone versus placebo in reducing alcohol-associated sexual risk 
behaviors, we will use GEE Poisson models with robust standard errors for the four monthly 
ACASI assessments on numbers of male anal sex partners, HIV-serodiscordant unprotected anal 
sex partners, unprotected anal sex partners while intoxicated with alcohol, and unprotected anal 
sex events with serodiscordant partners, including the baseline value. In the event that these 
outcomes are severely over-dispersed, we will analyze indicators for any self-report of each 
behavior, using GEE logistic models.    
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a double-blind, placebo-controlled, two-arm trial in which 120 binge-drinking MSM will 
be randomly assigned to receive 12 weeks of oral naltrexone 50 mg or placebo, to be taken on an 
as needed basis. This efficacy study will enroll binge-drinking MSM because they are the most 
likely population to benefit from this intervention. A study clinician from the Center for Public 
Health Research (CPHR) will perform the Structured Clinical Interview for the DSM-IV (SCID) 
to determine eligibility and rule out alcohol dependence (the SCID for DSM-V will be used when 
it becomes available). Upon enrollment, 120 participants will be randomized 1:1 to naltrexone or 
placebo for targeted administration. Participants will be seen weekly for behavioral surveys, 
urinalyses, study drug dispensing and alcohol use counseling. Safety laboratory assessment, vital 
signs, and the audio computer assisted survey instrument (ACASI) will be completed monthly. 
Efficacy, tolerability, and acceptability (Specific Aims 1-4) will be assessed upon trial completion 
as measured by number of binge drinking occasions and numbers of drinks on drinking days via 
timeline follow-back at weekly visits; number of ethyl glucuronide-positive urine samples; sexual 
risk behavior data through monthly surveys via ACASI; frequency of adverse clinical events by 
treatment arm, and cumulative medication adherence data at week 12. Primary analyses are 
designed as “intention-to-treat” with evaluation of outcomes according to random assignment, 
regardless of whether participants took the medication.  
 
5 CRITERIA FOR EVALUATION: 
5.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is to detect 27% reductions in numbers of binge drinking 
occasions, as well as 10% reductions in the average numbers of drinks on drinking days among 
treatment arm compared to placebo arm.  Using the assumptions for loss to follow-up for the 
primary endpoint, as well as estimates based on biomarker data from Batki et al’s study on 
Topiramate for alcohol use disorders122 for the within-subject correlation and control group urine 
positivity rate, we estimate that the study will have 80% power in 2-sided tests with a type-I error 
rate of 5% to detect 15-23% reductions in the urine positivity rate in the treatment arm.  The time 
course for the endpoints will be assessed from baseline to end of treatment period.    
5.2 Secondary Efficacy Endpoints: 
The secondary efficacy endpoint is based on estimates of within-subject correlation and control 
prevalence from our Project Echo trial, we estimate that the study will have 80% power to detect 
31% reductions in numbers of male anal sex partners, 57% reductions in SDUA partners, 46% 


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reductions in UA partners while intoxicated with alcohol, and 56% reductions in UA events with 
serodiscordant partners. In analyses using GEE logistic models, we will have 80% power to detect 
reductions of 14%, 38%, 39%, and 30% in any report of these four sexual risk behaviors, 
respectively.      
 
5.3 Safety Evaluations 
Change in clinical laboratory findings, specifically the liver enzymes such as BUN or Creatinine. 
Incidence of adverse events 
6 
SUBJECT SELECTION 
6.1 
Study Population 
120 MSM cis-gender males who binge drink who meet the inclusion and exclusion criteria will be 
eligible for participation in this study.   
6.2 
Inclusion Criteria 
(1) Male gender; 
(2) self-reported anal sex with men in the prior three months while under the influence of alcohol; 
(3) at least one binge drinking (five or more drinks on a single occasion) session per week in the 
prior three months;  
(4) interested in reducing binge alcohol consumption;  
(5) HIV-negative by rapid antibody test or medical record documentation of HIV infection (HIV 
positive participants);   
(6) no current acute illnesses requiring prolonged medical care;  
(7) no chronic illnesses that are likely to progress clinically during trial participation;  
(8) able and willing to provide informed consent and adhere to visit schedule;  
(9) age 18-70 years;  
(10) baseline CBC, total protein, albumin, glucose, alkaline phosphatase, creatinine, BUN, and 
electrolytes without clinically significant abnormalities as determined by study clinician in 
conjunction with symptoms, physical exam, and medical history. 
(11) Written informed consent (and assent when applicable) obtained from subject or 
subject’s legal representative and ability for subject to comply with the requirements 
of the study. 
6.3 
Exclusion Criteria 
(1) Any psychiatric (e.g. depression with suicidal ideation) or medical condition that would 
preclude safe participation in the study;  
(2) known allergy/previous adverse reaction to naltrexone;  
(3) current use of/ dependence on any opioids or a known medical condition which currently 
requires/may likely require opioid analgesics; 
 (4) opioid-positive urine at  enrollment;  
(5) current CD4 count < 200 cells/mm3 ; 


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(6) moderate/severe liver disease (AST, ALT > 3 times upper limit of normal);  
(7) impaired renal function (creatinine clearance < 50 ml/min);  
(8) currently participating in another intervention research study with potential overlap;  
(9) alcohol dependence as determined by SCID criteria (participants with non-dependent alcohol 
use disorders/symptoms of alcohol abuse [per DSM-IV] are eligible)  
(10) any condition that, in the principal investigator and/or study clinician’s judgment interferes 
with safe study participation or adherence to study procedures;  
(11) not having a cell-phone that can send and receive text messages; 
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study period, as 
medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Standard therapy is allowed except for naltrexone treatments and opioid medications as noted in 
the exclusion criteria described above and as noted in the prohibited medications section below.   
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be considered a 
protocol violation: 
1) Opioid medications 
2) Naltrexone treatments 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
The Better Than Study will enroll 120-participants for the double-blinded placebo controlled trial 
where 60 eligible participants will be randomly assigned to the treatment group receiving 
Naltrexone and 60 participants will be randomly assigned to the control group receiving placebo in 
a 1:1 ratio using a computer-generated randomization scheme developed by our biostatistician.  
The study biostatistician will generate a random allocation sequence list with treatment 
assignments associated with order of enrollment, using randomly permuted blocks with randomly 
selected block sizes.  
 
