Conditions: Alcohol Use Disorder
Keywords: harm reduction, naltrexone, alcohol use disorder, homelessness
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 308
Healthy volunteers: no

Brief summary:
The goal of this study is to test the efficacy of extended-release naltrexone and harm reduction counseling in reducing alcohol-related harm among homeless people with alcohol dependence.

Detailed description:
Homelessness and alcohol dependence are commonly co-occurring and serious public health issues. Unfortunately, abstinence-based alcohol treatment approaches are minimally effective in engaging and successfully treating homeless individuals with alcohol dependence. There have therefore been calls for more flexible and client-centered approaches tailored to this population's needs. Innovative, low-barrier approaches (e.g., Housing First and alcohol management programs) have been applied with this population and are efficacious in reducing alcohol use and related problems as well as utilization of publicly funded services and associated costs. Such approaches have been referred to as harm-reduction interventions because they focus on reducing alcohol-related harm for affected individuals and their communities without requiring a commitment to abstinence-based goals. Although psychosocial, harm-reduction approaches are beginning to proliferate for this population, there are few pharmacological counterparts to support and enhance these efforts. One medication that could address this treatment gap is extended-release naltrexone (XR-NTX; marketed as Vivitrol®). XR-NTX is a 30-day, extended release formulation of the opioid receptor antagonist, naltrexone, and is administered monthly via gluteal intramuscular injection. The proposed Phase II study features a four-arm RCT (N=300) designed to test the efficacy of XR-NTX as a pharmacological adjunct to existing psychosocial harm-reduction services provided by community agencies to homeless people with alcohol dependence. The proposed study will include a 24-week follow-up and will test the relative efficacy of 3 active treatment combinations-1) XR-NTX+harm reduction counseling, 2) placebo+harm reduction counseling and 3) harm reduction counseling only (HRC)-compared to the services as usual (TAU) that all participants receive from community agencies. This proposed design will allow us to dismantle active treatment components and thereby detect potential "placebo effects" of both the administration of an injection and attention from a medical professional. In this study, there are three primary specific aims. First, we will test the relative efficacy of XR-NTX, placebo and HRC compared to TAU in decreasing alcohol quantity, frequency and alcohol-related problems. Second, we will test hypothesized mediators of the intervention effects. Specifically, we hypothesize that the active treatments will precipitate increases in motivation to change and decreases in craving, which, in turn, will mediate the active treatment effects on alcohol outcomes. Finally, we will test treatment effects on publicly funded service costs (i.e., emergency medical services, ER visits, hospital admissions, and county jail). It is hypothesized that XR-NTX, placebo and HRC groups will show greater decreases in publicly funded service costs than the TAU group.

Arms:
arm 1: Assessment-only control condition arm 2: Harm reduction counseling, which entails provision of feedback and support of harm reduction goals and safer drinking provided at one-month intervals over a 3-month period. arm 3: 3 doses of active medication (380 mg injection/month) + Harm reduction counseling at one-month intervals over three months. arm 4: 3 doses of placebo + harm reduction counseling at one-month intervals over a three-month period

Interventions: intervention 1: XR-NTX intervention 2: Placebo intervention 3: HRC
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
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STUDY PROTOCOL 
 
Clinical protocol title 
HaRP Study Protocol, Version 4 
 
Protocol date 
Updated most recently - 12/8/15 
 
Research project title 
Harm Reduction with Pharmacotherapy (HaRP) for Homeless People with 
Alcohol Dependence (Short title: Harm Reduction with Pharmacotherapy 
[HaRP]) 
 
Phase of investigation 
Phase 2 RCT assessing efficacy of extended-release naltrexone (XR-NTX) and 
harm-reduction counseling for alcohol harm reduction among homeless 
people with alcohol dependence 
 
IND number 
IND Exempt 
 
Principal investigator 
Susan E. Collins, PhD 
University of Washington - Harborview Medical Center 
325 9th Ave, Box 359911 
Seattle, WA 98104 
 
Medical Director/ 
Co-Investigator 
 
Richard Ries, MD 
University of Washington - Harborview Medical Center 
325 9th Ave, Box 359911 
Seattle, WA 98104 
 
Co-Investigators 
Andrew J. Saxon, MD 
Veterans Affairs Medical Center 
1660 S. Columbian Way 
Seattle, WA 98108 
 
Seema L. Clifasefi, PhD 
University of Washington 
1100 45th St., Box 354944 
Seattle, WA 98195 
 
Subcontract PIs 
Ron Jackson, MSW 
REACH 
1700 Airport Way S 
Seattle, WA 98134 
 
Daniel Malone, MPH 
Downtown Emergency Services Center 
515 3rd Ave 
Seattle, WA 98104 


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Harm Reduction with Pharmacotherapy (HaRP) 
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Other Key Personnel 
Joseph O. Merrill, MD 
325 Ninth Ave, Box 359780 
Seattle, WA 98195 
 
Antoinette Krupski, PhD 
325 Ninth Ave, Box 359911 
Seattle, WA 98195 
 
Jutta Joesch, PhD 
325 Ninth Ave, Box 359911 
Seattle, WA 98195 
 
External consultants 
James C. Garbutt, MD 
University of North Carolina at Chapel Hill 
Campus Box #7160 
Chapel Hill, NC 27599 
 
Patt Denning, PhD 
45 Franklin St, Ste 320 
San Francisco, CA 94102 
 
 
Study staff 
Cat Cunningham, MSW (Research Scientist II/Assessment personnel) 
University of Washington-Harborview Medical Center 
325 9th Ave, Box 359911 
Seattle, WA 98104 
 
Ali Bright, MD (Addiction Fellow) 
University of Washington-Harborview Medical Center 
325 9th Ave, Box 359911 
Seattle, WA 98104 
 
Jonathan Buchholz, MD (Addiction Fellow) 
University of Washington-Harborview Medical Center 
325 9th Ave, Box 359911 
Seattle, WA 98104 
 
Mark Duncan, MD (Senior study physician) 
University of Washington-Harborview Medical Center 
325 9th Ave, Box 359911 
Seattle, WA 98104 
 
Brian Smart, MD (Senior study physician) 
University of Washington-Harborview Medical Center 
325 9th Ave, Box 359911 
Seattle, WA 98104 
 


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Harm Reduction with Pharmacotherapy (HaRP) 
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Data Safety Monitoring 
Board 
 
Dave Atkins, PhD (Chair/Statistician) 
325 Ninth Ave, Box 359911 
Seattle, WA 98195 
 
Katherine Bradley, MD, MPH (Internal Medicine) 
Group Health Research Institute  
Group Health Cooperative  
Metropolitan Park East  
1730 Minor Avenue, Ste. 1600  
Seattle, WA 98101 
 
Margaret Shuhart, MD (Hepatologist) 
325 Ninth Ave, Box 359938 
Seattle, WA 98195 
 
Christine E. Yuodelis-Flores, MD (Psychiatrist) 
325 Ninth Ave, Box 359911 
Seattle, WA 98195 
 
 
Research Analyst 
Imara West, MPH 
325 Ninth Ave, Box 359911 
Seattle, WA 98195 
 
 
Clinical laboratories 
University of Washington Research Testing Services 
STERLING Reference Laboratory 
 
Pharmaceutical company  
Alkermes 
 
Research Sponsor 
NIH-NIAAA 


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Harm Reduction with Pharmacotherapy (HaRP) 
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HaRP Study Protocol 
1 Introduction 
 
1.1 XR-NTX Background 
 
Extended-release naltrexone (XR-NTX; Market name: Vivitrol®) is a 30-day, extended release formulation of the 
opioid receptor antagonist, naltrexone, and is a 380mg/vial suspension delivered monthly via intramuscular 
injection. It is chemically designated as morphinan-6-one, 17 (cyclopropylmethyl) 4,5-epoxy-3,14-dihydroxy-(5α) 
(CAS registry #16590-41-3). The molecular formula is C20H23NO4, and its molecular weight is 341.41 in anhydrous 
form. Its structural formula is shown in Figure 1. 
 
 
Figure 1. Molecular structure of naltrexone 
 
Naltrexone was first used clinically to block the rewarding effects of opiates, such as heroin.1 More recently it has 
been tested and FDA approved for the treatment of alcohol dependence.2,3 In research trials, naltrexone and XR-NTX 
have been shown to reduce craving, heavy drinking and relapse severity.4,5 Although its mechanism of action is not 
fully understood, research has suggested it may work as shown in Figure 2.6-9 
 
 
 
Repeated alcohol 
consumption
•Causes release 
of pleasurable 
chemicals called 
endorphins
•Endorphins are 
naturally 
occurring 
opiates that the 
body produces
Alcohol 
dependence 
•Repeated 
release of 
endorphins may 
increase alcohol 
cravings
•People with 
alcohol 
dependence 
experience 
strong, 
repeated 
alcohol cravings
XR-NTX
•Bonds to opioid 
receptors in the 
brain
•Blocks naturally 
produced 
endorphins in 
response to 
alcohol use
•Endorphins 
become less 
rewarding to 
the brain
Decreased alcohol 
craving/use
•Less rewarding 
effects of 
alcohol lead to 
less alcohol 
craving
•Without the 
same level of 
craving, people 
decrease their 
alcohol use
Figure 2. Naltrexone’s hypothesized mechanism of action 


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Harm Reduction with Pharmacotherapy (HaRP) 
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1.2 XR-NTX Effectiveness 
 
In understanding the effectiveness of XR-NTX, it is important to include a review of the substantial scientific 
literature on oral-dose naltrexone that served as its precursor. In two, initial, 12-week double-blind, placebo-
controlled trials, naltrexone (plus psychosocial treatment) was found to be well-tolerated by patients. Naltrexone 
was also associated with significantly less alcohol craving and fewer drinking days compared to placebo plus 
psychosocial treatment.2,3  Among participants who continued to drink, those who received naltrexone showed 
lower rates of relapse to heavy drinking,2,3 presumably because naltrexone blocked the rewarding effects of 
alcohol.6-9 A later, 6-month follow-up study showed that the naltrexone group continued to have significantly lower 
relapse rates and fewer alcohol dependence symptoms than the placebo group.10 Since the early nineties, there 
have been dozens of published, peer-reviewed trials that have documented the effectiveness and safety of 
naltrexone among thousands of participants with alcohol-use disorders.5 Larger reviews and meta-analyses have 
shown naltrexone’s modest yet consistent effects in reducing drinking rates, relapse severity and craving.4,11-14  
 
Although studies have shown support for oral naltrexone in reducing heavy-drinking outcomes, a sizeable barrier to 
its consistent use has been relatively low treatment compliance.15-17  XR-NTX was introduced to overcome these 
challenges: it is administered by a health-care provider once a month instead of self-administered once a day. To 
date, a handful of XR-NTX trials have been conducted and have shown promising effects.5,18,19 The first, large-scale 
randomized controlled trial of XR-NTX was conducted by Alkermes, Inc. within a multisite network of 24 US hospitals 
and tertiary medical centers. One of our study consultants, Dr. JC Garbutt, was the lead author on the primary 
publication from that trial. In addition to 12 psychosocial intervention sessions, participants (N = 626) were 
randomized to receive monthly intramuscular injections of either 380mg or 190mg of XR-NTX or matching placebo. 
Compared with placebo, the 380mg formulation resulted in a statistically significant 25% reduction in heavy 
drinking. The lower-dose (190mg) formulation did not result in statistically significant reductions compared to 
placebo. Participants who were initially abstinent evinced greater treatment gains.  Discontinuation rates due to side 
effects and adverse events were 14.1% in 380mg group, 6.7% in 190mg group and 6.7% in placebo group.5 
 
Secondary analyses conducted using data from the previous study indicated that XR-NTX was also associated with 
significant, self-reported improvements in quality of life (i.e., overall mental health, social functioning, general 
health, and physical functioning domains).20 In a more recent, open-label trial, XR-NTX was deemed to be acceptable 
and feasible for delivery in a health-care setting.21 XR-NTX was approved by the FDA for the treatment of alcohol 
dependence in 2006.22 
 
1.3 XR-NTX Safety 
 
Like oral-dose naltrexone, XR-NTX does not have addictive properties, and with the exception of opioids, evinces few 
interactions with other medications. Studies have shown XR-NTX to be well-tolerated and safe, even among actively 
drinking alcohol dependent participants.5 Possible side effects of XR-NTX, which occur in at least 5% of patients at 
least twice the rate of placebo, include pain, tenderness, swelling, bruising and/or itching at the injection site, 
nausea, headache, fatigue, dizziness, vomiting, decreased appetite, painful joints and muscle cramps.5,22,23 
 
Rare conditions that may be associated with XR-NTX can often be avoided with assessment and screening 
procedures. First, XR-NTX should not be taken by individuals with current opioid dependence because it will induce 
severe withdrawal. Similarly, because XR-NTX is an opioid antagonist, it reduces the effectiveness of opioid 
analgesics. There may also be a slightly elevated risk for eosinophilic pneumonia, depression and suicidality. As with 
any medication, there is a risk of drug hypersensitivity, although allergic reactions to XR-NTX are very rare. In some 
cases, reactions at the injection site may become severe. Injection sites should be monitored by a health-care 
provider for potential hardening, inflammation, nodules and swelling, and in extreme cases, necrosis. Injection site 
reactions can usually be avoided by ensuring that the needle passes through the superficial layer of fat tissue under 
the skin and into the gluteal muscle before the medication is injected.  
 


