Single-dose Interventions to Reduce Re-admissions for Hospitalized Patients With Refractory Alcohol Use Disorder: A Randomized Pilot Feasibility Study.
Phase: EARLY_PHASE1
Conditions: Alcohol Use Disorder, Severe
Sponsor: Denver Health and Hospital Authority

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ClinicalTrials.gov 
National Library of Medicine 
8600 Rockville Pike 
Bethesda, MD 20894 
November 2022 
 
 
To Whom it may Concern, 
 
 
This is a copy of the IRB-approved protocol for the clinical trial registered under 
NCT04562779. This is the latest version, approved on July 24, 2021. It underwent 
‘Continuing Review’ with no changes in August 2021 and August 2022. 
 
Sincerely, 
 
 
Dale Terasaki, MD MPH  
Internist and Addiction Medicine Specialist 
Denver Health & Hospital Authority 
dale.terasaki@dhha.org 
ClinicalTrials.gov login: TERASAKI.DALE 
971-259-3994 
 
 
 
 
 
 
 

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COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #: 
20-2008 
Project Title:  Single-dose interventions to reduce re-admissions for hospitalized patients with 
refractory alcohol use disorder: A randomized pilot feasibility study. 
 
 
 
Principal Investigator:  Dale Terasaki 
Version Date:  
07/24/2021 
  
 
 
I. Hypotheses and Specific Aims:   
 
Every year, alcohol use disorder (AUD) generates millions of emergency 
department (ED) visits and hospital admissions, costing the U.S. health sector 
over $90 billion.1 These hospital admissions are critical opportunities to start 
patients on addiction pharmacotherapy, but factors like medication non-adherence 
and post-discharge relapse contribute to frequent re-admissions. Two single-dose 
interventions are well suited to facilitate treatment retention and prevent re-
admissions due to their prolonged, adherence-independent effects: extended-
release (XR) naltrexone injection and intravenous (IV) ketamine infusion. These 
have not been thoroughly investigated in the hospital setting among high-utilizer, 
safety-net populations. Therefore, we aim to: 
1. Test the feasibility of randomizing hospitalized patients (n=45-60, age 
18-65) with multiple AUD-related admissions to treatment with either 
extended-release (XR) naltrexone, intravenous (IV) ketamine, or no 
single-dose medication, all with enhanced linkage to care. Feasibility 
outcomes such as recruitment rate, patient acceptability, post-discharge 
follow-up rate, and adverse events will help to identify key lessons for a 
future comparative effectiveness study.   
2. Estimate the 30-day re-admission rate for patients randomized to 
treatment with XR naltrexone, with IV ketamine, or no single-dose 
medication, all with enhanced linkage to care. We hypothesize that the 
re-admission rate will be lower for each of the two single-dose medication 
groups than for the “linkage-alone” group.   
 
 
II. Background and Significance:  
 
Alcohol use disorder (AUD) generates approximately 5 million U.S. 
emergency department visits every year, leading to 2 million hospital admissions 
and collectively costing the health sector over $90 billion dollars annually.1 
Because addiction treatment is seldom accessed,2 hospital admission represents 
a major opportunity for linkage to care3,4 and initiation of oral (PO) naltrexone,5 a 
first-line medication shown to improve outcomes such as number of drinking 