8.2 
Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be known to 
investigators, research staff, or patients.  The following study procedures will be in place to ensure 
double-blind administration of study treatments.   
• 
Access to the randomization code will be strictly controlled.   
• 
Packaging and labeling of test and control treatments will be identical to maintain the blind.  
The study blind will be broken on completion of the clinical study and after the study database has 
been locked.  


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During the study, the blind may be broken only in emergencies when knowledge of the patient’s 
treatment group is necessary for further patient management. When possible, the Investigator 
should discuss the emergency with the Medical Director prior to unblinding.   
 
Describe the procedures for unblinding. 
At the end of the study, the biostatistician will provide us with which study drug kits were 
naltrexone treatment and which study drug kits were placebo.  The study drug kits will be 
compared to the participant enlisted in the study.  Study Staff will inform the participant verbally 
of their study treatment assignment.  For those who do not respond by phone, a letter will be sent 
to their address to inform the participant of their treatment assignment.  
8.3 
Formulation of Test and Control Products 
The Safeway Compounding Pharmacy, which currently prepares our study drug for our ongoing 
clinical trials, will provide the study drug kits for the proposed trial. Drugs are over-capsuled in a 
locking capsule to ensure the same appearance across all study arms and maintain double-blind.  
Formulation of Test Product 
REVIA® (naltrexone hydrochloride tablets USP), an opioid antagonist, is a synthetic congener of 
oxymorphone with no opioid agonist properties. Naltrexone differs in structure from 
oxymorphone in that the methyl group on the nitrogen atom is replaced by a cyclopropylmethyl 
group. REVIA is also related to the potent opioid antagonist, naloxone, or n-allylnoroxymorphone. 
REVIA is a white, crystalline compound. The hydrochloride salt is soluble in water to the extent 
of about 100 mg/mL. REVIA is available in scored film-coated tablets containing 50 mg of 
naltrexone hydrochloride. 
REVIA Tablets also contain: colloidal silicon dioxide, crospovidone, hydroxypropyl 
methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, 
polyethylene glycol, polysorbate 80, synthetic red iron oxide, synthetic yellow iron oxide and 
titanium dioxide. 


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8.3.1 
Formulation of Control Product 
Placebo capsules will contain microcrystalline cellulose (Medisca). Placebo and active medication 
will be provided in capsules that are an exact match in color, so as to make the placebo and active 
medication indistinguishable from each other. 
 
8.3.2 
Packaging and Labeling 
Study drug was initially provided by UCSF Compounding and Research Support Pharmacy, 3333 
California Street, Suite 216E, San Francisco, CA, 94118. Since that pharmacy has closed, Safeway 
Compounding Pharmacy, 6100 Hellyer Ave Ste 100, San Jose, CA, 95138, is used to provide 
study drug. Each treatment bottle from the UCSF pharmacy was labeled with the study drug 
number, prescribing physician name (medical director), required FDA warning statement, 
emergency pager number, directions for participant use and storage, and expiration information. 
Each treatment bottle from Safeway pharmacy is labeled with the study drug number, principal 
investigator name, prescribing physician name (medical director), required FDA warning 
statement, emergency pager number, directions for participant use and storage, and lot and 
expiration information. 
 
Sample label from UCSF Pharmacy: 
 
 
 
 
 
 
 
 
 
8.4 
Supply of Study Drug at the Site 
Study medication will be supplied to the Center on Substance Use and Health (CSUH) on an as-
needed basis, usually 5 or 10 study drug kits at a time. A record of drug receipt will be kept in the 
investigational drug accountability log. Study drug will be stored in a locked pharmacy with 
temperature monitoring. Study drug kits provided by the pharmacy will already be randomized, so 
blinding will be maintained for all staff at the study site. 
8.4.1 
Dosage/Dosage Regimen 
The dose of naltrexone being investigated for potential as a pharmacotherapeutic on an as-needed 
basis to reduce binge drinking is 50 mg. It is recommended participants take one capsule of 
medication by mouth 1 to 2 hours before starting an episode of binge drinking. Participants will be 
instructed to take no more than one capsule in a 24-hour period. No adjustments for weight, age, 
or meals is required. The dose of naltrexone being investigated for potential as a 
pharmacotherapeutic on an as-needed basis to reduce binge drinking is 50 mg. It is recommended 
participants take one capsule of medication by mouth 1 to 2 hours before starting an episode of 
binge drinking. Participants will be instructed to take no more than one capsule in a 24-hour 
period. No adjustments for weight, age, or meals is required. 
 


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8.4.2 
Dispensing 
Study medications will be dispensed by the study clinician (licensed medical practitioner) in 
treatment bottles that are labeled with the study drug number, principal investigator name, 
prescribing physician name (medical director), required FDA warning statement, emergency pager 
number, directions for participant use and storage, and lot and expiration information. 
 