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Harm Reduction with Pharmacotherapy (HaRP) 
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Finally, until recently, there was a ‘‘black-box’’ warning on XR-NTX regarding potential hepatocellular injury. This 
warning was rescinded in late July 2013. The warning had originally followed from early naltrexone studies, which 
prescribed daily oral doses of up to 350mg for treatment of obesity and dementia—seven times the currently 
recommended oral dose.24 Although current FDA labeling indicates that XR-NTX may be associated with liver injury 
primarily if it is administered in “excessive doses” or to patients with “acute hepatitis or liver failure,”22 there are no 
reports of hepatotoxicity involving XR-NTX.25 The large-scale, randomized controlled trial (RCT) of XR-NTX mentioned 
above indicated no significant differences in participants’ liver function throughout the study, even among 
participants with previously elevated liver enzymes.23 Gamma-glutamyl transferase (GGT) levels were lower among 
those receiving XR-NTX compared to placebo during the study, likely due to decreased drinking.23 Further, because 
XR-NTX is injected intramuscularly, it eliminates first-pass metabolism, further reducing the risk of hepatotoxicity 
and fluctuations in plasma naltrexone levels.26 In fact, it has been suggested that there is greater risk of 
hepatotoxicity from continued, heavy alcohol use than from appropriate naltrexone administration.27 That said, XR-
NTX has not yet been extensively studied in patients with pre-existing, severe liver damage. 
 
1.4 Study Rationale 
 
Alcohol dependence among homeless individuals is a serious public health issue. A meta-analysis of international 
studies showed a mean of 38% of homeless individuals are affected by alcohol dependence,28 which is ten times the 
prevalence of alcohol dependence in the general US population (3.8%).29 Alcohol dependence interferes with tasks 
of daily living, such as attaining and maintaining housing, employment and social networks.30-32 The more severe 
alcohol dependence that often affects homeless individuals is associated with both acute (e.g., accidents, falls, 
violence) and chronic (e.g., chronic liver disease, cancer, cardiovascular disease, encephalopathies) alcohol-related 
harm,30,33 which places increased burden on the health-care and criminal justice systems,34 and puts individuals at 
greater risk for alcohol-related mortality.35-37 Considering the extent and cost of negative consequences for both 
affected individuals and their communities, effective approaches are needed to engage and address the issues 
facing homeless people with alcohol dependence. 
 
Current abstinence-based programs do not optimally engage and treat this population. Alcohol abstinence has 
long been assumed to be the sine qua non of effective treatment, particularly for more severely affected and 
homeless populations. However, findings have been mixed for abstinence-based treatments among homeless 
individuals, ranging from no to modest improvements on substance-use outcomes.32,38,39 Further, these 
improvements are only experienced by the few who are engaged and retained in treatment.32 In fact, studies show 
that few homeless people start treatment (15-28%),40,41 and even fewer complete it (2.5-33%).42 An NIAAA review 
showed that treatment engagement in this population decreased as program demands—particularly abstinence—
increased.42 The end result is that the majority of homeless individuals with alcohol dependence never go to, are 
turned away from, or drop out of the treatments that are currently available. 
 
Recent research has elucidated reasons why abstinence-based treatment is not optimally engaging and effectively 
treating this population. First, our own and other research groups’ studies show that many of the most severely 
affected individuals do not find abstinence-based goals or treatments to be acceptable or desirable.43,44 Such 
negative evaluations of abstinence-based treatment are correlated with decreased treatment attendance45 and 
poorer outcomes.46 Thus, even if these individuals do present for treatment, they are less likely to stay in treatment 
and achieve positive effects. Relatedly, both theory and empirical data suggest that repeated failed treatment 
attempts erode self-efficacy and self-control for later behavior change.47,48 This observation is particularly relevant 
for this population: one of our recent studies showed a mean of 16 past alcohol treatment attempts in a sample of 
homeless individuals with alcohol dependence.49 Additionally, inpatient detoxification, typically a medical necessity 
for this population, is expensive and can lead to a “revolving door” of treatment,50,51 in which abstinence-based 
treatment episodes are regularly alternated with resumed use. The revolving door effect is a concern in this 
population because an increasing number of alcohol withdrawals and medical detoxifications can precipitate 
increasingly severe and potentially fatal alcohol withdrawal symptoms (i.e., kindling effect),52 which may make 
abstinence-based treatment a more harmful course of action for some more severely affected individuals. 


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Harm Reduction with Pharmacotherapy (HaRP) 
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New approaches are necessary that are compatible with this population’s needs. New approaches, which remove 
the barrier of abstinence to treatment engagement, have recently begun to be applied with chronically homeless 
individuals with alcohol problems.30,49,53,54 Such approaches have been referred to as harm-reduction interventions, 
because they focus on reducing alcohol-related harm without requiring abstinence.55 Such interventions, including 
low-barrier housing programs and managed alcohol programs,30,56 have shown preliminary effectiveness in reducing 
both alcohol-related harm and alcohol use.57,58 However, there are few pharmacological counterparts to further 
enhance the effects of these promising interventions. In response to this gap in the literature, we are proposing to 
test a promising medication, XR-NTX, to support alcohol harm reduction among homeless people with alcohol 
dependence. 
 
XR-NTX appears to be a good fit to this population’s needs and harm-reduction goals. Unlike other 
pharmacotherapies for alcohol dependence (e.g., disulfiram), naltrexone and XR-NTX are safe and effective among 
both individuals who are abstinent10,59 and current heavy drinkers,5 which makes it compatible with the drinking 
patterns of this population. Further, in accordance with harm-reduction principles, XR-NTX has been shown to 
reduce craving and heavy drinking without requiring abstinence from alcohol prior to administration.5,60 Moreover, 
recent studies conducted with other populations have shown that naltrexone may be safely and effectively used in 
the context of drinking moderation treatments.61,62 Finally, because it is a monthly injectable versus a daily oral 
medication, XR-NTX may help support medication adherence and greater follow-up with health-care professionals, 
which often poses a challenge for homeless individuals.63-65 Taken together, these features make XR-NTX compatible 
with the needs and goals of this population and with the existing harm-reduction approaches used by the 
community-based agencies that serve them. 
 
Our preliminary pilot study supports the use of XR-NTX in this population. In advance of the HaRP Study, the 
research team conducted a single-arm, open-label, 12-week pilot trial (N=24). The pilot was conducted together 
with 2 Seattle-based, nonprofit agencies on the forefront of harm-reduction service provision for homeless people: 
the Downtown Emergency Service Center (DESC) and Evergreen Treatment Service’s REACH Program. Both agencies 
expressed interest in developing and evaluating alcohol-specific treatments designed to help clients reduce their 
alcohol-related harm. This interest was sparked by their clients’ high prevalence of alcohol dependence 
(approximately 33% of DESC clients and 85% of REACH clients) and the acknowledgment that most of their clients 
are not ready, willing and/or able to engage in abstinence-based treatment. 
 
The aims of this pilot study were two-fold. The first aim was to develop and pilot procedures for the proposed study 
(i.e., study protocol, IRB application, population-appropriate measures, manuals). The second aim was to assess the 
initial feasibility, safety and effectiveness of XR-NTX with 2 agencies that provide services to homeless individuals 
with alcohol dependence. During this pilot, the proposed measures, procedures, protocols and manuals were 
developed and implemented and have been shown to be feasible. Of the 45 individuals approached, 42 consented 
to study participation, and 31 qualified for participation. Twenty-four participants received the full, 3-month 
treatment course. The medication and study procedures were discontinued for one participant because he 
voluntarily enrolled in inpatient detoxification and long-term alcohol treatment following his second injection, which 
was considered a positive treatment outcome. Three other participants refused the second injection due to 
discomfort at the injection site. All did, however, agree to continue with follow-up procedures. Additionally, one 
individual died (determined to be unrelated to the study medication), and two others were lost to follow-up when 
they were jailed over an extended period. 
 
The extent of adverse events as measured by the Systematic Assessment for Treatment Emergent Effects 
(SAFTEE)66,67 remained stable (i.e., participants endorsed a median of 6 symptoms) from baseline through the follow-
up period, although the severity of these symptoms decreased over the treatment course. Serious adverse events 
were determined to be unassociated with the study medication. Despite the small sample size, findings showed 
significant baseline-to-posttest improvements on alcohol outcomes. Specifically, participants decreased their 
median peak drinking quantity from 29 to 19 standard drinks (Wilcoxon signed rank z=-3.00, p=.003) and their 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
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median frequency from 30 to 25 days a month (z=-2.07, p=.04).  Participants also reported a 60% reduction in 
alcohol-related problems (z=-3.87, p<.001), and a 33% reduction in alcohol craving (z=-3.31, p=.001). Regarding 
acceptability of XR-NTX, 15 of the 24 participants who completed the treatment course wanted to continue XR-NTX 
off-study. These participants credited the treatment for their reduced alcohol craving and for support in making 
changes in their drinking. One participant said, “I swear to God your program is really helping me a lot because I 
don’t need [the alcohol]. I think your program is great. It’s working on me.” Another participant noted, “This 
program is really helping. My daughter asked me the other day, ‘Mom, why didn’t they make this drug years ago? 
You’re doing so good, and I’m so proud of you.’ That means a lot to me.” 
 
2 Study Objectives 
 
The proposed Phase II study will expand upon the pilot findings within a larger, randomized controlled trial (RCT). 
The 4-arm RCT (N=300) will include a 24-week follow-up and will test the relative efficacy of 3 active treatment 
combinations—1) XR-NTX+harm reduction counseling, 2) placebo+harm reduction counseling and 3) harm reduction 
counseling only (HRC)—compared to the services as usual (TAU) that all participants receive from community 
agencies. This design will allow us to dismantle active treatment components and thereby detect potential “placebo 
effects” of both the administration of an injection and attention from a medical professional that have been found in 
previous studies.68,69 This study is clinically significant and innovative because it seeks to engage homeless 
individuals, regardless of whether they have abstinence, drinking moderation or harm-reduction goals and will use a 
harm-reduction rather than an abstinence-based framework to guide the accompanying counseling and medication 
management. 
 
 
Specific aim 1 is to test the relative efficacy of XR-NTX, placebo and HRC compared to TAU.  
 
Hypothesis 1A: Compared to the TAU group, the 3 active treatment (XR-NTX, placebo, HRC) groups will 
evince significantly greater decreases in alcohol quantity, frequency and alcohol-related problems. 
 
Hypothesis 1B: The XR-NTX group will evince greater decreases in alcohol quantity, frequency and 
alcohol-related problems than the placebo group. 
 
Specific aim 2 is to test theory-based mediators of treatment effects. 
 
Hypothesis 2A: Because the 3 active treatments include personalized feedback, client-driven, harm-
reduction goal setting and collaborative planning for safer drinking, these groups will experience 
significant increases on motivation to change drinking in a way that reduces harm. In turn, these 
increases in motivation to change will mediate the active treatment effects on alcohol outcomes. 
 
Hypothesis 2B: Given naltrexone’s putative clinical mechanisms, the XR-NTX group will experience 
significant decreases on craving compared to the placebo group. In turn, these decreases in alcohol 
craving will mediate the effects of XR-NTX versus placebo on alcohol outcomes. 
 
Specific aim 3 is to test treatment effects on publicly funded service costs. 
 
Hypothesis 3A: It is hypothesized that the XR-NTX, placebo and HRC groups will show greater decreases 
in publicly funded service costs (i.e., costs resulting from emergency medical services, ER visits, hospital 
admissions, and county jail) than the TAU group. 


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Harm Reduction with Pharmacotherapy (HaRP) 
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3 Methods 
 
3.1 Proposed design 
 
The proposed study involves a 4-arm RCT (N=300) testing the relative efficacy of XR-NTX+harm reduction 
counseling (XR-NTX), placebo+harm reduction counseling (placebo), and harm reduction counseling alone (HRC) 
compared to supportive services (TAU) provided by community-based agencies (see Figure 3). Within this design, 
we will also compare the efficacy of XR-NTX and placebo with both participants and researchers blind to 
medication condition. The study features a 12-week active treatment trial with a 24-week follow-up to test for 
potential delayed treatment effects or treatment decay. 
 
After careful consideration of the potential benefits and drawbacks (e.g., sample size, study cost) of conducting the 
proposed 4-arm design versus a more traditional 2-arm (XR-NTX and placebo) design, we decided on the former for 
a few important reasons. First, naltrexone and XR-NTX are well-researched, FDA-approved medications for the 
treatment of alcohol dependence.4,24,70,71 Therefore, it was deemed appropriate to integrate more differentiated 
research questions into the current study, which seeks to expand the evidence base for the use of this medication. 
Second, the COMBINE study evinced a “significant placebo effect” for naltrexone, which researchers attributed to 
participants’ expectancies regarding medications as well as the effects of alcohol counseling from a medical 
professional, which was embedded within medication management sessions68,69 and has become de rigueur in 
clinical drug trials for alcohol dependence.5,71-73 It is therefore important to methodologically control for these 
“placebo effects” to account for the active components facilitating participants’ behavior change. Third, because 
there is currently no generic formulation, the expense of the prescription and administration of XR-NTX is 
considerable. It is therefore important to determine whether the medication is not only superior to a placebo, but 
whether it is superior to harm-reduction counseling alone, which could be provided at lower cost. This study was 
therefore designed to determine the relative contributions of a) harm-reduction counseling (HRC) with a medical 
professional, b) the placebo effect (placebo), and c) the medication effect (XR-NTX) relative to the usual 
psychosocial, harm-reduction services provided by community-based agencies (TAU). 
3.2 Participants 
 
Figure 3. Intervention delivery and assessment timeline. TAU = psychosocial services as usual; HRC= harm reduction counseling only. MM = 
medication management. 
Week 1 check-in 


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Harm Reduction with Pharmacotherapy (HaRP) 
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Participants (N = 300) will be adults (21-65 years old) with alcohol dependence who are or have been homeless in 
the past year. The McKinney-Vento Homeless Assistance Act74 defines homelessness as lacking a fixed, regular and 
adequate nighttime residence; having a primary nighttime dwelling that is not a regular sleeping accommodation; 
living in a supervised shelter or transitional housing; exiting an institution that served as temporary residence when 
the individual had previously resided in a shelter or place not meant for human habitation; or facing imminent loss 
of housing when no subsequent residence is identified and insufficient resources/support networks exist. 
 