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days,6 drinks per day,6 and health care utilization.5,7 Denver Health (DH) provides 
a dedicated addiction consult service (ACS) to assist in these efforts, and the ACS 
sees hundreds of new consults per month. Yet alcohol-related admissions at DH – 
estimated at nearly 2,000 per year8 – show a higher 30-day re-admission rate than 
the hospital-wide average (Figure 1). This is consistent with a nationally reported 
re-admission rate for alcohol-related disorders of 21% compared to 14% overall in 
2014,9 ranking it 4th among common diagnoses.9 Additionally, there is low post-
discharge treatment engagement for these patients: one sample of hospitalized 
DH patients with AUD demonstrated an 11.8% follow-up rate at addiction clinic 
(chart review).  
These sub-optimal transitions of care underscore the limited benefit of oral 
naltrexone for high-utilizer, safety-net populations who may have social contexts 
that compromise medication adherence.10 Different tools are needed that can 
facilitate post-discharge treatment engagement and reduce re-admissions, goals 
in line with the DH Center for Addiction Medicine (CAM) and upcoming Hospital 
Transformation Project11 application.  
The following two pharmaceutical options are well-suited to the hospital 
setting and complementary to the myriad behavioral strategies to improve 
treatment compliance and linkage to care:12 
1. An extended-release (30-day, “XR”), intramuscular injection of naltrexone 
(Vivitrol®). Studies on XR naltrexone have shown better long-term 
medication continuation compared to oral naltrexone13 and reduced heavy 
drinking days compared with placebos.14 Additionally, one meta-analysis 
showed a trend toward fewer admissions compared to oral naltrexone.15 
One ongoing clinical trial16 is directly comparing oral to XR naltrexone for 
AUD in a safety-net hospital in Boston, and it is expected to evaluate the 
results in late 2020. Regardless, data from multiple centers and regions are 
needed, and our study uniquely targets high-utilizer patients.  
2. A single infusion of intravenous ketamine, a dissociative anesthetic used in 
general anesthesia and pain management. At sub-anesthetic doses, 
ketamine provides rapid effects on mood that extend weeks beyond 
administration,17,18 and in 2019 the FDA approved an intranasal formulation 
for treatment-resistant depression.19 For AUD, treatment with ketamine 
decreased cravings and drinking at 10 days post-infusion in a human 
laboratory study that excluded patients with depression.20 In a recent 
randomized trial, AUD patients were given one ketamine infusion and 
subsequently showed a higher rate of abstinence at 21 days beyond 
treatment and better attendance at the final study visit compared to the 
control group (100% vs 74%, respectively), with no serious adverse events 
reported.21  
Both single-dose interventions hold great potential for improving AUD post-
hospital transitions and reducing immediate re-admissions, but more data on 
feasibility and effectiveness are needed.   
 
 

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III. Preliminary Studies/Progress Report:   
 
There have been no preliminary studies. However, an initial Tableau query 
showed that at Denver Health, patients admitted to the hospital with an alcohol 
related diagnosis had a 30-day readmission rate of between about 10 and 40 
percent (see Figure 1). This is notably an underestimation, given that patients may 
have had readmissions at hospitals outside of Denver Health, which would not 
have been captured in those data.  
There is also low outpatient treatment engagement following discharge for 
these patients. I reviewed a cohort of 17 patients that I cared for in August and 
September 2019, all of whom I referred to outpatient addiction clinic for treatment 
of alcohol use disorder. Only 2 presented within the following month. Among the 9 
who were prescribed oral naltrexone, only 1 presented.  
 
 
 
IV. Research Methods 
 
A. Outcome Measure(s):  
See table 1 for primary and secondary outcomes. In brief, our primary outcomes will be 
those related to feasibility as well as risk of 30-day all-cause hospital re-admissions. 
Secondary outcomes include risk of 30-day all-cause emergency department visit, 
0%
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Figure 1 DH hospital re-admissions. Obtained via Tableau with assistance from Mara Prandi-Abrams. Alcohol 
admissions based on All-Patients-Refined-Diagnosis-Related-Groups (APR-DRG) 775 and 280. 

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differences in readiness-to-change, and likelihood of having an alcohol metabolite (EtG) in 
the urine at follow-up.   
 
Table 1 Primary and secondary outcomes 
 
Study 
Aim  
Description 
Instrument(s) 
1’ feasibility 
outcomes  
 
1 
Recruitment rate (# enrolled / month), follow-
up rate, patient acceptability, adverse effects 
 
Chart review, 
questionnaires 
 
1’ clinical 
outcome 
2 
Risk of 30-day all-cause hospital re-
admissions 
 
Chart review 
2’ clinical 
outcomes  
 
2 
Risk of 30-day all-cause ED visits 
Chart review 
2 
Within-subject difference in readiness-to-change22  Questionnaire 
2 
Laboratory(+) for alcohol at SUDS 
Urine EtG 
2 
Percent of binge drinking days23 since discharge 
Questionnaire 
 
 
B. Description of Population to be Enrolled:   
 
See Table 2 and 3 for inclusion and exclusion criteria. Rationales are also listed.   
 