Further, at time of study drug dispensing, the study clinician will review with the participant how 
to take the study medication, possible side effects they may encounter, and how to access the 
study clinician by emergency pager if necessary. The study clinician will also answer any 
questions the participant might have. 
8.4.3 
Administration Instructions  
Training on targeted medication dosing:  
During enrollment, participants will be trained on medication dosing and be provided a brief 
instructional leaflet for reference. Participants will be encouraged to intermittently use at least 3 
capsules per week, when they believe that drinking is imminent or anticipate a session of binge 
drinking. At baseline and follow-up visits, study staff will assess each participant’s drinking 
pattern and develop a plan to support intermittent dosing of study drug and maximize medication 
efficacy. Participants will be given twenty-eight 50 mg tablets per month and will be instructed to 
not exceed 1 tablet every 24 hours. This dosing is similar to the usual administration of naltrexone 
for alcohol dependence, except that participants will be taking study drug on an as needed basis 
instead of daily. Participants will be briefed about the importance of not sharing medications. We 
will offer participants a wallet card that explains that they may be taking naltrexone. The card 
provides contact information for medical professionals to seek further information from the study 
clinician should they have questions. 
 
8.4.4 Storage 
Study drug should be stored by the study site at controlled room temperature, Store at 15° to 
30°C (59° to 86°F).  If the temperature of study drug storage in the clinic/pharmacy exceeds or 
falls below this range, this will be reported to the research program manager and PI and captured 
as a deviation. Subjects will be instructed to store the medication in the MEMs cap containers at 
room temperature according to the instructions outlined on the Drug Administration Instructions. 
8.5  Study Drug Accountability 
An accurate and current accounting of the acquisition, dispensing, return, and destruction of study 
drug for each participant will be maintained in an investigational drug accountability log by study 
staff throughout the course of the study. 
8.6 Measures of Treatment Compliance 
Study medications will be dispensed by the study clinician in MEMS cap dispensers with dosing 
instructions, date of dispensing, prescribing clinician, a 24-hour telephone study phone number for 
medical emergencies, and advisements against drug combinations.  Each dispenser opening is 
recorded as a medication event in a remote database in real time. MEMs cap dispensers have been 
shown to be reliable for real time monitoring of medication adherence, even in resource-limited 
settings.117 We have had great success with electronic medical monitoring devices in prior studies 
among MSM.53, 84 The Subjects will be asked to bring in their study drug at in-office visits.  The 
Subjects will be asked to document any adverse events that occur during the week.  
 


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9. STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the duration 
of the study.  Prior to conducting any study-related activities, written informed consent and the 
Health Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be obtained 
prior to conducting any study-related activities. 
 
9.1 Clinical Assessments 
9.1.1 Concomitant Medications   
All concomitant medication and concurrent therapies will be documented at Baseline/Screening 
and at Month 1, Month 2 and Month 3 safety lab visits.  Dose, route, unit frequency of 
administration, and indication for administration and dates of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases will be recorded at Screening. 
9.1.4 Physical Examination 
A complete physical examination will be performed by the clinician at Enrollment, Month 1, 
Month 2 and Month 3 visits.   Qualified staff (MD, NP, RN, and PA) may complete the 
abbreviated physical exam at all other visits.  New abnormal physical exam findings must be 
documented and will be followed by a physician or other qualified staff at the next scheduled visit. 
9.1.5 Vital Signs 
Body temperature, blood pressure, pulse and weight will be performed after resting for 5 minutes 
on Screening, Enrollment and Month 1, Month 2 and Month 3 visits.  
9.1.6 Safety Lab Assessment 
Safety lab assessments will take place at screening, months 1, 2, and 3 visits.  Blood specimens 
will be collected for monthly safety lab assessments via venipuncture by clinicians or research 
associates with certified phlebotomy training. Medications taken 30 days prior to enrollment and 
while enrolled in the study will be documented on a concomitant medications form. 
9.1.7 HIV risk reduction counseling and testing 
All participants will receive standard HIV risk reduction counseling at enrollment and month 3 
with HIV rapid antibody test and pooled viral load (HIV-negative participants) and CD4 testing 
(HIV-positive participants).104 Participants with positive rapid tests will be given a confirmatory 
Western Blot assay and will receive HIV-counseling and referrals to HIV service providers. 
Participants newly diagnosed with HIV at screen will be referred to community resources and will 
be contacted for rescreening in the subsequent month. 


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9.2 Other Clinical Procedures 
9.2.1 Medical Management (MM) counseling for alcohol use:  
This study’s aim is to determine efficacy of a pharmacologic intervention to reduce binge 
drinking, against a background of relatively brief counseling that would be feasible in a clinical 
setting with limited resources. Thus, we will adapt a manualized version of the MM brief 
counseling platform used in NIAAA’s COMBINE study.72, 105 In that trial, naltrexone with MM 
showed the most significant reductions in heavy drinking days (Hazard Ratio: 0.72; p=0.02) 
compared to 7 other treatment conditions.72 MM has been used in a targeted pharmacotherapy 
trial81 and our team has successfully used MM in alcohol pharmacologic trials. MM is a low-
intensity supportive program designed to increase problem recognition and enhance motivation to 
change maladaptive alcohol use patterns. Participants will receive individual 20 minute MM 
sessions weekly from trained staff supervised by a clinical psychologist, with monthly quality 
assurance sessions. 
9.2.2 Behavioral survey measurements:   
Standardized and validated behavioral measures106-109, 111, 112, 115 will be assessed using audio 
computer administered surveys (ACASI) to minimize underreporting of risk activities and 
standardize data collection.106, 107 To minimize potential social desirability bias, staff will not have 
access to data during the trial.  
 