We will not limit the sample to currently homeless individuals for the following reasons. First, agencies serving 
homeless individuals prioritize assisting their clients to achieve housing. It would therefore be neither ethical nor 
practical to limit our recruitment to only those clients who remain consistently homeless versus those who become 
sheltered, transitionally or permanently housed after years of chronic homelessness. Further, because a return to 
homelessness is not uncommon,75,76 the proposed population is likely to be more representative of the often cyclic 
nature of homelessness. On the other hand, it is clinically important to understand whether treatment effects 
differ according to housing status. We will therefore include current housing status as a time-varying covariate in 
outcome analyses. 
3.2.1 
Inclusion criteria 
 
Inclusion criteria will include receiving services from one of the named partnering agencies, being 
between 21 and 65 years of age, agreeing to use an adequate form of birth control (if female and in 
childbearing years; includes oral, injectable or implanted hormonal contraceptives, intrauterine devices 
(IUDs)/intrauterine systems (IUSs), barrier method of condoms plus spermicidal foam, true abstinence), 
and fulfilling criteria for current alcohol dependence according to DSM-IV-TR criteria as determined by 
the SCID-I/P.77 
 
3.2.2 
Participant exclusion criteria 
 
Exclusion criteria will include refusal or inability to consent to participation in research, constituting a 
risk to safety and security of other clients or staff, known sensitivity or allergy to naltrexone/XR-NTX, 
current treatment with naltrexone/XR-NTX, being pregnant or nursing, concurrent participation in a 
clinical study involving an unapproved, experimental drug, suicide attempts within the past year, renal 
insufficiency/serum creatinine level > 2, current opioid dependence according to the DSM-IV-TR 
criteria, liver transaminases (AST, ALT) > 5 times the upper limit of normal (ULN), a clinical diagnosis of 
decompensated liver disease, or other condition deemed by Principal Investigator and/or Medical 
Director to make study participation clinically unsafe. 
 
To increase external validity of the findings and to recruit in accordance with harm reduction 
principles, we have limited the exclusion criteria to only those that are necessary to minimize risks to 
participants’ health and safety. To further reduce these potential risks, we will a) regularly assess 
health and safety (e.g., monthly collection/monitoring of blood and urine tests, urine toxicology and 
pregancy tests at baseline and prior to injections, regular suicide assessments, hospital/agency records, 
etc.); b) discuss participants’ cases weekly; c) consult with an addiction medicine specialist and 
internist (Merrill) on a weekly basis to evaluate participants’ health status; and d) meet and review 
reports biannually with a Data Safety Monitoring Board, including a psychiatrist, internal medicine 
physician, hepatologist (liver specialist), and clinical psychologist/statistician. By decreasing the barriers 
to participation, we will maximize the generalizability of the current findings to more severely affected 
populations78 and will act in accordance with the agencies’ existing and effective low-barrier, harm 
reduction approaches.43,49,56,79 
 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
11 
 
3.3 Measures and Materials 
 
3.3.1 
Measures 
 
Please see Table 1 below for the assessment schedule for each of the following measures. 
 
Measures for determining eligibility. Ability to consent will be assessed during the information session 
using the UCSD Brief Assessment of Capacity to Consent (UBACC).80 This 10-item, 3-point Likert-scale 
measure ensures participants understand the study protocol, potential risks/benefits and their rights as 
participants prior to study enrollment. The Alcohol Use Disorders Inventory Checklist – Consumption 
(AUDIT-C),81,82 which is a three-item, psychometrically sound measure of hazardous and harmful 
patterns of alcohol consumption, will be used to screen participants for alcohol dependence prior to 
study recruitment. We will use a cut-off score of ≥ 4 points, which has optimal sensitivity and specificity 
for detecting alcohol-use disorders.83,84 The Beck Scale for Suicidal Ideation (BSS) is a reliable and valid 
tool to assess suicidal ideation and behavior.85 It will be used to assess participants’ current suicidality to 
determine fulfillment of exclusion criteria at baseline and will be regularly assessed in weeks 4-36. 
Further, the Self-injurious Thoughts and Behaviors Interview-Suicide Attempts subscale (SITBI-SA), which 
measures lifetime experience of suicidal behaviors, will likewise help determine fulfilment of exclusion 
criteria at baseline and will be administered at all subsequent assessment timepoints (weeks 4-36).86 
The alcohol and opioid dependence parts of the DSM-IV-TR SCID-I/P77 will be used to document 
fulfillment of inclusion/exclusion criteria and will be administered again in Weeks 4-36. 
 
Measures for sample description. The Personal Information Questionnaire (PIQ) will assess age, gender, 
race, ethnicity, education, employment, military experience, other research study participation and 
experience of homelessness in the past year.87 The Housing Timeline Followback (TLFB-H)88,89 is a set of 
calendars that documents housing status by recording where participants resided/spent the night each 
day in the past 30 days or since the previous assessment, as applicable. The TLFB-H will be used to 
describe the baseline sample and as a time-varying covariate in efficacy analyses. The Tracking 
Information Sheet will collect contact information from participants to facilitate follow-up 
communication and tracking over the course of the study. 
 
Measures of motivation outcomes. Motivation outcomes will serve as potential mediators of the 
hypothesized treatment effect. The Motivation-to-change Ruler comprises four, 10-point scales 
assessing participants’ motivation, readiness, importance and confidence to change their alcohol use in 
a way that reduces harm. Such 10-point, single-item motivation scales have been shown to be valid and 
clinically useful measures of motivation across various populations.90-92 
 
Measures of alcohol-use outcomes. The Alcohol and Substance-use Frequency Assessment questions 
were adapted from the ASI,93 and will be used to assess frequency of use of alcohol and other drugs. The 
Alcohol Quantity Use Assessment (AQUA) was created in the context of a previous study with this 
population,49 and was refined in the Project Vivitrol® pilot study. As necessary due to cognitive deficits, 
we will also use a set of monthly calendars to allow for prospective or retrospective evaluation of 
alcohol and other drugs for each day of the previous month.88 The Short Inventory of Problems (SIP-2R) 
is a 15-item, Likert-scale questionnaire that measures social, occupational and psychological alcohol-
related problems.94 The summary score will serve as the alcohol-related problems outcome measure. 
Alcohol craving will be measured using the psychometrically valid, 5-item, Likert-scale Penn Alcohol 
Craving Scale (PACS).95 The alcohol craving summary score will be used as a mediator of the 
hypothesized treatment effects. 
 
Measures of quality-of-life outcomes. The Short Form – 1296 is a well-validated, 12-item questionnaire 
that assesses quality-of-life outcomes in two primary areas: physical and mental health.   


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Harm Reduction with Pharmacotherapy (HaRP) 
12 
 
 
Measures supporting medication management. The Case Report Form (CRF) will be used to a) 
summarize clinically relevant assessment data for the study physician/nurse (e.g., alcohol-use disorder 
diagnosis, fulfillment of inclusion/exclusion criteria); b) compile and centralize key lab test findings; c) 
provide an outline during the physical exam and medication management; and d) record clinical data 
during the physical exam and medication management sessions. The Systematic Assessment for 
Treatment Emergent Effects (SAFTEE) interview,66,67 which was tailored for use with this medication, 
includes open-ended, categorical and Likert-scale questions assessing symptoms that correspond to 
potential adverse events associated with XR-NTX. This measure will be embedded in the CRF. 
 
Assessment Schedule
S
B
0
1
4
8
12
24
36
Administered by assessment staff
UBACC
.
AUDIT-C
.
Tracking Information Sheet
.
.
.
.
.
.
PIQ
.
TLFB-H
.
.
.
.
.
.
Alcohol and Substance-use Frequency
.
.
.
.
.
.
AQA/AOD calendars
.
.
.
.
.
.
PACS
.
.
.
.
.
.
SIP-2R
.
.
.
.
.
.
DSM-IV-TR alcohol/opioid dependence
.
.
.
.
.
.
MTC Rulers
.
.
.
.
.
.
Suicide assessment (BSS and SITBI)
.
.
.
.
.
.
SF-12
.
.
.
.
.
.
Participant Satisfaction Assessment
.
Administered by study physician/nurse
CRF
.
.
.
.
.
.
.
.
SAFTEE
.
.
.
.
.
.
.
.  
 
Measures for utilization and cost analysis. Administrative data on publicly funded service utilization will 
be obtained from the King County Correctional Facility, King County Medic One/Emergency Medical 
Services, Harborview Medical Center (HMC), and the Washington State Comprehensive Hospital 
Abstract Reporting System (CHARS) for the 2-year pre-study period through the follow-up period. We 
will obtain participant consent and HIPAA authorizations for these data at the information session. We 
will collect the following data: a) number of Medic One/EMS dispatches and associated costs; b) number 
of ER visits and associated costs; c) number of inpatient hospital admissions, outpatient visits and total 
costs per admission (CHARS and HMC); d) number of bookings, length of stay and daily cost for the King 
County Correctional Facility. These data will be used to create overall cost outcomes.  
 
Treatment integrity materials and measures. Manual adherence and competence for the HRC, placebo 
and XR-NTX sessions will be measured using the HaRP Adherence and Competence Coding Manual and 
the HaRP Coding Scale. The coding system, which is based on the COMBINE Study Medical Management 
Adherence Checklist and coding schema,73,97 consists of 7 dimensions to assess delivery of the HaRP 
style and content (i.e., informativeness, direction, authoritativeness, warmth, manual adherence, 
avoidance of nonmanualized components, overall). Dimensions will be rated on 7-point Likert scales, 
where 0=absence of the characteristic and 6=very high levels of the characteristic (within top 10% of 
providers). The Participant Satisfaction Assessment is a semistructured interview with open-ended 


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13 
 
questions and prompts to assess participants’ receipt of and satisfaction with the study procedures at 
the final assessment. 
 
Research staff, including bachelor-level research assistants, graduate students and postdoctoral fellows, 
will conduct treatment integrity rating under the supervision of the PI, who is a licensed clinical 
psychologist with 15 years of experience conducting treatment integrity ratings and analysis. An 
extensive training protocol developed during prior evaluations will be utilized. Raters will receive 16 
hours of training and supervision before they begin independently recruiting and assessing participants. 
Training will include written instructions and group coding sessions with feedback from the PI. Sessions 
will be coded independently; however, regular supervision and periodic interrater consistency analyses 
will be conducted to reduce the risk of rater drift. 
3.3.2 
Lab Tests and Materials 
 
Blood tests will be conducted on all participants at baseline and weeks 4, 8, 12, 24 and 36, and will 
include a complete blood count (CBC), a basic metabolic panel (CHEM 7), and a liver panel (AST, ALT, 
ALP, albumin, bilirubin total and direct). These tests will be conducted to assess liver and renal 
functioning and to detect other medical conditions that may contraindicate the use of XR-NTX or may be 
important to monitor during its administration. If participants in the two medication arms evince 
AST/ALT greater than 5 x ULN, they will be retested a week prior to the next scheduled injection. In the 
case AST/ALT have not decreased below that point, the study medication will be discontinued to ensure 
participant safety. 
 
Urine tests will include a) complete urinalysis (UA), which will be used to detect further contraindicating 
conditions (e.g., renal damage) at baseline and monthly; b) a urine toxicology dipstick, which will be 
used in the XR-NTX and placebo conditions to detect the presence of opiates at baseline and prior to 
each injection; c) an hCG dipstick pregnancy test for women in childbearing years at baseline and prior 
to each injection; and d) ethyl glucuronide (EtG) tests,98 which will be used to biovalidate self-reported 
alcohol use at each assessment and will be administered at baseline and monthly thereafter. The 
concentration of EtG, which is a metabolite of ethyl alcohol formed in the body by glucuronidation after 
ethanol exposure, will be used as a quantitative measure. Previous studies have shown that EtG is 
positively associated with self-reported alcohol quantity.99,100 
 
3.4 Randomization Scheme 
 
The current study will involve four treatment arms. Participants will be randomized to one of the four treatment 
arms using a permuted block randomization with stratification. The study PI created the scheme and randomization 
lists in advance using the ralloc program in STATA MP 11.2 (Statacorp, 2009). This program provides a sequence of 
treatments randomly permuted in blocks of constant or varying size with the ability to stratify the allocation. For the 
current study, equal blocks of four were used to minimize the risk of potential imbalance in the treatment arms, and 
the allocation was stratified by agency and housing status (i.e., housed or homeless at time of randomization). 
 
The randomization scheme will be given to the University of Washington Investigational Drug Services (IDS) in the 
form of a series of spreadsheets. The IDS will be responsible for randomizing qualifying participants by filling the 
participant IDs into the corresponding spreadsheets. The two arms of the study receiving injections will be double-
blinded in that the investigators will not know which participants are allocated to which group (placebo versus active 
medication). Further, IDS staff--not the investigators--will administer the randomization scheme so as to minimize 
selection bias for all groups. 
 
3.5 Study Treatment 
 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
14 
 
This study comprises four treatment conditions. The most minimal condition is TAU, which will comprise the 
agencies’ harm-reduction oriented “supportive services as usual” that will be provided to all participants in all 
groups for the duration of the trial and beyond. One of the partnering agency’s programs includes provision of 
emergency shelter and/or permanent, supportive housing. Both agencies provide supportive services that are 
tailored to the needs of individual clients and include outreach; case management; nursing/medical care; access to 
external service providers, as needed (e.g., more intensive medical or psychiatric treatment, chemical dependency 
counseling, etc); and/or assistance with basic needs (i.e., food, clothing, income, housing). Like the other treatment 
conditions, participants in the TAU condition will also undergo regular assessments at baseline and weeks 4, 8, 12, 
24, and 36. 
 