Table 2 Inclusion criteria 
 
INCLUSION criteria 
Rationale 
 
Age 18-65 
Limiting study scope to adult 
patients 
 
1+ alcohol-related* admission(s) OR 2+ alcohol-related 
ED visits in past 12 mo.  
 
*Admission diagnoses includes any of following:  
- 
alcohol use / intoxication  
- 
alcohol withdrawal 
- 
alcohol use disorder / dependence 
- 
seizure thought to be related to alcohol 
withdrawal 
- 
encephalopathy thought to be related to alcohol 
- 
pancreatitis thought to be related to alcohol 
- 
liver disease thought to be related to alcohol 
- 
cardiac arrhythmia or heart failure thought to be 
related to alcohol 
- 
gastrointestinal bleed thought to be related to 
alcohol 
 
Limiting study scope to high-
utilizer patients 
 
Has insurance (public or private) 
Can follow-up at SUDS clinic 
 
Seen by addiction consult 
Part of recruitment plan 
 
Table 3 Exclusion criteria 
 
EXCLUSION criteria 
Rationale 
 
Known or suspected active COVID-19 infection 
 
Staff safety and ability to 
immediately follow up at SUDS 
clinic 

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Hepatic: AST/ALT >5x upper-limit of normal, 
decompensated liver failure 
Naltrexone can rarely cause 
hepatotoxicity. 5x ULN used by 
study by Collins et al (2015) 
 
Renal: Glomerular filtration rate <30ml/min 
Naltrexone not recommended in 
renal failure 
 
Cardiovascular: History of acute coronary syndrome, 
cerebrovascular event, hypertensive crisis, known 
cardiomyopathy  
Ketamine can transiently raise 
blood pressure 
 
Known elevated intracranial pressure 
Ketamine can transiently raise 
blood pressure 
 
Thrombocytopenia (<50/microliter) 
Naltrexone can potentially 
worsen thrombocytopenia 
 
Active moderate/severe withdrawal (based on hospital 
withdrawal protocol) 
May need acute care that would 
interfere with intervention and 
discharge planning 
 
Active delirium (alcohol-related or otherwise) 
Ketamine’s dissociative effects 
could theoretically worsen 
delirium 
 
Already enrolled in study 
 
A-priori decision to only enroll 
patients once 
 
XR naltrexone or IV ketamine in last 30 days 
 
Prior administration could affect 
ability to distinguish effect of 
current intervention. Recent 
receipt of intervention would 
also be evidence that 
intervention not effective for 
them.   
 
Known intolerance to naltrexone or ketamine 
 
Avoid harm to patient 
 
Other active severe substance use disorder (tobacco, 
cannabis excluded) 
 
Limiting study scope to AUD 
 
Pregnant or breast-feeding, or planning.  
 
Risk of harm to fetus not well 
established for naltrexone or 
ketamine 
 
Opioids: physical dependence or anticipated use in the 
next 30 days 
 
Naltrexone is an opioid-
antagonist 
 
Unstable psychiatric illness (active psychosis, active 
suicidality) 
 
Ketamine’s dissociative effects 
could worsen psychiatric 
decompensation 
 
Moving from region within 30-days of discharge 
 
Cannot have immediate follow 
up at SUDS 
 
Discharge to acute/residential treatment 
 
Cannot have immediate follow 
up at SUDS 
 
Involuntary hold 
Cannot have immediate follow 
up at SUDS 
 
C. Study Design and Research Methods   
 
We propose an open-label, pilot feasibility trial (n=45-60), randomizing 
hospitalized patients to receive XR naltrexone, IV ketamine, or neither prior to 
hospital discharge, along with enhanced linkage to care. The primary clinical 