9.2.3 Measures of adherence:  
The study will collect self-reported adherence via weekly modified TLFB assessments, similar to 
prior targeted naltrexone studies11, 81 and via daily SMS text messages. Pill counts at weekly visits 
will also assess adherence. MEMs cap dispensers will be used to track medication adherence 
daily; each dispenser opening is recorded as a medication event in a remote database in real time. 
MEMs cap dispensers have been shown to be reliable for real time monitoring of medication 
adherence, even in resource-limited settings.117 We have had great success with electronic medical 
monitoring devices in prior studies among MSM.53, 84 
 
9.2.4 Ecological Momentary Assessments:  
As with our Project iN pilot study, participants will receive daily SMS texts to collect data on 
alcohol consumption, number of drinks on drinking days, and targeted medication administration 
prior to anticipated drinking sessions. Messages will use short-hand notations to maintain 
participant confidentiality. Participants will be trained on text-messaging procedures and receive a 
reference guide during enrollment (see sample from Project iN study in the appendix). Participants 
will be encouraged to regularly delete text messages and encrypt their phone with passwords for 
privacy.  
 
9.2.5 Adverse Events 
Potential AEs will be monitored using a checklist of most common AEs associated with 
naltrexone similar to prior Phase IV naltrexone studies11 and will follow the “Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events” and UCSF IRB  reporting 
guidelines.116 Safety monitoring will include the assessment, follow-up, and reporting of 
clinical/serious AEs (start and stop dates and times), severity/grade, outcome, treatment and 
relation to study drug will be recorded on the case report forms as well as in the electronic 
database. 


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9.3 Clinical Laboratory Measurements  
9.3.1 Hematology 
Blood will be obtained and sent to San Francisco General Hospital laboratory for a complete blood 
count (hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell 
differential, and platelet count). 
9.3.2 Blood Chemistry Profile 
Blood will be obtained and sent to San Francisco General Hospital Laboratory for determination 
of (list as applicable) serum sodium, potassium, chloride, bicarbonate, random glucose, BUN, 
creatinine, aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), 
alkaline phosphatase, total bilirubin, direct bilirubin, gamma-glutamyl transferase (GGT), albumin 
and LDH. 
9.3.4 Pregnancy Test 
A urine pregnancy test will be obtained from female subjects who are of childbearing age prior to 
their participation in the study and during the safety lab visits at month 1, month 2 and month 3 
visits. 
9.3.5 Urinalysis 
9.3.5.1 Urinalysis for other classes of substance use: Urine samples will be collected weekly 
and tested for methamphetamine, cocaine, opioids, and other substances of abuse using MEDTOX 
EZ-SCREEN cups. Positive results will be confirmed by further urine testing through the 
laboratory at San Francisco General Hospital. 
 
9.3.5.2 Urinalysis for novel alcohol biochemical markers: Urine samples will be collected at 
enrollment and monthly and tested for ethyl glucuronide (EtG) to determine recent alcohol 
consumption. EtG is a relatively novel, highly sensitive indicator for recent alcohol consumption; 
this alcohol biomarker is detectable in urine for approximately 72 hours).118-121 The PI has used 
EtG to evaluate the efficacy of another pharmacologic intervention in reducing alcohol 
consumption in a trial funded by the Department of Defense 122 with Dr. Batki, a consultant in the 
proposed study. Urine samples will be tested via liquid chromatography-mass spectrometry 
through the Redwood Toxicology Laboratory, Inc., the same lab used by Dr. Batki’s ongoing 
pharmacologic trials on alcohol dependence at the San Francisco Veteran’s Affairs Medical 
Center. EtG quantitative results will be dichotomized using established cutoff values 
recommended by the Substance Abuse and Mental Health Services Administration (SAMHSA) to 
distinguish between positive and negative specimens.119, 121 Whenever possible we will schedule 
participants for their weekly visits on Mondays and Tuesdays, given that binge drinking is likely 
to be higher over the weekend compared to the remainder of the week. 
9.3.6 Dried Blood Spot (DSB) Testing for Phosphatidyethanol:  
Phosphatidylethanol (PEth)—a phospholipid formed only in the presence of alcohol—is a novel, 
direct biochemical marker of alcohol that has shown high (>95%) sensitivity and specificity to 
detect heavy drinking over a period of 2-3 weeks in several studies of dependent patients and 
abstainers. In persons with HIV, recent validation studies found that PEth, using a cutoff of >8 
ng/mL, was 88% sensitive and 89% specific for alcohol consumption in the prior 21 days (3 
weeks), and 95% sensitive and 73% specific for heavy alcohol consumption (i.e., exceeding the 
NIAAA cutoffs). DSB samples will be collected at enrollment, weeks 3, 6, 9, 12, and post-


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treatment visits at month 1, 3, and 6. Staff will use sterile lancets for fingersticks (or we will 
aliquot blood from a venipuncture specimen tube) to collect drops of blood (less than 5ml) to 
apply onto Whatman 903 filter paper (Whatman, Maidstone, UK). Samples will be dried overnight 
inside a drying box using standardized methods. PEth testing of DBS samples will be conducted at 
the United States Drug Testing Laboratories in Des Plaines, IL, one of the few laboratories that 
conduct this test worldwide. The testing will be conducted using an Agilent 6460 liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) system following extraction into 
methanol, as previously published. 
 