The remaining three conditions (XR-NTX, placebo and HRC) are considered active treatment conditions and will all 
include monthly, alcohol-specific, harm-reduction counseling sessions that will be delivered by study 
physicians/nurses. A harm reduction style, which will involve a nonjudgmental, empathetic stance, unconditional 
positive regard, and acceptance of clients wherever they fall on the spectrum of readiness to change,60 will be 
utilized. This style has been chosen for a few reasons. First, it is compatible with the agencies’ current clinical and 
case management approaches. Second, the research team’s preliminary findings in these settings indicate that a 
client-centered style helps providers best align with clients and build appropriate and positive rapport to support 
behavior change.43 Third, research has confirmed the superior efficacy of a client-centered versus confrontational 
style in therapeutic interactions.101-103 Finally, a client-centered style has been shown to be helpful in other 
interventions involving homeless individuals.104 
 
The HRC condition will involve harm-reduction counseling components. At appointments, study physicians/nurses 
will a) provide personalized feedback about alcohol assessments and lab tests, b) assess vital signs and concomitant 
medications, c) obtain medical history (baseline only), d) assess for adverse events using the SAFTEE, e) conduct a 
physical exam (baseline and as clinically indicated), f) elicit participants’ harm reduction goals and progress made 
towards them, and g) discuss and secure commitment for safer drinking using the Safer Drinking Strategies 
worksheet. These components have been tested in the pilot study and are based on both harm reduction theory55 
and clinical practice60 as well as evidence-based motivational enhancement.92,105 Study physicians/nurses will use the 
HaRP treatment manual to guide the session and will record participants’ in-session data on the CRF. 
 
The XR-NTX and placebo conditions will receive harm-reduction counseling components + medication 
administration/management. At each appointment, study physicians/nurses will a) provide personalized feedback 
about alcohol assessments and lab tests, b) assess vital signs and concomitant medications, c) obtain medical history 
(baseline only), d) assess for adverse events using the SAFTEE, e) conduct a brief physical exam (baseline and as 
clinically indicated), f) provide medication management (discuss the medication, side effects and ways to manage 
them, including provision of 2, 25mg tabs of over-the-counter antihistamine meclizine; ensure participants have 
medication bracelets/dogtags; provide emergency contact information), g) elicit harm reduction goals and progress 
made towards them, h) discuss and secure commitment for safer drinking using the Safer Drinking Strategies 
worksheet, and i) administer XR-NTX/placebo. Study physicians/nurses will use the HaRP treatment manual to guide 
the session and will record participants’ in-session data on the CRF. 
 
Participants will take urine toxicology and pregnancy dipstick tests immediately prior to the first injection. If 
participants test negative for pregnancy and opioids, study physicians/nurses will administer the injection into the 
gluteal muscle, alternating buttocks for each subsequent injection. If participants test positive for hCG, they will be 
withdrawn from the study. If participants test positive for opioids, the injection will not be administered, the 
positive test result will be discussed, and current opioid dependence will be assessed using the SCID-I/P. If 
participants do not meet criteria for opioid dependence, they will be rescheduled for an additional urine toxicology 
test the following week. If participants test positive for opioid dependence on the repeat test, they will be 
withdrawn from the study. If participants test negative for opioids on the repeat test, they will receive the injection. 
 
All participants who receive an injection will attend the Week 1 safety check-in to assess and address potential 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
15 
 
adverse events using the SAFTEE and to allow study physicians/nurses to check for potential injection site irritation. 
They will also be given research staff contact information in case they need to discuss any further 
questions/concerns regarding the study medication/procedures at any time throughout the study. For the three 
active treatment groups, Week 1 appointments will also include a check-in regarding participants’ progress towards 
their harm reduction goals and safer drinking plans. 
 
3.6 Treatment Adherence and Compliance 
 
Treatment adherence and study compliance will be measured by follow-up appointment attendance. If participants 
do not attend appointments, their absence will be noted, and research staff will work together with program staff to 
reschedule with participants. If this is not feasible after five failed scheduling attempts (no-shows), the participant 
will be counted as “noncompliant.” The exception to this will be for the safety check-in at Week 1. We will work to 
contact participants until we can schedule them. Participants will not be withdrawn from participation or analyses 
unless they expressly request to be.  
 
3.7 Study Medication 
 
3.7.1 
Formulation and labeling 
 
XR-NTX (380 mg/vial) (n=225), which is FDA-approved and commercially available, and placebo (n=225) 
formulations will be provided to the investigator per agreement from Alkermes. The preparation will 
consist of microspheres of 100-μm diameter that either contain naltrexone or do not (placebo) and are 
suspended prior to administration in a PLG polymeric matrix. PLG is a common biodegradable medical 
polymer with an extensive history of human use in extended-release pharmaceuticals. Following the 
injection, naltrexone is released from the microspheres, yielding peak concentrations within three days. 
Thereafter, by a combination of diffusion and erosion, naltrexone is released for more than thirty days. 
Also provided by Alkermes, the placebo preparation will consist of an identical formulation of 
microspheres (not containing naltrexone) within a PLG polymeric matrix to ensure study staff and 
participants are blind to medication condition. 
 
The UW IDS will receive the study medication from Alkermes and will blind and label the doses in the 
two intervention arms involving placebo and active medication.  
 
3.7.2 
Preparing and dispensing 
 
XR-NTX/placebo will be dispensed by the UW IDS. IDS will randomize participants according to the 
prepared scheme, and will inform the research staff of participants’ randomization to receive a) 
medication (blinded active or placebo), b) HRC or c) TAU. Research staff will pick up the blinded 
medication from IDS prior to the Week 0 appointment, as applicable.  
 
Prior to administration, XR-NTX and placebo will be prepared by the study physician/nurse. Both 
formulations must be refrigerated prior to use, but allowed to reach room temperature before injection 
(removing from refrigeration approximately 45 minutes prior to use). It must be suspended in the 
accompanying diluent in the carton by using the preparation needle to inject the diluent into the vial 
containing the microspheres and shaking until the mixture is milky white in appearance (approximately 
one minute). At this point, XR-NTX (or the placebo formulation) is ready for administration. 
 
3.7.3 
Drug storage and accountability 
 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
16 
 
XR-NTX/placebo doses will be blinded and stored in locked and secure refrigerators (2-8ºC or 36-46º F) 
at the IDS prior to use. Doses can be stored at room temperature (not exceeding 25ºC or 77º F) for no 
more than 7 days prior to administration. Doses may not be frozen. 
 
Accurate recording of all study medication administration will be recorded at each transaction and each 
participant’s sessions. The IDS will maintain records on Vivitrol dispensation, and the PI and Medical 
Director will maintain accurate and current records of all administered and returned medication. All 
remaining, unused XR-NTX/placebo doses will be returned to the IDS pharmacy. 
 
3.7.4 
Concomitant Medications 
 
 
Naltrexone antagonizes the effects of opioid-containing medicines, including some cough and cold 
remedies, some antidiarrheal preparations and opioid analgesics. For this reason, use of opiates 
(prescription medication or street drugs) is an exclusion criterion for participation at baseline. If 
participants have positive opiate drug screens (after retesting) and/or fulfill opioid dependence criteria 
according to the DSM-IV-TR, XR-NTX/placebo administration will not proceed at week 0.  
 
In emergency situations requiring analgesia, the use of regional anesthesia or non-opioid analgesics is 
recommended. If opioid therapy is required, patients should be continuously monitored in an anesthesia 
care setting by persons not involved in the conduct of the surgical or diagnostic procedure. Opioid 
therapy should be managed by anesthesiologists trained in the management of the respiratory effects of 
potent opioids (e.g., establishment and maintenance of a patent airway and assisted ventilation). In this 
study, patients in need of analgesia will be referred for consultation to the UW Anesthesiology & Pain 
Medicine Department at Harborview Medical Center. At study enrollment, all participants in the 
medication conditions will be given ID tags and wallet-size medical emergency information cards 
indicating the possible presence of the study medication. Participants will be encouraged to wear the ID 
tags and carry the cards with them for the duration of the study. 
 
3.7.5 
Breaking the Blind 
The principles guiding the breaking of the blind must balance the protection of participants in medical 
emergencies with the need to maintain the integrity of the double blind for study validity. Until the 
study is completed, this will only be done in the event of a medical emergency where the information is 
necessary for the provision of care. In the absence of specific information to the contrary, it is often 
sufficient to assume that participants might be receiving XR-NTX, with a 50% probability among those 
who are receiving an injection. However, if local treatment providers believe that an emergency medical 
situation exists and that exact information about the participants’ medication dose is required to 
provide emergency care, then the dose codes can be obtained. All participants will be provided with 
emergency information cards and ID tags and will be informed about investigator and emergency 
contact information. They will also be informed that identification of their blinded medication condition 
will not be available (except in emergency situations when the health-care provider deems it necessary) 
until after all participants at all sites have completed the study, including follow up visits. 
 
The UW IDS will have the individual dose codes for each randomized participant so the dose conditions 
for that participant may be identified without compromising the dose codes for other participants. This 
information will be accessible 24 hours per day, 7 days per week. The UW IDS will contact the study PI 
and/or Medical Director for authorization to break the blind in the event of an emergency. 
 
Once blind dose codes are revealed to emergency medical personnel, efforts should be made to contain 
the information from reaching the research staff, to the extent that such containment is possible. 
Prudent clinical follow-up should occur to maximize participant protections, as should sufficient 
investigation about the causes and consequences of the emergency event for documentation and 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
17 
 
adverse event reporting. Participants will continue to receive the medication and harm reduction 
counseling for the duration of their appointments, and data will continue to be collected; however, 
these participants will not be included in primary analyses. 
 
If the blind is broken, a note will be placed in the participant’s study record. This note will indicate the 
dose code that was revealed, a brief description of the emergency situation, and the extent to which 
study personnel have been informed of the dose code information. Examples of emergency descriptions 
may include the participant’s admission to a hospital intensive care unit or the need for high dose 
opiates due to severe pain or injuries. In almost all cases, a situation that requires breaking the blind 
would also warrant completion of a Serious Adverse Event (SAE) form that should be turned in to the 
UW IRB within 24 hours. 
 
Note: Although there may be perceived clinical advantages to individual participants to know what 
medication they received, the necessity of minimizing subject-expectancy effects during the study 
procedures and follow-up period requires maintenance of the double-blind until study completion. In 
most cases, nonemergency adverse events can be managed without breaking the blind (e.g., by 
discontinuing study medication). If, in a nonemergency situation, a local clinician feels it is in the best 
interest of the participant to break the study blind, this individual will need to contact the study PI and 
Medical Director to discuss the specific case. 
 
3.8 Study Procedures 
 
3.8.1 
Screening/baseline assessment 
 
As shown in Figure 4, agency and research staff will notify agency clients of the opportunity to 
participate in the study, and informational flyers will be posted throughout the agencies and/or 
distributed to individuals. Soon thereafter, research staff will be onsite at agency centers in planned 
rotations to conduct information sessions and baseline assessments with interested agency clients. 
During the information sessions, research staff will briefly explain the study and will ask individuals 
about their initial interest in participation. If interested, research staff will obtain verbal consent to 
administer the AUDIT-C to screen for alcohol dependence. If participants meet the initial screening cut-
off (≥4), the research staff will explain the study procedures, participants’ rights and informed consent 
materials. Next, the UBACC will be administered to assess capacity to provide informed consent. 
Potential participants will receive $5 for attending the information session, regardless of their decision, 
ability or qualification to participate. If they initially screen in and agree to participate, written informed 
consent for the study will be obtained, and participants may elect to complete the baseline assessment 
or schedule it for a later date. Based on our pilot study findings, we anticipate needing to screen 480 
individuals at baseline to achieve the proposed sample size (N = 300).  
 
One primary purpose of the baseline interview with the research staff is to determine whether 
participants meet initial criteria for the study (see sections 4.1 for inclusion criteria and 4.2 for exclusion 
criteria). The baseline interview will be administered by trained research staff holding at least a 
bachelor-level degree in the health or social sciences. Baseline assessment sessions will take 
approximately 30-45 minutes and will be audio recorded (if participant agrees). Audio recordings will 
facilitate weekly supervision conducted by the PI and other investigators. The measures (see section 3.3) 
will be administered verbally in-person with participants. Responses will be recorded by the interviewer 
on paper-and-pencil forms. 
Next, the study physician/nurse will assess the study participant in an interview that will take 
approximately 50 minutes. During this appointment, study physicians/nurses will a) open the session 
with an introduction; b) assess vital signs; c) conduct a medication reconciliation; d) take a medical 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
18 
 
history; e) administer the SAFTEE; f) conduct a physical exam (i.e., assessment of general appearance; 
head, eyes, ears, nose, and throat exam; heart, lung, and abdominal exam; musculoskeletal and 
dermatologic exam, and neurological assessment); and g) collect blood (1 EDTA and 1 red or gold top 
tube for ca. 15 ml for each blood draw during the study) and urine samples for initial lab tests, labeling 
them with study IDs. Participants will then be scheduled for a follow-up appointment the following week 
(i.e., Week 0) and will be paid $20 for their time. 
Following the baseline appointment, a member of the research study staff will then bring the samples to 
the UW Research Testing Services. The EtG samples will be returned to Sterling labs. Both the UW 
Research Testing Services and Sterling labs will conduct the lab testing using only study ID and will not 
have access to participants’ identifying information. It will take approximately three days for the results 
of the lab tests to be processed and returned to the study staff.  
During the interim week, investigators (including the PI and Medical Director) will review participants’ 
Case Report Forms, including results from the baseline interview, physical exam and lab test results, to 
consider the safety and appropriateness of proceeding with the study procedures/treatments (i.e., 
based on the inclusion/exclusion criteria listed in sections 3.2.1 and 3.2.2). Participant information for 
qualifying participants will be provided to the UW IDS who will randomize participants according to the 
scheme described in section 3.4. 
3.8.2 
Follow-up 
 
At the Week 0 appointment, the study physician/nurse will discuss findings from the baseline interview, 
physical exam and lab tests with participants and will discuss the participants’ participation course. 
Participants who do not qualify for study participation will be provided with feedback regarding their lab 
tests, exam and assessment; will be told why they do not qualify for participation; and will be provided 
with brief counseling regarding safer drinking steps. They will be thanked for their time, referred back to 
their agency staff/primary care provider and will be paid $20 for the session. 
 