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outcome compared across each of the groups will be 30-day re-admission rates 
ascertained by chart review (Table 1).  
To reduce variability, all participants will undergo a standard addiction 
consultation that includes behavioral components such as supportive therapy and 
motivational interviewing. They will also receive enhanced linkage to care (hereon 
“linkage”) which includes being met by a staff member while in the hospital to 
begin the clinic intake process and assign a follow-up appointment date. Linkage 
will also include a contingency management24–26 (monetary incentive to follow-up) 
in their post-hospital transition and receive standard case management and 
counseling at Substance Use Disorder Services (SUDS) clinic.  
ACS team members will identify patients meeting inclusion criteria (Table 
2), and – after conducting their usual consultation – approach them about the 
study. Approximately 900 patients met similar inclusion criteria in 2019 (Query by 
Josh Durfee). After screening for exclusion criteria, informed consent will occur, 
and initial baseline data will be obtained by “Treatment on Demand” (TOD), a 
grant-funded team of counselors who are already linking hospitalized patients to 
addiction care. Consented patients will then be randomized, and the ACS will work 
with the primary team to order and administer the assigned intervention close to 
discharge. Meanwhile, a TOD counselor will work to establish a follow-up date 
within seven days post-discharge. Additional data will be collected immediately 
after the intervention (for those in one of the two medication groups), at SUDS 
follow up, and 30-days post-discharge by chart review.  
 
Medications 
 
XR naltrexone is produced by Alkermes. Due to the cost (~$1300 on 
GoodRx for one dose), we will receive samples from Alkermes in a process that 
has been pre-arranged between DH inpatient pharmacy and their Colorado-based 
representative, Chris Thurnauer. We received preliminary approval on 12/3/19 
from DH Pharmaceuticals and Therapeutics Committee to use these samples in 
the hospital for this purpose.  
 
IV ketamine is currently utilized at DH at sub-anesthetic doses for pain 
control, with guidance from PolicyStat27 #5253340. Its use in pain management is 
currently limited to ICU settings and utilizes boluses and infusions titrated to pain. 
According to discussions with inpatient pharmacy, approval for an infusion dose 
modeled after randomized trials18,28–30 may be granted for use on floor units with 
specific contingencies: physician/investigator will be present at bedside during the 
infusion and nursing staff are educated on the protocol. This was discussed at 
Denver Health’s Medication Administration Forum (MAF) meeting on 3/5/20.   
 
Data Collection 
Data will be primarily collected at four time-points (Table 4). Data will be 
entered by staff into a REDCap database on tablet computers in the hospital and 
at SUDS clinic. Data collected at enrollment will primarily be descriptive, including 
demographics, recent drinking history,31 readiness to change, and various 
contributing factors to drinking. Immediately after intervention, vital signs, 

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symptoms, and acceptability will be recorded. Data collected on post-discharge 
arrival to SUDS clinic will include most 2’ clinical outcomes. We will obtain re-
admission rate (1’ clinical outcome) through chart review, conducted by research 
team members at 30-days post-discharge.  
 
Table 4 Patient flow and data collection points 
Step 
Who  
Notes 
Data collected – staff entered 
Patient 
identified on 
consult list 
 
ACS  
Quick screen that 
meets inclusion 
criteria 
 
 
 
 
Addiction 
consult 
performed 
 
ACS 
Evaluation, withdrawal 
management, 
medication (though if 
patient consents to 
study, will not be 
prescribed an 
addiction medication 
at discharge), brief 
therapy, referrals, 
disease 
screening/harm 
reduction 
 
 
 
 
Screen, 
consent, 
randomization 
 
ACS 
Formal screen to 
identify any exclusion 
criteria. Simple 
randomization by 
algorithm 
• 
E-Consent (should include 
consent to see records in “care 
everywhere” – some hospitals 
require permission – when 
checking for ED visits and re-
admissions) 
• 
Screening documentation 
(inclusion and exclusion criteria) 
• 
Alcohol-related admissions in last 
12 months (date, location, top 3 
diagnoses) 
• 
Assigned group 
 
 
 
Baseline 
data, referral 
to SUDS 
[data 
collection 
point #1] 
 
ToD 
ToD collects baseline 
data first, then 
performs 
“biopsychosocial 
intake” and sets up 
SUDS appointment 
within 1 week of 
discharge.  
 