9.3.7 Genetic and Biomarker Testing: Blood samples will be stored at the University of 
California San Francisco, School of Nursing Genomics Lab for future genetic, epigenetic and 
micro RNAstudies, as well as other studies that elucidate the biologic processes by which alcohol 
use may contribute to morbidity and mortality. Research studies will be restricted to health 
conditions associated with alcohol use. These may include testing to determine the presence of the 
A118G SNP and other mutations relevant to the moderation of naltrexone’s effects on the μ-opioid 
receptor gene (OPRM1). Additionally, we may test for the expression of biomarkers associated 
with innate immune activation (i.e., sCD14, neopterin, and tryptophan/kynurenine ratio) and 
inflammation (i.e., IL-6, TNF- R1). 
10 EVALUATIONS BY VISIT 
10.1 VISIT 1 (SCREENING VISIT—WEEK 1 ) 
Review the study with the subject (subject’s legal representative) and obtain written informed 
consent and HIPAA authorization and assent, if appropriate. 
Assign the subject a unique screening number. 
Record demographics data. 
Record medical history, including a history of mental health, sexual behaviors and substance use, 
diagnosis date, and prior Alcohol treatments. 
Record concomitant medications. 
Perform a complete physical examination. 
Collect urine sample for alcohol, opiates, and other substances test.  If capable of becoming 
pregnant then a pregnancy test.  Record results. 
10.2 Visit 2 (Screening Visit – week 2) 
Perform and record vital signs. 
Perform and record results of blood pressure testing. 
Collect blood for clinical laboratory tests (chemistry, hematology, HIV test, pooled viral load test.  
If HIV positive, a CD4 test). 
Collect blood for Genetic and Biomarker Testing if you agreed to participate in a genetic and 
biomarker sub-study that will involve storage of blood samples to be used for testing. Testing will 
be confined for genes and biomarkers of health conditions related to alcohol use.  
Collect and record contact information 
10.3 Visit 3 (Enrollment Visit – month 1) 
 Assign randomization.  You are assigned by a computer by chance to either thnaltrexone or 
placebo groups.  
Collect urine to test for alcohol, opiates, and other substances.     


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If capable of becoming pregnant, we will collect urine and perform a pregnancy test. 
Provide study medication (naltrexone or placebo) in medical monitoring devices (“MEMS” 
containers). MEMS devices will record each time you open the container to retrieve a study 
medication capsule.   
Provided with a Wallet Card that explains that you may or may not be on a study medication 
(naltrexone or placebo). This card will provide the study clinician’s pager number who can 
provide information to other doctors in the event of an emergency.  The card will also instruct the 
emergency room or other doctor providing treatment to provide information to the study clinician 
about the care they provide. 
Collect blood sample to test for alcohol (PEth test). 
Perform ACASI questionnaire on a computer.   
Meet with counselor about alcohol consumption 
Initiate Ecological Momentary Assessments 
10.4 Visit 4 (weeks 1, 2, 3, 5, 6, 7, 9, 10, and 11)) 
Record any Adverse Experiences and dosing compliance by downloading MEMs cap dispenser. 
Meet with the counselor regarding alcohol consumption and use of the study medication. 
Collect urine sample to test for alcohol, opiates and other substances.  If capable of becoming 
pregnant, we will also conduct a pregnancy test. 
Answer ACASI questions on a compute 
Receive the study medication: if needed, you will be given more of the study medication (except 
at the week 12 visit). 
Meet with the study doctor or nurse: to talk about any problems with the study medication or any 
changes in your health or medications if needed. A physical exam may be done.  
Collect a blood sample (weeks 3, 6, & 9): to test for alcohol. A few drops of blood will be 
collected by a lancet stick to your finger or a venipuncture blood draw.  
 
10.5 Visit 5 (Month 1, 2 and 3 with visit window 2 weeks before visit and 2 weeks 
after visit) 
All the same procedures as the weekly visits PLUS these additional procedures:  
Answer ACASI questions on a computer about your mood, your recent sexual behavior and 
drug use, and your feelings about being in the study.  
Record any Adverse Experiences and dosing compliance. 
Record changes to concomitant medications. 
Meet with the study doctor or nurse: to talk about any problems with the study medication or 
any changes in your health or medications if needed. A physical exam may be done. 
Collect blood for clinical laboratory tests (chemistry, hematology).  At month 3 visit, collect 
blood for HIV test, pooled viral load test.  If HIV positive, a CD4 test. 
Collect a blood sample: to test for alcohol. A few drops of blood will be collected by a lancet 
stick to your finger or a venipuncture blood draw.  


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10.6 Early Withdrawal Visit 
Record any Adverse Experiences and/or Review subject diary for adverse experiences and 
exclusionary medication use. 
Record changes to concomitant medications. 
Perform complete physical examination. 
Perform and record vital signs. 
Collect blood for clinical laboratory tests:  Chemistry, Hematology, Urinalysis, Pregnancy (urine 
or serum). 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with the treatment.  An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether or not related to that investigational product.  An 
unexpected AE is one of a type not identified in nature, severity, or frequency in the current 
Investigator’s Brochure or of greater severity or frequency than expected based on the information 
in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each 
subject visit and record the information in the site’s source documents.  Adverse events will be 
recorded in the patient CRF.  Adverse events will be described by duration (start and stop dates 
and times), severity, outcome, treatment and relation to study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0 should be used to assess and grade AE severity, including laboratory abnormalities 
judged to be clinically significant. The modified criteria can be found in the study manual.  If the 
experience is not covered in the modified criteria, the guidelines shown in Table 1 below should 
be used to grade severity.  It should be pointed out that the term “severe” is a measure of intensity 
and that a severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 


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AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines 
in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per UCSF 
CHR Guidelines.  The collection period for all SAEs will begin after informed consent is obtained 
and end after procedures for the final study visit have been completed. 
11.3  Medical Monitoring 
John Walker, RN, FNP-C, research clinician, should be contacted directly at these numbers to 
report medical concerns or questions regarding safety. 
 