Participants randomized to the TAU will receive feedback regarding blood/urine tests that is deemed 
clinically relevant, will be referred to their primary care provider (as necessary), paid $20 and scheduled 
for their next appointment time (i.e., Week 4 follow-up). Participants in the XR-NTX, placebo or HRC 
conditions will receive their specified Week 0 treatment content as described in section 3.5. They will 
then be scheduled for the Week 1 safety check-in and paid $20. At the Week 1 safety check-in, the study 
physician/nurse will perform a physical exam if clinically indicated and will complete the case report 
form, which will primarily comprise the SAFTEE, goals and safer drinking steps sections. This meeting will 
further ensure participants’ safety (for those in the medication conditions) and enhance participant 
engagement and follow-through. All active treatment groups (XR-NTX, placebo, HRC) will receive the 
same treatment components they received during week 0 (see section 3.5) at weeks 4, 8 and 12. At each 
follow-up visit, research staff will confirm with the participants that they are in possession of their wallet 
cards and study ID tags, if they receive injections. If they do not have them in their possession, research 
staff will supply new ones to the participants.  
 
All participants will attend assessment sessions identical to the baseline appointment at weeks 4, 8, 12, 
24 and 36 (see Figure 3 and 4). Participants will be paid $20 for each appointment they attend. At the 
final 36-week appointment, an additional measure will be added to the assessment battery—the 
Participant Satisfaction Assessment—to assess participants’ receipt of and satisfaction with study 
procedures. At the end of the final session, participants will receive a study completion certificate. 
 
To ensure participant retention, we will use procedures honed in previous studies with these agencies. 
At each session, participants will be asked to update their contact information and will receive 
appointment slips including the time, place and contact person for their next appointment. Prior to all 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
19 
 
appointments, reminder calls will be made to participants, or with their written permission, to agency 
staff at their respective sites and/or contacts of their choosing. 
 
Further, if participants are unable to attend their sessions at the original study location or if there is 
concern that they may be lost to follow-up if required to come to the original location, the study 
treatments and other procedures may conducted at an alternate location (e.g., housing project, shelter, 
treatment center, hospital, etc.) as long as the implementation of study procedures in the alternate 
location is deemed safe and feasible by study staff. 
 
If participants fail to appear at their follow-up appointments, we will make up to five attempts to 
contact them using the information provided in on the tracking form to reschedule their appointments 
before we consider them lost to follow-up. We will also reschedule participants for missed 
appointments up to 5 times before considering them lost to follow-up. For the safety appointment at 
Week 1, we will continue to make contact attempts until contact is made. 
 
Given their extensive familiarity with their clients and their clients’ routines, we will primarily rely on 
agency staff to help us locate participants. In the unlikely event they are unaware of their clients’ 
whereabouts, we will be prepared to additionally search jail databases for King County, Pierce County, 
Snohomish County, Washington State Prison System, and the Federal Prison System; Harborview 
Medical Center; online resources (e.g., zabasearch.com, google, white pages); and death records using 
the Social Security Death Index or via http://www.digitalarchives.wa.gov/ for WA-specific records. 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
20 
 
 
Program staff 
inform potential 
participants (Ps) 
about study
Potential Ps 
contact/are 
introduced to study 
staff by program 
staff
Positively screen 
in with AUDIT-C≥4 
and receive 
information about 
the study
Refuse to or 
cannot provide 
informed consent
Thanked for their 
time, paid $5
Ps provide written 
informed consent
Paid $5 for 
attending the 
information 
session
Baseline interview, 
physical 
exam/labs, paid 
$20
TAU
Week 0: no 
meeting
Week 1: no 
meeting
Week 4: follow-up 
interview, lab tests, 
paid $20
Week 8: follow-up 
interview, lab tests, 
paid $20
Week 12: follow-up 
interview, lab tests, 
paid $20
Week 24: follow-up 
interview, lab tests, 
paid $20
Week 36: follow-up 
interview, lab tests, 
paid $20
HRC
Week 0: HRC, 
paid $20
Week 1: HRC, 
paid $20
Week 4: follow-up 
interview, lab tests, 
HRC, paid $20
Week 8: follow-up 
interview, lab tests, 
HRC, paid $20
Week 12: follow-up 
interview, lab tests, 
HRC, paid $20
Week 24: follow-up 
interview, lab tests, 
paid $20
Week 36: follow-up 
interview, lab tests, 
paid $20
Placebo+HRC
Week 0: receive 
injection, HRC, 
med mgmt, paid 
$20
Week 1: safety 
check-in, HRC 
paid $20
Week 4: follow-up 
interview, lab tests, 
injection, med mgmt, 
HRC, paid $20
Week 8: follow-up 
interview, lab tests, 
injection, med mgmt, 
HRC, paid $20
Week 12: follow-up 
interview, lab tests, 
HRC, paid $20
Week 24: follow-up 
interview, lab tests, 
paid $20
Week 36: follow-up 
interview, lab tests, 
paid $20
XR-NTX+HRC
Week 0: receive 
injection, HRC, 
med mgmt, paid 
$20
Week 1: safety 
check-in, HRC, 
paid $20
Week 4: follow-up 
interview, lab tests, 
injection, med mgmt, 
HRC, paid $20
Week 8: follow-up 
interview, lab tests, 
injection, med mgmt, 
HRC, paid $20
Week 12: follow-up 
interview, lab tests, 
HRC, paid $20
Week 24: follow-up 
interview, lab tests, 
paid $20
Week 36: follow-up 
interview, lab tests, 
paid $20
Ps don't qualify for 
study, referred back to 
program staff/PCP if 
clinical care needed; 
paid $20
Ps scheduled for a 
later screening/ 
baseline appt


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
21 
 
4 Schedule of activities (Study Table) 
 
Year 1
Year2
Year 3
Year 4
Year 5
2
4
6
8
10
12
2
4
6
8
10
12
2
4
6
8
10
12
2
4
6
8
10 12
2
4
6
8
10
12
Hire project staff
.
Study organization and preparation
.
.
Interviewer and therapist training
.
Participant recruitment (cohort 1)
.
Baseline assessments
.
12-wk intervention and/or assessment only period
.
.
.
Posttest follow up
.
.
24-wk follow-up
.
.
36-wk follow-up
.
.
.
Participant recruitment (cohort 2)
.
Baseline assessments
.
12-wk intervention and/or assessment only period
.
.
.
Posttest follow up
.
.
24-wk follow-up
.
.
36-wk follow-up
.
.
.
Participant recruitment (cohort 3)
.
Baseline assessments
.
12-wk intervention and/or assessment only period
.
.
.
Posttest follow up
.
.
24-wk follow-up
.
.
36-wk follow-up
.
.
.
Participant recruitment (cohort 4)
.
Baseline assessments
.
12-wk intervention and/or assessment only period
.
.
.
Posttest follow up
.
.
24-wk follow-up
.
.
36-wk follow-up
.
.
.
Treatment integrity training and supervision
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Treatment integrity coding
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Administrative data management and analysis
.
.
.
.
.
.
.
Alcohol outcome data management and analysis
.
.
.
.
Dissemination
.
.
.  
 
 
5 Safety Assessments 
 
XR-NTX and oral naltrexone have been shown to have a favorable safety profile among adults with alcohol 
dependence and among current alcohol users. The known risks of taking XR-NTX are small when compared to the 
risks of untreated alcohol dependence. The safety assessments we have planned for the current study should 
provide adequate safeguards to quickly identify and respond to adverse events, should they occur. 
 
5.1 Screening/baseline assessments 
 
Participants will undergo extensive baseline screening procedures before they are deemed eligible for study 
participation. After providing written informed consent, participants’ substance use will be assessed by trained 
research staff. Participants will also meet with the study physician/nurse and will undergo assessment of vital signs, 
weight, medical history, medication reconciliation, and physical exam. Clinical laboratory tests (blood chemistry, 
hematology, liver function, and urinalysis) will also be performed during the screening/baseline appointment. 
Clinical laboratory testing will be performed during the screening/baseline appointment to determine if participants 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
22 
 
are healthy enough to receive the study medication. The laboratory testing will include a complete blood count, a 
basic metabolic panel, a liver panel, and a urinalysis. Urine drug screens and the SCID I/P will be used to rule out 
current opioid dependence prior to injections. Women who are in their childbearing years will be required to agree 
to use effective methods of birth control for the duration of the study. Women will undergo a serum hCG 
(pregnancy) test during the screening/baseline assessment. Neither pregnant nor lactating women will be included 
in the study. Additionally, both assessment staff and study interventionists will assess for suicidal ideation, intent, 
and attempts to exclude people who have made an attempt in the past year and set a baseline level of suicidal 
ideation for each participant and thereby facilitate tracking over time. Additionally, there is a standard suicide 
intervention protocol in place to be used as necessary. 
 
5.2 Ongoing safety monitoring 
 
Participants will undergo monthly clinical laboratory testing which will include a complete blood count, a basic 
metabolic panel, a liver panel, and urinalysis. Research staff will record self-reported drug and alcohol use, side 
effects and adverse events (as measured by the SAFTEE) at each follow-up visit. All serious adverse events and 
potential serious adverse events will be reported to the Medical Director and PI for determination of whether they 
are reportable under 45 CFR part 46 (see section 6.4 below for more information about reportable events). The 
study medication/placebo will be discontinued in the case of serious adverse events that are determined to be likely 
due to the study medication, and participants will be referred to their PCP and/or clinical case managers at the 
corresponding programs for appropriate follow-up care. 
 
Women will undergo hCG tests at the baseline, and those who are in the XR-NTX/placebo groups will be tested 
throughout the administration period (Weeks 0, 4, 8). Women who become pregnant during the study will be 
withdrawn from XR-NTX/placebo and will be referred to their PCP and/or clinical case manager on the program staff 
for appropriate care. 
 
Known potential side effects of XR-NTX include pain, tenderness, swelling, bruising and/or itching at the injection 
site; nausea; headache; fatigue; dizziness; vomiting; decreased appetite; painful joints and muscle cramps. Potential 
symptoms will be monitored closely during sessions with the study physician/nurse to avoid adverse consequences 
of participation in this study. Research staff will assess for and will help participants manage side effects during the 
course of the study and each of these will be explained during the informed consent process orally and in writing. 
 
Naltrexone/XR-NTX do not have addictive properties, and with the exception of opioids, they evince few interactions 
with other medications. Studies have shown naltrexone/XR-NTX to be well-tolerated.5 Rare conditions that may be 
associated with XR-NTX can often be avoided with assessment and screening procedures, and such procedures will 
be used in this study. First, XR-NTX should not be taken by individuals who are opioid dependent because it may 
induce withdrawal. Similarly, because XR-NTX is an opioid antagonist, it reduces the effectiveness of opioid 
analgesics. For these reasons, we will be conducting urine toxicology at baseline and prior to each injection and will 
not inject participants who are positive for opioids (see procedures described in section 3.5). There may also be a 
slightly elevated risk for eosinophilic pneumonia, depression and suicidality. For these reasons, research staff will 
conduct regular physical exams as clinically indicated and assessment of depression/suicide using the SAFTEE, BSS 
and SITBI. Additionally, there is a standard suicide intervention protocol in place in case a person has acute suicidal 
ideation and intent. As with any medication, there is a risk of drug hypersensitivity, although allergic reactions to XR-
NTX are very rare. All participants will be told to call 911 in the case of an allergic reaction. In some cases, reactions 
at the injection site may become severe. Injection sites should be monitored by a health-care provider for potential 
hardening, inflammation, nodules and swelling, and in extreme cases, necrosis. The research staff will make 
concerted efforts to avoid injection site reactions by ensuring that the needle passes through the superficial layer of 
fat tissue under the skin and into the gluteal muscle before the medication is injected.  
 
Finally, until recently, there was a ‘‘black-box’’ warning regarding potential hepatocellular injury. This warning was 
removed from XR-NTX in July 2013 given a lack of evidence of hepatotoxicity at the approved dosage. The warning 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
23 
 
had followed from early naltrexone studies, which prescribed daily oral doses of up to 350mg for treatment of 
obesity and dementia—seven times the currently recommended oral dose.24 Although current FDA labeling 
indicates that XR-NTX may be associated with liver injury primarily if it is administered in “excessive doses” or to 
patients with “acute hepatitis or liver failure,”22 there are no reports of hepatotoxicity involving XR-NTX.25 The large-
scale, randomized controlled trial (RCT) of XR-NTX mentioned above indicated no significant differences in 
participants’ liver function throughout the study, even among participants with previously elevated liver enzymes.23 
Gamma-glutamyl transferase (GGT) levels were lower among those receiving XR-NTX compared to placebo during 
the study, likely due to decreased drinking.23 Further, because XR-NTX is injected intramuscularly, it eliminates first-
pass metabolism, further reducing the risk of hepatotoxicity and fluctuations in plasma naltrexone levels.26 In fact, it 
has been suggested that there is greater risk of hepatotoxicity from continued, heavy alcohol use than from 
appropriate naltrexone administration.27 Research staff will, however, be monitoring liver function throughout the 
study and will discontinue the study medication if liver enzymes exceed acceptable limits (AST/ALT > 5 x ULN after a 
repeat test). 
 
In addition to the research study data collection, biannual reports on adverse events (i.e., deaths, hospitalizations, 
illness) experienced by study participants will be compiled. These reports will be reviewed by the PI and Co-Is as well 
as the Data Safety Monitoring Board. Additionally, on a biannual basis, Dr. David Atkins (DSMB statistician and chair) 
will review the study’s safety and effectiveness using a blinded, grouped analysis, which will be shared with the 
DSMB. Based on this review, the DSMB will make a recommendation for continuing or terminating the trial. Copies 
of these recommendations will be sent to the PI, Medical Director and IRB committee. 
 