Discharge date is not 
always predictable; 
• 
Demographics 
• 
Baseline clinical data 
• 
Depression symptoms baseline 
(PHQ9 2 wks) 
• 
Drinking History 7-days prior to 
admission (TLFB) 
• 
Readiness to change 
(SOCRATES-8A) 
• 
ACE Questionnaire 

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ACS to review active 
hospitalized research 
participants and 
contact ToD/update 
date in RedCap as 
needed.    
 
 
 
Intervention 
administered 
[data 
collection 
point #2] 
 
RN, ACS 
For ‘linkage-alone’ 
group, data to be 
entered following 
consult.  
 
For NTX group, 
intervention 
administered prior to 
discharge (could be 
same day as consent). 
Vitals immediately 
preceding and 40 min 
post- injection. Data 
collected after 
administration. 
 
For KET group, 
intervention 
administered prior to 
discharge (could be 
same day as consent), 
though should have no 
food for at least 3 
hours (~50% gastric 
emptying). Vitals 
immediately 
preceding, after 
completion, and 2 
hours following end of 
intervention.  
 
• 
Vital signs (HR, BP, O2): linkage-
alone group- baseline only, 
recorded after consult. NTX 
group- baseline, 40 min after 
administration. KET group- 
baseline, end of administration 
(~40min), 2 hours after end of 
administration.  
• 
Most recent AST, ALT 
• 
UDS-5 data 
• 
[for KET] Dissociative symptoms 
(CADSS) after administration (40 
min) 
• 
[for NTX and KET] Acceptability of 
intervention (10-point Likert) after 
administration 
• 
[for NTX and KET] Readiness to 
change (SOCRATES-8A) after 
administration (40 min) 
 
ORDER: CMP (if not already obtained), 
UDS-5 (if not already obtained) 
 
ORDER in discharge orders (outpatient): 
CMP, UDS-5, urine EtG (if not already 
ordered) 
 
 
 
 
Presentation 
to SUDS, 
data entered, 
contingency 
management 
reward 
administered 
[data 
collection 
point #3] 
 
SUDS 
staff 
Upon presentation, 
staff to collect study 
data. After completion, 
will receive 
contingency 
management reward. 
 
Then patient to 
complete standard 
intake/follow-up visit, if 
willing.  
 
• 
Drinking History since discharge 
(TLFB since discharge) 
• 
Depression symptoms (PHQ9 
modified to read “since 
discharge.”)  
• 
Readiness to change 
(SOCRATES-8A) 
• 
[for KET] Dissociative symptoms 
(CADSS) 
• 
Adverse Events (Modified PRISE) 
• 
Acceptability of intervention (10-
point Likert) 

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Staff to instruct patient 
to present to the clinic 
laboratory (e.g. pav G) 
for CMP after the visit. 
• 
Contingency management 
feedback (10-point Likert, open 
ended) 
 
 
 
30-day chart 
review 
[data 
collection 
point #4] 
Research 
staff 
 
Should check 
encounters tab as well 
as “care everywhere” 
for Denver Metro 
region.  
• 
Admissions (up to 5) within 30 
days of discharge date (date, 
location, up to top 3 main 
diagnoses based on 
documentation available).  
• 
ED visits (up to 5) within 30 days 
of discharge date (date, location, 
up to top 3 main diagnoses based 
on documentation available).  
• 
AST, ALT obtained at SUDS f/u (if 
available) 
• 
Urine EtG obtained at SUDS f/u (if 
available) 
 
 
 
 
Screening: The addiction consult team will attempt to screen patients meeting the inclusion 
criteria during inpatient admission. We anticipate 10 patients will meet inclusion criteria weekly. 
They will be assessed for clear exclusion criteria documented in the chart, and if none are 
noted the patient will be asked if they would like to join the study and complete the screening. If 
still no exclusion criteria are met and the patient expresses interest, they will be engaged in 
informed consent. The primary team will be notified by the addiction medicine team. Each 
combined process of screening and consent is anticipated to require 15 minutes at the end of a 
typical consultation. The screening window is anticipated to last 5 months. 
 
Randomization: Patients will undergo a simple randomization algorithm to one of three arms.  
 