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Phone:  (628) 217-6227 
 
 
 
Pager:  (415) 356-8980 
 
Phillip Coffin, MD MIA FACP FIDSA, medical director, should be contacted directly at this 
number to report medical concerns or questions regarding safety. 
Phone: (510) 407-2603  
   
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject or the investigator 
feels that it is not in the subject’s best interest to continue.  The following is a list of possible 
reasons for study treatment discontinuation: 
Subject withdrawal of consent (or assent) 
Subject is not compliant with study procedures 
Adverse event that in the opinion of the investigator would be in the best interest of the subject to 
discontinue study treatment 
Protocol violation requiring discontinuation of study treatment 
Lost to follow-up 
PI or clinician request for early termination of study 
Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and 
treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation visit as 
soon as possible and then should be encouraged to complete all remaining scheduled visits and 
procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  
The reason for the subject’s withdrawal from the study will be specified in the subject’s source 
documents Refer to Section 10 for early termination procedures. 
12.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject or the investigator feels that 
it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  
The reason for the subject’s withdrawal from the study will be specified in the subject’s source 
documents.  As noted above, subjects who discontinue study treatment early (i.e., they withdraw 
prior to Week 8 Visit ) should have an early discontinuation visit. Refer to Section 10 for early 


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termination procedures.  Subjects who withdraw after Week 8 Visit  but prior to Week 12 Visit  
should be encouraged to come in for a final visit (and the procedures to be followed would include 
those for their next scheduled visit).   
12.3 Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant protocol 
requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria.  
Protocol violations for this study include, but are not limited to, the following: 
Failure to meet inclusion/exclusion criteria 
Use of a prohibited concomitant medication (such as opiate medications) 
 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The PI will determine if a protocol violation will result in withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a Sponsor 
representative and the Investigator. A copy of the form will be filed in the site’s regulatory binder 
and in the Sponsor’s files. 
14 DATA SAFETY MONITORING  
The PI along with the site physician Dr. Coffin, will be responsible for ensuring proper monitoring 
of the safety and efficacy of this trial, including the execution of the DSM plan, and complying 
with the reporting requirements, including reports to the IRB, DSMB, NIDA and (where 
applicable) the FDA (see Figure 1 below). 
 
The research team including the PI, clinicians, data manager, research associates, and recruitment 
coordinator, meets weekly to discuss all aspects of the study such as recruitment and retention, 
clinical or counseling issues, and any regulatory or operation issues.  All study documents are 
monitored by the study coordinator for quality assurance on a weekly basis to ensure timely 
 
PI (Santos) and 
Medical 
Director 
(Coffin) 
oversight: 
reports to IRB, 
NIDA, and FDA 
as required 
Subjects enroll and complete study visits 
Medical staff members evaluate subjects during 
trial 
Figure 1: 
Initial protocol review: NIDA, IRB; 
approve data safety monitoring process 
for the trial
DSMB: Two 
members review 
medical progress; 
statistician reviews 
symptom 
complaints; reports 
to PI (Santos), IRB, 
NIDA, FDA as 
required 
 


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corrections to charting such as missing initials or cross-outs with error-correction.  Although there 
is no outside monitor, the clinicians review each other’s charts for accuracy, consistency, and 
adherence to protocol. Regular audits will be conducted as well on consent forms, laboratory logs 
and other data collection forms. 
 The interim DSMB report will contain a brief description of the trial, baseline socio‐demographic 
characteristics of participants, retention and disposition of study participants, a description of any 
quality assurance or regulatory issues, a report of AEs and SAES, and the status of outcome data.  
 Members and affiliation:  We will use the existing University of California, Los Angeles (UCLA) 
Data & Safety Monitoring Board for Addiction Medicine (DSMBAM), which has extensive 
experience in monitoring pharmacologic interventions, including among vulnerable populations. 
The DSMBAM has monitored all of our pharmacologic trials for substance users.    
 To ensure that the DSMB oversight of the study remains independent from the proposed study, 
the PI(Santos) as well as others who serve on the DSMBAM that might be linked with the study in 
some way recuse themselves from review of the present study.  
 The purpose of the DSMBAM is to provide oversight and monitoring of Phase I and Phase II 
clinical trials of pharmacological and behavioral treatments for stimulant dependence. There are 
three fundamental charges of the board, which are:  
• 
To ensure the safety of trial participants   
• 
To preserve validity and integrity of research data   
• 
To facilitate the availability of timely as well as reliable findings to the broader clinical 
community   
Below are members who serve as committee chairs as well as clinical research experts:  
• Steven Shoptaw, PhD, is Professor in both the Department of Family Medicine and the 
Department of Psychiatry and Biobehavioral Sciences at UCLA. Over the past 20 years, Dr. 
Shoptaw has conducted a series of clinical studies in community clinic settings, primarily on 
topics that involve developing medical and behavioral interventions to treat substance abusers.  
• Timothy M. Hall, MD, PhD, is Health Sciences Assistant Clinical Professor at UCLA 
Department of Family Medicine and Center for Behavioral and Addiction Medicine. His research 
expertise is in sexual identity formation, social/sexual MSM networks, non-gay-identified MSM, 
ethnography and MSM substance use.  
• Gayle Baldwin, PhD, is Associate Professor in the Department of Medicine at the University of 
California, Los Angeles. Her research focuses on how specific immune cells fight infectious 
diseases and cancer.  
• Dominick Frosch, PhD, is an Associate Staff Scientist in the Department of Health Services 
Research at the Palo Alto Medical Foundation’s Research Institute. He is also an Assistant 
Professor of Medicine at the University of California, Los Angeles. His research is focused on 
developing and implementing interventions to increase patient participation in clinical decision 
making and understanding the effects of health information in the media on behavior.  
 