6 Adverse Event Reporting 
 
6.1 Adverse event definitions 
 
• 
Adverse event: Any untoward medical occurrence in a clinical study, regardless of the causal relationship of the 
event with the study treatment. 
• 
Associated with the study treatment: Reasonable possibility that the adverse event may have been caused by 
the study treatment. 
• 
Disability: A substantial disruption of a person’s ability to conduct normal life functions. 
• 
Life-threatening adverse event: Any adverse event that places participants, in the view of the investigators, at 
immediate risk of death from the event as it occurred (i.e., does not include an adverse event that, had it 
actually occurred in a more severe form, might have caused death). 
• 
Serious adverse event: Any adverse event that results in any of the following outcomes: death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, congenital anomaly/birth defect, or threat to participants’ health that may require medical 
or surgical intervention to prevent the previous outcomes 
• 
Hospitalization: Any initial admission to a healthcare facility as a result of a precipitating clinical adverse event, 
including transfer within the hospital to an intensive care unit. Hospitalization or prolongation of hospitalization 
in the absence of a precipitating, clinical adverse event (e.g., for a preexisting condition not associated with a 
new adverse event or with a worsening of the preexisting condition; admission for a protocol-specified 
procedure) is not, in itself, a serious adverse event. 
• 
Unanticipated problem: OHRP designation for an adverse event that a) is unexpected in nature, severity or 
frequency; b) is related or possibly related to participation in the research; and c) may place participants or 
others at a greater risk of physical or psychological harm. Under 45 CFR part 46, unanticipated problems must be 
reported to the IRB for report to the OHRP within 2 weeks. If the unanticipated problem is also a serious or life-
threatening adverse event, it must be reported to the IRB for report to the OHRP within 1 week. 
 
6.2 Eliciting adverse event information 
 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
24 
 
Contact information for the research team and the IRB will be provided in all consent materials, and participants will 
be encouraged to report adverse events to research staff. Participants will be routinely questioned about adverse 
events at study visits using the SAFTEE, which was tailored specifically for use with the study medication. Further, 
lab tests and physical exams will be used to detect potential adverse events. These will be regularly reviewed by the 
PI and Medical Director in weekly meetings. Adverse events or abnormal test findings believed to be associated with 
the study treatment will be followed until the event (or its sequelae) or the abnormal test finding resolves or 
stabilizes at a level acceptable to the PI and Medical Director. 
 
In the case of a suspected unanticipated problem or serious adverse event, research staff will promptly call the PI or 
Medical Director, and will follow a detailed protocol which ranges from encouraging or assisting the participant to 
speak with his or her onsite case manager (assigned to all clients of DESC and REACH) to calling 911 or a county 
Mental Health Professional to assess for involuntary hospitalization, depending on the nature of the event. Research 
staff will record all observed or volunteered serious adverse events using the designated form in the CRF, which will 
be turned in to the PI and Medical director for review before it is submitted to the IRB. 
 
If upon review, it is unclear whether an adverse event meets criteria for an unanticipated problem or serious 
adverse event, the PI and Medical Director will promptly seek out and review further documentation and/or 
abnormal test findings to determine 1) if they should be classified as adverse events; 2) if there is a reasonable 
possibility that the adverse events were caused by the study treatment; and 3) if the adverse events meet criteria 
for a serious adverse event or unanticipated problem. If causality is determined to be of “unknown and of 
questionable relationship” to the study treatment, the adverse event will be classified as associated with the study 
treatment for reporting purposes. If the determination of causality is “unknown but not related to the study 
treatment,” this determination and its rationale will be documented in the study log. If serious adverse 
events/unanticipated problems are deemed to be due to the study medication, it will be discontinued and 
appropriate follow-up care will be coordinated. 
 
Research staff will also obtain HIPAA authorizations/releases of information for agency and local hospital records of 
potential adverse and serious adverse events (e.g., hospitalizations, death, disability). Safety data will be compiled 
on a biannual basis and will be monitored by the PI and Co-Is as well as the Data Safety Monitoring Board. On a 
biannual basis during the study, the DSMB chair will generate a recommendation for continuing or terminating the 
trial. Copies of these reviews will be sent to the PI (Collins), the Medical Director (Ries) and the UW IRB. The report 
and recommendations will be discussed with research and agency staff in research meetings during the course of 
the RCT.  
 
6.3 Recording requirements 
 
 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, regardless of 
treatment group or suspected causal relationship to the study treatments will be recorded in the participants’ CRF in 
the appropriate space or using the adverse event form. For all adverse events, sufficient information will be pursued 
and/or obtained so as to permit 1) an adequate determination of the outcome of the event (i.e., whether the event 
should be classified as a serious adverse event) and; 2) an assessment of the casual relationship between the adverse 
event and the study treatment. Adverse events or abnormal test findings believed to be associated with the study 
treatment will be followed until the event (or its sequelae) or the abnormal test finding resolves or stabilizes at a 
level acceptable to the PI and Medical Director. 
 
6.3.1 
Abnormal test findings, side effects and other study occurrences 
 
An abnormal test finding, side effect or other study occurrence will be classified as an adverse event if 
one or more of the following criteria are met: 
 
• 
It is accompanied by clinically significant symptoms. 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
25 
 
• 
It necessitates additional diagnostic evaluation(s) or medical/surgical intervention; including 
significant additional concomitant drug treatment or other therapy  
(Note: simply repeating a test finding, in the absence of any of the other listed criteria, does not 
constitute an adverse event.) 
• 
It leads to a change in study dosing or discontinuation of participant participation in the study 
• 
It is considered an adverse event by the PI and Medical Director 
6.3.2 
Causality and severity assessment 
 
The investigators (including the PI and Medical Director) will promptly review documented adverse 
events and abnormal test findings to determine 1) if the abnormal test finding should be classified as an 
adverse event; 2) if there is a reasonable possibility that the adverse event was caused by the study 
treatment/procedures; and 3) if the adverse event meets the criteria for a serious adverse event. 
 
Relationship 
Criteria for assessment 
 
Definitely related 
There is evidence of exposure to the study drug AND 
• 
The temporal sequence of the AE onset relative to the 
administration of the study drug is reasonable 
• 
The AE is more likely explained by the study drug than by another 
cause 
• 
Dechallenge (if performed) is positive 
• 
Rechallenge (if performed) is positive 
• 
The AE shows a pattern consistent with previous knowledge of the 
study drug or study drug class 
 
Probably related 
There is evidence of exposure to the study drug AND 
• 
The temporal sequence of the AE onset relative to the 
administration of the study drug is reasonable 
• 
The AE is more likely explained by the study drug than by another 
cause 
• 
Dechallenge (if performed) is positive 
 
Possibly related 
There is evidence of exposure to the study drug AND 
• 
The temporal sequence of the AE onset relative to the 
administration of the study drug is reasonable 
• 
The AE could have been due to another equally likely cause 
• 
Dechallenge (if performed) is positive 
 
Probably not related 
There is evidence of exposure to the study drug AND 
• 
There is another, more likely cause of the AE 
• 
Dechallenge (if performed) is negative or ambiguous 
• 
Rechallenge (if performed) is negative or ambiguous 
 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
26 
 
Definitely not 
related 
The participant was not exposed to the study drug OR 
• 
The temporal sequence of the AE onset relative to administration of 
the study drug is not reasonable OR 
• 
There is another obvious cause of the AE 
6.4 Reporting of adverse events   
 
Any observed or volunteered adverse event that is determined to be a serious adverse event or an unanticipated 
problem will be reported by the PI to the IRB and Alkermes within 24 hours of receipt of this information. This will 
be done even if a serious adverse event is determined to be “probably not related” or “definitely not related” to the 
study medication/study procedurs, although it is understood that it typically must not be officially reported unless it 
is found to be a serious adverse event that is possibly due to the study medication/study procedures. Follow-up 
information to the reported serious adverse event or unanticipated problem will be submitted to the IRB and 
Alkermes as soon as the relevant information is available—particularly regarding the association of the study 
medication or procedures with the serious adverse event. It is conceivable that further investigation could show that 
a serious adverse event or unanticipated problem that was initially determined to not require reporting does, in fact, 
meet the requirements for reporting. Such events will be reported to the IRB as soon as possible and no later than 
24 hours after the determination was made. Unanticipated problems will be reported to OHRP as specified under 
federal law (45 CFR part 46). 
 
6.5 Withdrawal of Participants Due to Adverse Events 
 
Participants will be withdrawn from the XR-NTX/placebo treatment course if they experience an adverse event 
determined qualify as a serious adverse event or unanticipated problem and probably due to the medication. Other 
reasons for withdrawal from the medication treatment course include participants’ decision to discontinue study 
medication; pregnancy; elevated liver enzymes (AST/ALT > 5x normal after repeat test); renal insufficiency (serum 
creatinine level > 2; and/or physical illness/injury that precludes following the prescribed XR-NTX/placebo course. In 
this case, the reason for discontinuation of medication will be noted on the participants’ CRF and will be noted in 
safety reports. The study medication will be discontinued, and participants will be encouraged to discuss their 
medical condition/lab test findings with their assigned clinical case manager on the program staff and primary care 
physician for follow-up care. In the case participants do not have a primary care provider, they will be referred to 
local primary care clinics. In the case of an observed or self-reported adverse event of questionable severity, 
research staff will immediately contact the medical director and PI. If it is determined to fit the definition of a 
serious adverse event or unanticipated problem, this will be reported to the IRB as discussed in previous sections. In 
case of life-threatening event, research staff will immediately inform the medical director, the PI and the 
participants’ clinical case manager at the program agency, who will take immediate, clinically appropriate action. 
Unless participants explicitly request to withdraw their participation altogether or the adverse event prevents 
participation, they will continue with follow-up assessment subsequent to treatment discontinuation. 
 
7 Statistical Methods/Data Analysis: 
 
7.1 Study endpoints 
 
Primary and secondary endpoints for the current study will include alcohol (i.e., peak alcohol quantity, drinking 
frequency, alcohol-related problems, EtG/creatinine ratio, liver tests) and quality-of-life outcomes; 
process/mediational variables (i.e., motivation to engage in harm reduction, craving); and publicly funded service 
utilization and associated costs (i.e., Medic One/EMS dispatches; ER visits; inpatient hospital admissions; bookings, 
length of stay and daily cost for the King County Correctional Facility). 
 
7.2 Sample size determination 
 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
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Using Mplus 6.11,106 we conducted Monte Carlo studies to estimate power for the primary outcome analyses to be 
conducted in Specific Aims 1 and 3. Data were generated from a population with hypothesized parameter values, 
10,000 samples were drawn at random, and model parameters were estimated for each sample. A significance level 
of α = .05 was assumed for the hypothesized treatment effects for each of the outcome variables. Residual variance 
was set at .09, which is a representative value for this model type107 and corresponds to calculations based on data 
from our prior studies in a similar population.49,56 For Hypothesis 1a, assuming a follow-up attrition rate of 20%,49 a 
Monte Carlo study indicated power (β-1) of .92 to detect a small-to-medium effect (γ=.15) for HRC and placebo and 
β-1=.99 to detect a medium effect for XR-NTX (γ=.2; corresponding to Cohen’s d=.63; following suggestions by 
Muthén and colleagues107) compared to TAU for our proposed sample size (N=300). For Hypothesis 1b, power was 
adequate (β-1=.83) to detect a medium effect (γ=.2) for XR-NTX compared to placebo (N=150). These estimated 
effect sizes were deemed appropriate given findings from prior studies with this population49,56 and with the study 
medication.5,68 
 
For specific aim 3, assuming no missing utilization data, a Monte Carlo study indicated adequate power (β-1=.81) to 
detect a medium effect (γ=.2) for XR-NTX compared to TAU.107 This test will, however, be underpowered to detect 
the hypothesized small-to-medium (γ=.15) effects for placebo and HRC (β-1=.57). The fact that the weaker 
treatment effects are underpowered is not unexpected for cost analyses in smaller clinical trials.108 Although the 
proposed population comprises relatively high utilizers of EMS, ER, inpatient hospital and jail services, the frequency 
of emergency and criminal justice system utilization is still statistically rare. 
 
 
7.3 Proposed analyses 
 
Outcome analyses will comprise a series of latent growth curve models utilizing appropriate probability distributions 
for the outcome variables (e.g., Poisson, negative binomial, Gaussian, logistic). Growth modeling examines 
individuals’ outcome trajectories and covariate effects on these trajectories over time.109 Growth modeling will be 
conducted using Mplus 6.11, which incorporates a generalized latent framework and allows for a wide array of 
variable types, estimation methods and longitudinal modeling options.106 Mplus uses a multivariate approach to 
growth modeling in contrast to the multilevel approach proposed by Raudenbush and Bryk.110  
 
Outcomes measured at each time point will serve as indicators of the intercept (i.e., baseline) and slope (i.e., change 
in outcomes over time). Treatment group will serve as the primary predictor of slope. Covariates (e.g., housing 
status, agency) will serve as additional predictors of intercept or slope, as necessary. Outcome variables are based 
on established standards in the alcohol-use literature111-113 and our own studies on alcohol-use in similar 
populations.49,56 
 
Analyses for Specific Aim 1 will feature growth models to test treatment effects on 3, 30-day alcohol outcomes: peak 
alcohol quantity, drinking frequency and alcohol-related problems. In secondary analyses, we will additionally test 
the treatment effects on the EtG/creatinine ratio and liver values to biovalidate the primary, self-report outcomes. 
Although the proposed alcohol outcomes differ from those typically encountered in clinical drug trials, they were 
deemed appropriate for the proposed study aims and population. First, most naltrexone studies have used an 
abstinence-based treatment model and have thereby employed complementary, abstinence-oriented outcomes 
(e.g., days to relapse, percent days abstinent). Because we have proposed a harm-reduction treatment model, we, 
too, deemed it important to focus on complementary outcomes: reduced alcohol-use and -related harm. Second, 
the baseline assessment during our pilot study indicated participants had a 30-day median drinking frequency of 30 
days and a peak alcohol quantity of 30 drinks. Given the extent of alcohol use in this population, abstinence-based 
outcomes would be blunt instruments that would not capture nuanced longitudinal changes in alcohol-use and -
related problems. Finally, in keeping with the harm-reduction philosophy, we are proposing to assess multiple 
outcomes to reflect the various pathways by which individuals might change their drinking to achieve reductions in 
alcohol-related harm.  
 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
28 
 
To test Hypothesis 1a, we will conduct growth models comparing the relative effects of the three active treatment 
groups with the TAU group on alcohol outcomes (see Figure 5). It is hypothesized that the three active treatment 
groups will evince significantly greater decreases across alcohol outcomes than TAU. To test Hypothesis 1B, we will 
conduct a second set of growth models directly comparing the XR-NTX and placebo effects on alcohol outcomes. It is 
hypothesized that the XR-NTX group will evince significantly greater decreases than the placebo group on alcohol 
outcomes over the follow-up period. 
 