 
Intervention: 
- 
Arm 1: Receive a single dose of XR naltrexone (380mg) prior to discharge. 
- 
Arm 2: Receive a single infusion of IV ketamine (0.5 mg/kg over 40 minutes) prior to 
discharge.  
- 
Arm 3: No single-dose medication 
- 
All groups will receive enhanced linkage to care that includes contingency 
management, initiation of biopsychosocial intake, and appointment scheduling. This 
aspect alone surpasses the current standard of care.  
 
Contingency Management: Patients will receive a debit card prior to discharge from the 
hospital. We will utilize a pre-existing system - ClinCard by Greenphire. Participants will receive 
$10 upon completion of baseline data, and $20 upon completion of follow-up data (at SUDS 
clinic). 
 
Follow up: Patients will be assigned a follow-up within 7 days of discharge at the outpatient 
addiction clinic (Denver Health SUDS clinic in pavilion K).  
 
 

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Standard of care: Current standard of care for alcohol use disorder in the hospital includes 
offer of medications (usually oral naltrexone) and addiction medicine consultation which can 
result in brief counseling and referral to SUDS clinic or other treatment program.   
  
 
D. Description, Risks and Justification of Procedures and Data Collection Tools: 
 
Table 5 Overview of risks and justifications of procedures and data collection tools  
Procedure/Tool 
Description, Risks 
Justification 
Injection of IM 
medication 
(naltrexone) 
 
Risks include minimal pain and discomfort 
at the injection site which will occur on the 
lateral thigh or the buttock. One study 
suggested that the discomfort of an 
injection itself deterred a large number of 
participants.32 If that is the case for our 
study, this decision will be honored with no 
repercussion aside from not enrolling in the 
study. More serious risks such as infection, 
blood clot, bleeding and/or allergic reaction 
are rare.  
 
These risks are justifiable as 
there is very little risk of 
serious or permanent harm, 
and potential benefits in terms 
of preventing the 
consequences of heavy 
drinking are almost certainly 
greater. 
Medication-
related risks of 
naltrexone 
 
Risk of opioid withdrawal if the patient is 
taking opioids concurrently (an exclusion 
criteria); Liver injury can be seen, but is 
usually mild and self-limiting. Patients with 
AST/ALT >5x ULN, hepatic failure, or 
decompensated cirrhosis will be excluded. 
Nausea, sleepiness and headache are the 
other most common medication side 
effects.  
 
These risks are justifiable as 
there is very little risk of 
serious or permanent harm, 
and potential benefits in terms 
of preventing the 
consequences of heavy 
drinking. It is a single dose 
which limits exposure. 
 
Medication-
related risks of 
ketamine 
 
 
 
Risk of unpleasant dissociative symptoms, 
delirium, hallucinations; high blood 
pressure which could lead to adverse 
cardiac events if patients are not screened 
carefully; initiation of ketamine abuse after 
discharge.  
These risks are justifiable as 
there is very little risk of 
serious or permanent harm, 
and potential benefits in terms 
of preventing the 
consequences of heavy 
drinking. It is a single dose 
which limits exposure. 
Patients who experienced 
delirium during hospital stay 
will be excluded. Patients with 
known cardiovascular disease 
will be excluded. The most 
recent randomized trial using 
ketamine found no initiation of 
ketamine “abuse” following 
administration.21 
 
Data collection 
tools – 
questionnaires, 
urine Etg 
All questionnaires have the potential to 
bring up unpleasant memories of their use 
and strong emotions related to their 
motivations to change. Gathering re-
admission data from insurance claims has 
These risks are justifiable as 
strict precautions to safeguard 
protected health information 
will be applied.  

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the potential for a breach of confidentiality. 
However, precautions to safeguard 
protected health information in accordance 
with international standards for human 
subjects research will be applied.  
 
 
 
 
 
 
 
E. Potential Scientific Problems:   
 
One potential limitation is the small sample size. As a pilot study, our main 
aim is to test feasibility. A more robust, precise demonstration of clinical 
effectiveness will be pursued in a future project with data used from this study to 
inform sample size estimates as well as timelines. 
 