Below are members who serve as experts in biostatistics and epidemiology:  
• Scott Comulada, PhD  
• Sung-Jae Lee, PhD  
• Jesse Fletcher, PhD  


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Below are members who serve as clinical research experts:  
• Adam Carrico, PhD  
• David Farabee, PhD  
• Timothy Fong, MD  
• Liz Evans, PhD  
• Lara Ray, PhD  
 
Administrative support staff:  
• Uyen Kao, MPH, Director  
• Oluwadamilola O. Jolayemi, MSc, Coordinator  
 
The DSMC evaluates known risks to subjects’ participation, the safety of the subjects as pre-
specified in the protocol, and monitors the operational performance of the trial. The DSMC makes 
recommendations to continue, amend, or terminate the trial based on their findings. 
Recommendations are made in writing to the study investigators. The DSMC are given blinded 
trial data, but may request unblinding if safety data warrant. The initial review includes a review 
of the following items: statement of the protocol design, characteristics of the study data collection 
site, inclusion/exclusion criteria, randomization plan, definition of participants (e.g., screened, 
enrolled, randomized, treated, drop-out, lost to follow-up), intervention definition, dosage and 
frequency of study drug, reasons to discontinue study or to terminate individual participants, 
reasons to discontinue treatment, outcome measures, sample size target, key adherence and safety 
variables, and the data analysis plan.  
Subsequent ongoing reviews include: enrollment data, including those screened, enrolled, and 
active; subject eligibility; demographic characteristics of participants (total, and by group), 
recruitment and retention (total and by group). Protocol compliance are evaluated by reviewing: 
the expected recruitment rate, study drop-outs and reasons for leaving the study, data quality 
assurance reports, overall data flow procedures, CRFs collected, received, and entered; protocol 
deviations; protocol violations; missing data; staff omissions; subject refusal to provide data; 
adherence to stopping rules. The data safety report are provided in total and by group, and include 
any relevant medical, psychosocial or laboratory data, AEs summarized in tables, individual SAE 
reports, concomitant medications, and concomitant illnesses. The outcome data report includes 
outcome data analyzed by group, masked or unblended, with or without statistical analyses, and 
include all outcome variables. 
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed.  The SAP will contain any modifications to 
the analysis plan described below.   
15.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least one dose of the study 
drug (the Safety Population) will be included in the safety analysis. 


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15.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized by treatment group: race, 
gender, age, educational attainment, employed, and HIV positivity.  
15.3 Analysis of Primary Endpoint 
To determine the efficacy of targeted naltrexone versus placebo in reducing binge drinking among 
non-dependent MSM, as determined by number of binge drinking days in timeline follow-back 
(TLFB), by arm. GEE Poisson models with robust standard errors will be used to assess reductions 
on weekly drinking outcomes. Baseline TLFB results will be included in the analysis.   Minimum 
detectable effects (MDEs): In calculating minimum detectable effects, we hypothesized on 
pharmacologic grounds that oral naltrexone will reach full efficacy against alcohol use almost 
immediately; accordingly we expect treatment-control differences to be approximately constant 
over the 12 weeks of the trial. Based on the prior trial (93% retention), we estimate that 90% of 
participants will be retained at 12 weeks. Using estimates based on data from Project ECHO92 for 
the within-subject correlation and over-dispersion of the outcomes, as well as the mean frequency 
among controls, we estimate that the proposed study will have 80% power in 2-sided tests with a 
type-I error rate of 5% to detect 27% reductions in numbers of binge drinking occasions, as well as 
10% reductions in the average numbers of drinks on drinking days.   
To determine the efficacy of targeted naltrexone versus placebo in reducing alcohol consumption 
among non-dependent MSM, as determined by the proportion of ethyl glucuronide (EtG) positive 
urines, by arm.  GEE logistic models with robust standard errors will be used to assess reductions 
frequency of positive urine tests, accounting for within-subject correlation.   MDEs: Using the 
assumptions for loss to follow-up for Aim 1, as well as estimates based on biomarker data from 
Batki et al’s study on Topiramate for alcohol use disorders122 for the within-subject correlation and 
control group urine positivity rate, we estimate that the study will have 80% power in 2-sided tests 
with a type-I error rate of 5% to detect 15-23% reductions in the urine positivity rate in the 
treatment arm. 
15.4 Analysis of Secondary Endpoints 
The analysis of the secondary endpoint to determine the efficacy of targeted naltrexone versus 
placebo in reducing alcohol-associated sexual risk behaviors, we will use GEE Poisson models 
with robust standard errors for the four monthly ACASI assessments on numbers of male anal sex 
partners, HIV-serodiscordant unprotected anal sex partners, unprotected anal sex partners while 
intoxicated with alcohol, and unprotected anal sex events with serodiscordant partners, including 
the baseline value. In the event that these outcomes are severely over-dispersed, we will analyze 
indicators for any self-report of each behavior, using GEE logistic models.   MDEs: Based on 
estimates of within-subject correlation and control prevalence from our Project Echo trial, we 
estimate that the study will have 80% power to detect 31% reductions in numbers of male anal sex 
partners, 57% reductions in SDUA partners, 46% reductions in UA partners while intoxicated with 
alcohol, and 56% reductions in UA events with serodiscordant partners. In analyses using GEE 
logistic models, we will have 80% power to detect reductions of 14%, 38%, 39%, and 30% in any 
report of these four sexual risk behaviors, respectively.    
Safety and tolerability data will be summarized by treatment group.   
Adverse event rates will be coded by body system and MedDra classification term.  Adverse 
events will be tabulated by treatment group and will include the number of patients for whom the 
event occurred, the rate of occurrence, and the severity and relationship to study drug.   