For Specific Aim 2, we will be testing 
longitudinal changes on secondary, theoretical 
variables as mediators of the treatment effects 
on alcohol outcomes. To test Hypothesis 2a, 
growth analyses will be conducted to 
determine whether the 3, active treatment 
groups are associated with significant increases 
in motivation to change drinking in a way that 
reduces harm as represented by the DBP and 
readiness, motivation, importance and 
confidence rulers. If this is the case, the alcohol 
growth model established in analyses for 
Specific Aim 1 and the motivation growth 
model will be combined into a single parallel 
process growth model.114 The mediation effect 
will be tested by taking the product of 
coefficients (αβ), where α=the regression of the 
slope of the mediator on the dummy-coded 
intervention variables and β=the regression of 
the slope of the alcohol outcome variable on 
the slope of the mediator, using the asymmetric confidence interval (CI) approach.115 This same procedure will be 
used to test hypothesis 2B or whether XR-NTX produces significantly greater decreases on alcohol craving than the 
placebo group, and whether those decreases in craving are in turn associated with decreases on alcohol outcomes. 
 
Because homeless people with alcohol dependence disproportionately utilize costly medical and criminal justice 
services,49,116,117 it is important to assess the impact of interventions for this population on publicly funded service 
costs. Specific Aim 3 will therefore assess relative effects of the 3 active treatments (i.e., XR-NTX, placebo and HRC) 
compared to TAU on costs stemming from: a) the number of emergency medical service dispatches; b) number of ER 
visits; c) number of inpatient hospital admissions; d) number of bookings and length of stay at the King County 
Correctional Facility. As in Specific Aim 1, this analysis will feature a growth model in which the mean monthly costs 
during 3 timepoints (i.e., 2 years prior to baseline, during the 12 weeks of treatment, and during the 24-week follow-
up) will serve as indicators of the latent variables. We will use the mean monthly costs to account for the differing 
lengths of the time points. The 3 active treatment groups will serve as dummy-coded variables predicting the cost 
slope, which is expected to decrease at a significantly greater rate for the XR-NTX, placebo and HRC groups (in 
descending order) compared to the TAU group. 
 
 
8 Quality Control and Quality Assurance 
 
This protocol and other study documentation will be reviewed and approved by the UW IRB prior to study start 
date. The study will involve qualified and trained professionals who will administer the clinical interviews, physical 
exams and study treatment according to the guidelines laid out in this protocol and in the HaRP treatment manual. 
Specifically, study physicians will be licensed medical doctors who have completed their residencies in psychiatry 
and have either completed or are completing an addiction psychiatry fellowship. Study nurses will be registered 
Figure 5. Hypothesized primary intervention model. “Intercept” is the baseline 
measurement of the outcome variable (DV). “Slope” represents change in the 
DV over time. DV= outcome or dependent variable. D=latent variable 
disturbance (error). E=measured  variable error. 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
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nurses who are completing an advanced Doctor of Nursing Practice program at the UW. Research staff conducting 
assessments will have at least a bachelor-level degree in the health or social sciences. All study staff will receive 
training and weekly supervision from the PI and Co-Investigators. Training on treatment and assessment delivery will 
comprise 16 hours of in-person training, including review of the manual, role-plays, and feedback. Study staff will 
audio record all participant sessions to facilitate supervision and treatment integrity analyses, including manual 
adherence, therapist competence, and participants’ receipt and enactment of the HaRP principles. 
 
All adverse events will be recorded on the CRF and/or on the adverse event reporting form. These will be reported 
to the PI and medical director in weekly meetings and by personal consultation so the team may determine whether 
it constitutes an unanticipated problem and/or serious adverse event that warrants reporting to the IRB and OHRP. 
Additionally, the scientific team and DSMB will review the safety data on a biannual basis in report form. The DSMB 
will then make a recommendation, which will be sent to the PI and IRB, regarding the appropriateness of continuing 
the study. 
 
9 Data Handling and Record-Keeping 
 
9.1 Data recording/Case Report Forms   
 
Assessment packets and Case Report Forms (CRF) will be completed for each participant enrolled into the clinical 
study.  During weekly meetings, the PI and Medical Director will review, approve and sign/date each completed CRF. 
These signatures will serve as attestation of their responsibility for ensuring that all clinical and laboratory data 
entered on the CRF are complete, accurate and authentic. 
 
Source Data are the clinical findings and observations, laboratory and test data, and other information contained in 
Source Documents.  Source Documents are the original records (and certified copies of original records); including, 
but not limited to lab test results, physician or nursing session notes, evaluation checklists, participants’ self-
reported data, and agency/hospital records. When applicable, information recorded on the CRF shall match the 
Source Data recorded on the Source Documents.   
 
9.2 Record maintenance and retention  
 
The investigators will maintain records in accordance with Good Clinical Practice guidelines. These will include: 
 
• 
FDA correspondence related to the IND status  
• 
IRB correspondence (including approval notifications) related to the protocol, including copies of adverse 
event reports and annual or interim reports 
• 
Current and past versions of the IRB-approved clinical protocol and corresponding IRB-approved consent 
form(s) and, if applicable, participant recruitment advertisements 
• 
Financial disclosure information (investigators) – Note: this is now reported and maintained in online 
databases through the UW FIDS 
• 
Biosketches (investigators) 
• 
Certificates of required training (e.g., human participant protections, HIPAA, etc.) for PI and Co-Is 
• 
Listing of printed names/signatures of investigators 
• 
Normal value(s)/range(s) for medical/laboratory/technical procedures or tests included in the clinical 
protocol 
• 
Instructions for on-site preparation and handling of the investigational drug(s), study treatment(s), and 
other study-related materials (i.e., if not addressed in the clinical protocol) 
• 
Signed informed consent forms 
• 
Completed Case Report Forms; signed and dated by investigators 
• 
Source Documents or certified copies of Source Documents 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
30 
 
• 
Copies of investigators’ correspondence among one another regarding notifications of safety information 
and adverse events 
• 
Participant screening and enrollment logs 
• 
Participant identification code list 
• 
Investigational drug accountability records, including documentation of drug disposal. 
• 
Final clinical study report 
 
Great care will be taken to maintain the confidentiality of data provided by participants contained in these records. 
Direct subject identifiers, including participants’ names and contact information, will be collected to facilitate follow-
up communication and thereby assess intervention safety and efficacy over time. However, all records—including 
lab tests—will be identified only with a randomly generated, unique ID. Master lists of IDs and direct identifiers will 
be stored in locked file cabinets and password-protected computers with restricted access. These lists will be 
available only to research staff on this project. All UW research staff (including IDS personnel) will be required to 
sign a confidentiality statement and complete HIPAA and human subjects training before having contact with 
participants or participants’ identifiable private information. The linkage will be destroyed one year after study 
completion. All data will be collected specifically for the proposed research study.  
 
10 Ethics 
 
10.1 
Institutional Review Board (IRB) approval 
 
The investigators will obtain, from the UW IRB, prospective approval of the clinical protocol and corresponding 
informed consent form(s); modifications to the clinical protocol and corresponding informed consent forms, and 
advertisements (i.e., directed at potential research participants) prior to study recruitment.    
 
The only circumstance in which a deviation from the current IRB-approved clinical protocol/consent form(s) may be 
initiated in the absence of prospective IRB approval is to eliminate an apparent immediate hazard to the research 
participant(s). In such circumstances, the investigators will promptly notify the UW IRB of the deviation using the 
appropriate designation(s) on the Report of Other Problems (ROOP) form based on IRB counsel (i.e., unanticipated 
problem, protocol deviation, protocol violation or other problem). 
 
10.2 
Ethical and scientific conduct of the clinical study 
 
This study will be conducted in accordance with the clinical protocol currently under review by the UW IRB and 
relevant policies, requirements, and regulations of the UW IRB, Washington State, and applicable federal agencies. 
 
10.3 
Participant informed consent  
 
The investigators will make certain that an appropriate informed consent process is in place to ensure that potential 
research participants are fully informed about the nature and objectives of the clinical study, the potential risks and 
benefits of study participation, and their rights as research participants.  Designated research staff will obtain the 
written, signed informed consent of each participant prior to performing any study-specific procedures. The date 
that the participant signs the informed consent form and a narrative of the issues discussed during the informed 
consent process will be documented on the consent form. The investigators will retain the original copy of the 
signed informed consent form, and a copy will be provided to the participant. 
 
The investigators will make certain that appropriate processes and procedures are in place to ensure that ongoing 
questions and concerns of enrolled participants are adequately addressed and that participants are informed of any 
new information that may affect their decision to continue participation in the study.  In the event of substantial 


University of Washington - Collins 
Harm Reduction with Pharmacotherapy (HaRP) 
31 
 
changes to the clinical study or the risk-to-benefit ratio of study participation, the investigators will obtain the 
informed consent of enrolled participants for continued participation. 
 
 


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32 
 
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ICF_001.pdf: 
 
1 
 
HaRP Study 
Consent Form 
V12 November 16, 2017 
UNIVERSITY OF WASHINGTON 
CONSENT / INFORMATION FORM 
Harm Reduction with Pharmacotherapy (HaRP) 
 
University of Washington Researchers: 
Susan E. Collins, Ph.D., Principal Investigator, Associate Professor, Dept. of Psychiatry and Behavioral Sciences, UW, 
206-744-9181, collinss@uw.edu** 
 
 
**Note: We cannot guarantee the confidentiality or security of email communication. 
 
In case of a study-related emergency, please contact 911, your case manager or call the Harborview Emergency 
Room at 206-744-3074. 
 
Case Manager: _____________________________________________ 
 
Researchers’ Statement 
We are asking you to be in a research study. The purpose of this consent form is to give you the information you will need 
to help you decide whether to be in the study or not. Please read the form carefully. You may ask questions about the 
purpose of the research, what we would ask you to do, the possible risks and benefits, your rights as a volunteer, and 
anything else about the research or this form that is not clear. When we have answered all your questions, you can decide 
if you want to be in the study or not. This process is called ‘informed consent.’ You will receive a copy of this form for your 
records. 
 
PURPOSE OF THE STUDY 
This is a combined medical and behavioral research study. The purpose of this study is to determine whether or not the 
study medication (Vivitrol®) and counseling are effective in reducing the harms associated with alcohol use among people 
who are dependent on alcohol and have been or are currently homeless. We plan on having 300 participants complete 
this study. The information you provide for this study will help us determine whether the study medication and/or 
counseling may help active drinkers reduce their alcohol-related harm. 
 
STUDY TREATMENTS  
 
The study medication is a 30-day, extended release form of naltrexone, which blocks opioid receptors in the brain. The 
study medication is given monthly via an injection into the gluteal (buttocks) muscle. The Food and Drug Administration 
(FDA) has approved the study medication for the treatment of alcohol dependence. Research has shown that the study 
medication may decrease alcohol cravings, alcohol use and alcohol problems as well as improve people’s quality of life. 
In harm-reduction counseling, health-care professionals help people reduce their alcohol-related harm and improve 
their quality of life. Harm reduction counseling does not require that people stop using alcohol or other drugs. In this study, 
staff will ask you about your personal and drinking goals. They will then help you figure out ways to work towards those 
goals. They will also talk to you about how to be safer if you choose to drink. 
 
STUDY PROCEDURES 
First, you will meet with UW research staff who will tell you more about the HaRP study. You will receive $5 just for 
meeting with the UW research staff—even if you decide not to participate. If you do decide to participate, you will be 
interviewed by research staff, which will take approximately 30 minutes. We will ask you about some personal 
characteristics (age, gender). We will also ask you about your alcohol use and your thoughts about your alcohol use. 
Some of these questions may seem private or uncomfortable. You are free to not answer any question you do not 
want to answer. Your answers to these questions will remain confidential and known only to the research staff. Then, you 
will be interviewed by the study physician/nurse, have a physical exam and provide urine and blood samples (we will draw 
2 small tubes of blood or 3 teaspoons) for lab tests including tests to find out if you are pregnant or if there are any opioid 
based medications in your bloodstream.. This will take about 60 minutes. The results of these tests will remain confidential 
and will only be used by research staff to determine if you are a good fit for this study and to track your progress over 


 
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HaRP Study 
Consent Form 
V12 November 16, 2017 
time. You will be scheduled to return one week later for another 45-minute meeting to discuss the findings with the 
research staff (Week 0). 
 
If you are not eligible for the study, we will discuss your lab test findings and give you a recommendation for next steps, 
including a referral for further care. Regardless of the outcome, you will be paid $20 for the Week 0 session. 
 
If you are eligible for the study, you will be assigned at random (like flipping a coin) to: 
• 
be interviewed, 
• 
receive counseling, 
• 
receive counseling + placebo (an injection with no medication in it) 
• 
receive counseling + study medication 
once a month for 3 months. Neither you nor the researchers will know which injection you are receiving (placebo or active 
injection). If you would like to know your group assignment, please let us know and will we provide that information to you 
at the end of the study. Each group’s experience is outlined in the figure below. At the end of each session, you will 
receive $20 for your time. 
 
 
 
 
COMMUNITY SERVICES DATA 
To keep you safe during the study, we will access records where you get your supportive and health care services 
(Downtown Emergency Service Center, Evergreen Treatment Services-REACH, Neighborcare Health, Catholic Housing 
Services, UW Medicine and/or other medical centers as applicable) about “adverse events” (hospitalization or illness) you 
have experienced from two years before the study (10/14/11) through the study end date (9/30/18). With your permission, 
we will be given records that show illnesses you have experienced, where you have used other treatment/hospitalization 
services, how many times you have used services, how long the services lasted, and what types of services you received. 
We will not share your personally identifiable private information with anyone but will use this data to compile reports to be 
sure the medication is safe for you to continue. This research study will have no effect on your ability to use community 
services in the future or the quality of services that you will receive. Finally, the site where we meet with you will write in 
your client file that you are participating in this study. However, we will not share any other study information with site staff 
without your permission, except in case of a serious or life-threatening situation. 
 