Secondly, patients may be re-admitted to hospitals that do not show up in 
our medical record system (Epic). Insurance claims data would be ideal, but at this 
stage the added value does not justify the costs required for acquisition. Notably, 
Epic “Care Everywhere” can detect admissions in the University of Colorado 
Health system (12 hospitals in Colorado), SCL Health (5), and Centura Health 
(17). This network of hospitals provides high coverage based on our population, 
many of whom are homeless and located in a small regional geography.    
 
Another potential limitation is a low follow-up rate at SUDS. This is one 
major reason for including contingency management26 as part of our enhanced 
linkage to care. Regardless, the primary quantitative outcome (hospital re-
admission) will not require data from SUDS attendance to measure.  
 
Alternative designs were considered but deemed beyond the scope of this 
proposal:  
• “Double dummy” placebos, which can minimize bias in both researcher and 
participant. However, this would be personnel and time-intensive, and due 
to ketamine’s unique psychoactive effect, patients are unlikely to be 
successfully blinded.  
• 2x2 factorial design, which could gain information on combinations of 
multiple interventions, but would unnecessarily weaken inferences and 
complicate statistical analysis due to interactions in this small sample.  
• 30-day in-person evaluation, which would facilitate additional longitudinal 
measurement. However, we are not confident that enough patients would 
show up (or be reachable by telephone) to allow for meaningful analysis.   
 
 
F.   Data Analysis Plan:   
 
Participants’ demographic and baseline clinical data will be tabulated, and 
differences between groups will be assessed using a Fisher’s Exact Test for 
categorical variables and a two-sample t-test for continuous variables. These tests 

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will help evaluate the effectiveness of randomization. Feasibility outcomes (Aim 1) 
such as adverse events and acceptability (Likert scale)33 will be compared for 
each group using a Fisher’s Exact Test and Wilcoxon-Mann-Whitney Test, 
respectively. Overall recruitment rate and follow-up rate will be tallied at the 
conclusion of data collection.  
For Aim 2, all-cause hospital re-admission within 30-days of discharge will 
be recorded as a binary outcome. Rates of the two medication intervention groups 
(XR naltrexone or IV ketamine) will be compared against the group that received 
enhanced linkage to care alone.   
This pilot study may not be sufficiently powered for robust hypothesis 
testing. By one crude estimate, we could have approximately 80% power to detect 
a difference between a medication group and the linkage-alone group with about 
60 participants assuming a re-admission rate is 25% vs 15%. A larger effect size 
would increase our power and/or reduce the number of participants required. 
Regardless, this will provide parameter estimates that can inform a future sample 
size calculation in a larger effectiveness trial.   
For further descriptive purposes, a secondary utilization outcome is risk of 
30-day all-cause ED visits. This will be evaluated in a similar manner as hospital 
re-admissions. Additionally, we are interested in the within-subject difference in 
readiness-to-change. For those who follow-up, a mean of pre/post differences will 
be calculated, and a paired t-test will be used to determine if the null hypothesis 
(H0: difference = 0) can be rejected. Drinking behavior will be measured using the 
Timeline Follow Back method.31 Binge drinking will be defined as 5+ drinks for 
men, 4+ for women,23 and the proportion of binge drinking days since discharge 
will be calculated for each group. Proportions of positive urine ethyl glucuronide 
(EtG) will also be tabulated for each group.  
Data will be analyzed in SAS.  
 
 
F. Summarize Knowledge to be Gained:   
 
We hope to demonstrate feasibility of two single-dose interventions 
given in the hospital setting and estimate their effects in terms of 
hospital readmissions. The knowledge gained will help inform a 
future, larger comparative effectiveness study. The data will also 
help CAM staff related to tracking and incentivizing transitions of 
care for patients with AUD.  
 
 
 
 H. References: 
 
1.  White AM, Slater ME, Ng G, Hingson R, Breslow R. Trends in Alcohol-Related Emergency 
Department Visits in the United States: Results from the Nationwide Emergency Department 
Sample, 2006 to 2014. Alcoholism: Clinical and Experimental Research. 2018;42(2):352–9.  

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2.  SAMHSA. Results from the 2012 National Survey on Drug Use and Health: Summary of 
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