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15.5 Interim Analysis 
There will be no interim analysis 
15.6 Sample Size and Randomization 
120 participants will be enrolled in the study.   
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug.   
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that 
visit is available.  Subjects will not be identified by name in the study database or on any study 
documents to be collected by the Sponsor (or designee), but will be identified by a  subject 
number and initials. 
For paper CRFs:  If a correction is made on a CRF, the study staff member will line through the 
incorrect data, write in the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this study.  All 
data collected during the course of this study must be reviewed and verified for completeness and 
accuracy by the Investigator.  A copy of the CRF will remain at the Investigator’s site at the 
completion of the study. 
16.2 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database lock will 
occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries are entered, 
tracked, and resolved through the EDC system directly.  For paper studies: Query reports (Data 
Clarification Requests) pertaining to data omissions and discrepancies will be forwarded to the 
Investigators and study monitors for resolution.  The study database will be updated in accordance 
with the resolved queries.  All changes to the study database will be documented. 
16.4 Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained.  
Databases are backed up by the database administrator in conjunction with any updates or changes 
to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures. 


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16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, UCSF IRB, and Regulatory 
Agency (e.g., FDA) inspectors upon request.  A file for each subject must be maintained that 
includes the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all 
source documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of two years following marketing of the 
investigational product or for two years after centers have been notified that the IND has been 
discontinued.  There may be other circumstances for which the Sponsor is required to maintain 
study records and, therefore, the Sponsor should be contacted prior to removing study records for 
any reason. 
16.6 Monitoring 
Monitoring visits will be conducted by representatives according to the U.S. CFR Title 21 Parts 
50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing this protocol, the Investigator 
grants permission) and appropriate regulatory authorities to conduct on-site monitoring and/or 
auditing of all appropriate study documentation. 
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a  subject number and subject initials will 
identify all study subjects on CRFs and other documentation submitted to the Sponsor.  Additional 
subject confidentiality issues (if applicable) are covered in the Clinical Study Agreement. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  All study records will be kept in a locked 
file cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet.  Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by the FDA.  The 
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the PI.  Protocol amendments cannot be 
implemented without prior written IRB/IEC approval except as necessary to eliminate immediate 
safety hazards to patients.  A protocol amendment intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately, provided the IRBs are notified within five 
working days. 
17.2 Institutional Review Board 
The protocol and consent form will be reviewed and approved by the IRB prior to study 
initiation.  Serious adverse experiences regardless of causality will be reported to the IRB 


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in accordance with the standard operating procedures and policies of the IRB, and the 
Investigator will keep the IRB informed as to the progress of the study.  The Investigator 
will obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB.  The IRBs written unconditional approval of the study 
protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB unconditional approval statement will be 
transmitted by the Investigator.  This approval must refer to the study by exact protocol 
title and number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB and written verification that the 
modification was submitted and subsequently approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if 
applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the 
IRB/IEC.  The consent form generated by the Investigator must be acceptable to the Sponsor and 
be approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will also 
comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the 
Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form and 
subjects (or their legal representatives) must be given ample opportunity to inquire about details of 
the study.  If appropriate and required by the local IRB, assent from the subject will also be 
obtained.  If a subject is unable to sign the informed consent form (ICF) and the HIPAA 
authorization, a legal representative may sign for the subject.   A copy of the signed consent form 
(and assent) will be given to the subject or legal representative of the subject and the original will 
be maintained with the subject’s records. 


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17.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions.  The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996.  
17.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. 
Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. 
Personally conduct or supervise the study (or investigation). 
3. 
Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. 
Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. 
Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. 
Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
9. 
Seek IRB approval before any changes are made in the research study, except when necessary 
to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 


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APPENDIX 1.  STUDY PROCEDURES 
 
 
 
a  
±2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 2:  REFERENCES 
1. 
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2. 
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TABLE 2. Study Procedures 
 
Visit Type 
 
SCR 
BL 
Wk 
Mos. 
1 & 2 
Mo. 3 
Informed consent 
X 
 
 
 
 
Safety lab assessment 
X 
 
 
X 
X 
Rapid HIV test* or CD4 
X 
 
 
 
X 
HIV risk reduction counseling 
X 
 
 
 
X 
Complete medical history, 
physical exam & SCID 
X 
 
 
 
 
Vital signs, weight  
X 
X 
 
X 
X 
Symptom driven physical exam 
 
X 
 
 
X 
Targeted Medication Training 
 
X 
 
 
 
Text messaging (SMS) 
Training 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
Urine testing for opiates 
X 
X 
 
 
 
Urine testing for ethyl 
glucuronide  (ETG) 
X 
X 
X 
X 
X 
Audio Computer Assisted 
Survey Instrument (ACASI) 
 
X 
X 
X 
X 
Adverse event assessment 
 
 
X 
X 
X 
Alcohol Use Medical 
Management Counseling  
 
X 
X 
 
 


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