We also want to learn about other community services that you have used and will use during the course of the study.  
Community services will include: 
• Harborview Medical Center inpatient, outpatient, Psychiatric Emergency Services, Emergency Department 
• King County Medic One/Emergency Medical Services  
Week1 Safety check-in


 
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HaRP Study 
Consent Form 
V12 November 16, 2017 
• King County Correctional Facility  
 
• Washington State Comprehensive Hospital Abstract Reporting System (CHARS) 
 
To do this, with your permission, we will be given records that show where you have used services, how many times you 
have used services, how long the services lasted, and how much these services have cost. For these records, we will not 
record specific treatment or diagnosis information beyond type of service (like ER visit), how many times you used it, and 
how much it cost. We will request this information for the two years prior to your study participation through your final 
follow-up appointment. We will not share information from one agency with another agency. This study will have no effect 
on your ability to use community services in the future or the quality of services that you will receive. You may also 
change your mind about this later and may write a letter to Dr. Susan Collins at 325 Ninth Ave, Box 359911, Seattle, WA 
98195 to say that you do not want any more information about you shared. 
 
AUDIO RECORDINGS OF SESSIONS 
We would also like to audio record sessions during the study to: 
• 
Be sure that the research staff are conducting the assessments and treatment sessions correctly and in the same 
way every time. 
• 
Train staff on how to do the sessions. 
• 
Assess how the sessions are being delivered by staff and received by you so we can change them in order to 
better fit your needs. 
 
Participating in audio recording is optional. You don’t have to give us permission to audio record if you don’t want to. If you 
do allow us to audio record sessions, you can review and delete any portion of the audio recordings at any time during the 
study. At the end of this consent form, we will ask you to mark whether or not you would like to participate in audio 
recording your sessions. Even if you choose to audio record now, you can change your mind at any time, and may also 
take away permission for us to keep any audio recordings. 
 
RISKS, STRESS, OR DISCOMFORT 
The Food and Drug Administration (FDA) has approved the study medication for the treatment of alcohol dependence. 
We are using the study medication off-label, and have submitted our protocol for FDA review. The risks associated with 
blood draws include pain at the place where the needle is inserted as well as the possibility of bruising and a risk of 
infection at the place where the needle is inserted. Some people feel anxious with blood draws and may faint. The side 
effects of the study medication may include headache, dizziness, decreased appetite, depressed mood, muscle cramps, 
nausea, fatigue, vomiting, painful joints.There may be pain, tenderness, swelling, bruising, and itching/irritation at the 
injection site which may be severe. If you experience any of these common side effects, you should contact Dr. Collins 
(206-744-9181). We will arrange for you to come in and be checked by a study physician/nurse and will help you manage 
the side effects. More serious adverse events experienced by a very small number of people in studies involving 
naltrexone have included liver damage or hepatitis, eosinophilic pneumonia or allergic reactions. If you experience these 
serious adverse events, we may contact your case manager/health-care provider to explain the situation and get you the 
proper follow-up care. Further, if we learn information during the study about conditions that pose immediate danger to 
your health and safety if you participate, we will share this information with you, and if necessary, agency staff and/or 
other public safety and health-care personnel to ensure your health and safety are protected. If a serious and/or life-
threatening event happens during the study, we will also discuss relevant information we have with agency staff and/or 
other public safety and health-care personnel, as necessary, to help keep you and other participants safe. In case of 
emergency, please contact 911, your case manager/health-care provider, or Harborview Medical Center (206-744-3074). 
 
The study medication should not be taken by people who are physically dependent on opioid-based medications 
(oxycodone, methadone) or street drugs (heroin) because it can trigger opioid withdrawal symptoms. Because the study 
medication blocks opiates from working, it may also reduce the effectiveness of pain medications. Please let the study 
staff know promptly if you are taking any type of pain medication or other opiates. 
Because the risks to the unborn baby from exposure to the study drug are unknown, pregnant or nursing women may not 
participate in this study. Women in their childbearing years must agree to use a reliable method of birth control while 
participating in this study. Reliable methods of birth control include birth control pills, intrauterine device, injectable or 
implanted contraceptives, tubal ligation, true abstinence, or diaphragm and condom plus spermicidal foam. We will also 
ask you to take a urine pregnancy test before starting to take the study medication, and throughout the 3-month treatment 
period, if you are assigned to counseling+study medication or counseling+placebo groups. If you suspect you have 
become pregnant while participating in this study, you should promptly contact the research staff and let us know. 


 
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HaRP Study 
Consent Form 
V12 November 16, 2017 
 
Other risks associated with participation are primarily related to the sensitivity of some of the questions. You will be asked 
about your alcohol use as well as thoughts, feelings, and personal difficulties that may be private. These questions may 
make you feel uncomfortable or seem intrusive, or you may become concerned about your alcohol use as you answer the 
questions. In addition, you will be asked to report on potentially illegal behaviors, such as opiate and other drug use. 
Answers to these questions could pose a risk if the information were known and linked to identifiable individuals. 
 
You may find that having your assessments and medication management sessions audio recorded during the study is a 
violation of your privacy. Participating in the audio recorded sessions is optional.  We will make every effort to keep the 
information you give us secure. You can review and delete any portion of the audio recordings at any time during the 
study. If you choose to participate now, you can change your mind at any time. 
 
ALTERNATIVES TO TAKING PART IN THIS STUDY 
Other kinds of treatments for alcohol dependence may be available to you outside of this study. If you choose not to 
participate in this study but have questions about alcohol or other health-related behaviors, we can provide you with 
information about resources located within the community.  
 
BENEFITS OF THE STUDY 
There may be no direct benefit to you for participating in this research, however, you may benefit by learning more about 
yourself through completing the study. If you are in a group receiving the medication and/or counseling, you may also 
notice a reduction in your alcohol cravings, alcohol use and/or alcohol problems. Because individuals respond differently 
to treatment, no one can know for sure if the study medication and counseling will be helpful in your particular case. 
However, research studies have shown that the study medication and brief counseling are safe and effective treatment for 
alcohol dependence. It has been FDA approved for this use. Benefits to society include the opportunity to contribute to 
research to test if the study treatments reduce alcohol-related harms for people who are currently using alcohol. 
 
SOURCE OF FUNDING 
 
The researcher for this study, Dr. Susan Collins, is receiving payment from the study sponsor, the National Institutes of 
Health, to support the study staff and study procedures. The study medication is being provided free of cost by Alkermes, 
Inc.  
 
FINANCIAL INTEREST 
Richard Ries, MD, has a financial relationship with Alkermes, Inc., who makes Vivitrol® (injectable naltrexone). Dr. Ries 
has attended trainings and given talks for Alkermes, Inc. Dr. Ries has received compensation for these activities in 
addition to his salary from the University of Washington. This financial interest and the design of the study have been 
reviewed and approved by the University of Washington. A Management Plan was developed to minimize any possible 
effect of this financial interest on your safety or welfare. The Plan will also protect the quality and reliability of the research. 
 
CONFIDENTIALITY OF RESEARCH INFORMATION 
All of the information you provide will be confidential. However, if we learn that you intend to harm yourself or others, we 
must report that to the authorities to keep you and others safe. 
 
Your name and other identifying information will be linked to a unique study ID number. The ID number is randomly 
generated for research purposes. Your study ID will not include any information that can identify you and will only be 
known to you and the researchers.  All of the data and samples (blood and urine) we collect from you will be coded with 
your study ID. 
 
The master list linking your identifying information to your study data and samples will be kept in a separate, secure 
location. Your name and contact information will be accessible only to research staff (including the UW Investigational 
Drug Service pharmacy) for the purposes of contacting you to complete the study, conducting random assignment and 
dispensing the study medication. We will keep your name and contact information until December 31, 2021 to ensure 
safety during the study and to ensure your payments and any messages about your participation can be delivered. As 
necessary, we will contact you using the information you provide us with and using your preferred contact methods (i.e., 
by phone, email, in person or via agency staff that you have designated in writing). The link between your identifying 


 
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HaRP Study 
Consent Form 
V12 November 16, 2017 
information and study data/samples will be destroyed on December 31, 2021. Your coded blood and urine samples will be 
destroyed after tests are completed. 
 
Audio recordings will be coded with your study ID only and will not include any information that can identify you. We will 
store the audio recordings on password protected computers and on a secure server supporting 128-bit encryption. The 
audio recordings will be transcribed and used for research purposes. De-identified transcriptions of audio recordings will 
be kept indefinitely. 
 
Your coded data may be shared with other researchers doing similar work at other hospitals, and/or be combined with 
data from other hospitals in some research reports. You will not be personally identified in any research reports or 
presentations of this research. Coded research data will be retained indefinitely. 
 
Government or university staff sometime review studies such as this one to make sure they are being done safely and 
legally. If a review of this study takes place, your records may be examined. The reviewers will protect your privacy. The 
study records will not be used to put you at legal risk of harm. The U.S. Food and Drug Administration (FDA) reserves the 
right to review study data that may contain identifying information. 
 
We will do everything we can to keep others from learning about your participation in this study. To further help us protect 
your privacy, we have obtained a Certificate of Confidentiality from the United States Department of Health and Human 
Services (DHHS). 
 
With this Certificate, we cannot be forced (for example by court order or subpoena) to disclose information that may 
identify you in any federal, state, local, civil, criminal, legislative, administrative or other proceedings. The researchers will 
use the Certificate to resist any demands for information that would identify you, except to prevent serious harm to you or 
others, and as explained below. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your family, from 
voluntarily releasing information about yourself or your involvement in this study. 
 
If an insurer, employer or health-care, service or treatment provider learns about your participation and obtains your 
consent to receive research information, then we may not use the Certificate of Confidentality to withhold this information. 
This means that you and your family must also actively protect your own privacy. 
 
There are some limits to this protection. We will voluntarily provide the information to: 
• 
DHHS employees for the purpose of audit or evaluation; 
• 
individuals at the University of Washington or the funding agency if they need the information to make sure the 
research is being done correctly; 
• 
the federal Food and Drug Administration (FDA), if required by the FDA; 
• 
the appropriate authorities to prevent serious harm to yourself, children or others. For example, if we learn of child 
abuse/neglect, elder abuse, or the intent to harm yourself or others.  
 
OTHER INFORMATION 
We have taken steps to protect you from the risks mentioned above. Your participation in this research study is voluntary, 
and you are free to skip over any questions you do not want to answer. You may refuse to participate, and you are free to 
withdraw from this study at any time without penalty or loss of benefits to which you are otherwise entitled. 
 
If it is more convenient for you and logistically possible for the research team, we may conduct interviews at a location 
outside of the study sites (e.g., shelters, housing, drop-in centers, medical clinics). If you do meet at a location outside of 
the study sites, there is a chance that others may become aware of your participation in the research. 
 
You or your insurer will not be charged for any study-related procedures. There are different pay schedules depending on 
the group you are assigned to, because some groups have a different number of sessions. If you are assigned to the 
counseling+medication or counseling+placebo groups, you can receive up to $165 for participating ($5 for the information 
session and $20 for completion of each of the eight meetings). If you are in the counseling-only or services-as-usual 
groups, you will receive up to $145 for participating ($5 for the information session and $20 for completion of each of the 
seven meetings). You will receive payment in cash at the end of each meeting you attend. 
 


 
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Consent Form 
V12 November 16, 2017 
To thank participants for their ongoing study participation, we will offer drawings every three months to win the 
participant's choice of a Subway or Starbucks gift card worth $50. If you complete all appointments from baseline through 
week 12 you will receive one drawing entry. If you complete the week 24 appointment, you will receive an additional 
drawing entry. If you complete the week 36 appointment, you will receive yet another drawing entry. This makes for 3 
possible entries over the course of the study. We will have a drawing once every three months through the end of the 
study. The odds of winning depend on the number of participants who complete the study in the specified time. Winners of 
the drawing will be notified through the contact methods given to us for appointment reminders. 
If you are in one of the two groups receiving an injection, we will give you ID tags and wallet cards. We will ask that you 
keep them on your person during the 12-week treatment period. They indicate you may be on the study medication and 
have Dr. Collins’s contact information for you and medical personnel, if necessary. 
  
If, at any time, you do not want to participate, or you have questions about the study, please contact Dr. Susan Collins at 
(206) 744-9181 or email her at collinss@uw.edu. In case of emergency, please contact 911, your case manager/health-
care provider, or Harborview Medical Center (206-744-3074). 
 
COMPENSATION FOR INJURY 
If you think you have an injury or illness related to this study, please contact Dr. Susan Collins. She will arrange for you to 
come in and be checked by a study physician. We may then refer you to your assigned agency staff member or primary 
care physician for appropriate treatment and follow-up care. In the case you do not have a primary care provider at the 
time, we will refer you to primary care clinics at Harborview Medical Center or the Pioneer Square Clinic. Your health 
insurance will be billed for your medical care in this case. No money has been set aside to compensate for things like lost 
wages, lost time, or pain. However, you do not waive any rights by signing this consent form. The UW will compensate up 
to $10,000 to reimburse for treatment of injury or illness resulting from the study. 
  
 
 
 
 
 
Printed name of study staff obtaining consent 
Signature 
Date 
 
Participant’s statement 
This study has been explained to me. I volunteer to take part in this research. I have had a chance to ask questions. If I 
have questions later about the research, I can ask one of the researchers listed above. If I have questions about my rights 
as a research participant, I can call the Human Subjects Division at (206) 543-0098. I give permission to the researchers 
to use my medical records as described in this consent form. I will receive a copy of this consent form. 
 
___ Yes 
___ No 
Please mark whether or not you would like to participate in the audio recording 
sessions. 
 
 
 
Printed name of participant 
Signature of participant 
Date 
 
Copies to: 
Researcher 
 
Participant