Effect of Prazosin and Naltrexone on Personalized Script-Induced Alcohol Craving in Individuals With Alcohol Use Disorders With and Without Comorbid PTSD
Phase: PHASE2
Conditions: Alcohol Use Disorder, Posttraumatic Stress Disorder (PTSD)
Sponsor: Seattle Institute for Biomedical and Clinical Research

“Effect of Prazosin and Naltrexone on Personalized Script Induced Alcohol Craving in Individuals with 
Alcohol Use Disorders with and without Comorbid PTSD” 
NCT02322047 
PaN Study Protocol (8-17-2020) 
 
Design Overview 
 
This is a 7-week double-blind, double-dummy, placebo controlled study of prazosin and naltrexone for 
Veterans with an AUD that includes two imaginal craving inductions at the final study visit, one oriented 
towards relief craving and the other towards reward craving. After passing an initial telephone screen, 
participants are seen for an in-person eligibility appointment that includes a physical and psychiatric 
examination, labs, and self-report measures.  One hundred twenty individuals who meet study 
inclusion/exclusion criteria will enter the medication phase of the study within 14 days of the initial assessment 
initiating prazosin/placebo as well as 50mg naltrexone/placebo treatment. Randomization is blocked by 
gender, PTSD status, and desire to abstain vs. desire to cut down. Prazosin is titrated to three times daily 
dosing (9 am: 4mg; 3pm: 4 mg; 9pm: 8mg) at the end of two weeks. Naltrexone is taken once daily 50 mg/day 
with no titration schedule. The stable dose of both medications continues for four more weeks and medication 
compliance is evaluated through pill counts and riboflavin trace in urine analysis. On approximately day 42 
participants come into the lab for the craving inductions (there is a two-week window after day 42 in which 
participants may still be seen if scheduling issues arise). The order of the craving inductions is 
counterbalanced, and their administration separated in time by 30 minutes to minimize carry over between 
them. Subjective responses to the craving inductions is obtained via relief oriented craving items and reward 
oriented craving items from the Desire for Alcohol Questionnaire. Participants are then assisted in returning 
their craving levels to baseline prior to debriefing. They are all offered DoD, VA, or community referrals to 
treatment. Both prazosin and naltrexone can be safely discontinued without tapering.  
 
Setting, Recruitment, Participants, and Inclusion/Exclusion Criteria 
Study Setting: 
There are three VAPS study sites including the Seattle Division VA, the American Lake Division VA, 
and the Mt Vernon CBOC VA. Clinical backup in case of emergencies is available at all sites.  
Participants and Recruitment: 
Potential subjects are Veterans with a DSM-V Alcohol Use Disorder (AUD) recruited from the VA, the 
community, and other local alcohol treatment programs via letters, flyers, VA TV monitors, and advertising in 
the local media. Potential Veteran subjects will also be identified via Corporate Data Warehouse or VISTA 
fileman pull. 
CDW/VISTA fileman: Access to the Corporate Data Warehouse is used to identify Veterans in the 
VAPSHCS area with an ICD-10 code for an active alcohol use disorder or a positive VA mandated alcohol 
screen (AUDIT-C) and without exclusionary diagnoses and/or medications. We retrieve potential participants’ 
names and current mailing addresses and, after reviewing key information regarding additional 
inclusion/exclusion criteria in CPRS, we mail those who are likely eligible a recruitment letter with an “opt out” 
card. A $2 bill is included in each envelope to thank Veterans for reading the letter. Those who indicate they 
are interested in the study are screened on the telephone under an already approved waiver of documentation 
of consent. Those who do not return the opt out card and do not call the study are contacted by phone with up 
to three messages left to ascertain whether they are interested in learning more about the study and possibly 
completing the telephone screen.  
Alcohol Clinical Reminder flag: IRB approval is in place to add the study as a treatment referral 
option for patients who screen positive on the annual AUDIT-C clinical reminder so that providers can discuss 
the study with patients at the time of screening and communicate with study staff regarding patients who are 
interested in learning more about the study.  
We anticipate conducting approximately 1500 telephone screens and enrolling approximately 240 
participants, approximately 70 of whom will fail to meet the study inclusion/exclusion criteria during the initial 
screen, and an additional 50 who will fail to meet the criteria later due to lab values that are of concern or poor 
compliance with the IVR monitoring. We plan to randomize 120 men and women with a current 12-month 
history of AUD who have recently consumed alcohol (see inclusion/exclusion criteria below) and want either to 
abstain or reduce their alcohol consumption.  

 
Inclusion and Exclusion Criteria:  
To move on from the in-person screening appointment, the following Inclusion/Exclusion criteria need 
to be met: 
Inclusion: To be enrolled in the study participants need to meet the following inclusion criteria: Veteran 
of the U.S. military or National Guard Reserve; current AUD by DSM-V criteria; > 14 drinks per week for 
females OR > 21 drinks per week for males for at least 2 weeks in the last 3 months and some drinking during 
the past two weeks immediately prior to in-person screening OR 3+ binge drinking days in the last month as 
defined by 4+ SDUs for females and 5+ SDUs for males; at least mild alcohol craving as assessed by the 
Pennsylvania Alcohol Craving Scale (PACS; score > 10) at baseline; age 18-80; English fluency and literacy; 
trying or planning to try to cut down on or abstain from alcohol; good general medical health, and capable of 
giving informed consent. 
Exclusion Criteria: The following characteristics exclude potential participants from being randomized into the 
study: DSM-IV* diagnosis of an uncontrolled psychiatric disorder with psychotic symptoms or cognitive 
impairment; if taking psychiatric medication, NOT on a stable dose for at least 30 days prior to randomization; 
any suicidal ideation in the past 7 days, plan or intent past 6 months, or suicide attempt past year; homicidal 
ideation with plan and intent in the past 30 days; PHQ-9 endorsement of hopelessness or self-harm/SI and/or 
sum score ≥ 19 on items 1-9; any use of prazosin or naltrexone past 30 days; currently taking disulfiram or 
acamprosate OR planning to take any of these medications (including prazosin or naltrexone) during the 8 
weeks of the study; current moderate or greater level of substance use disorder (past 30 days) on any 
psychoactive substance other than alcohol, nicotine, or cannabis; current diagnosis of any opioid or 
amphetamine use disorder, OR use of any amphetamine or opioid-containing medications during the previous 
30 days; UDA screen positive for amphetamine, opioids; significant acute or chronic medical illness including 
unstable angina, recent myocardial infarction, history of congestive heart failure, preexisting hypotension (sys 
<100) or orthostatic hypotension (sys drop of > 20 mmHg; after two minutes of standing, or any drop 
w/dizziness); insulin-dependent diabetes mellitus; chronic renal or hepatic failure; pancreatitis; Meniere’s 
disease; benign positional vertigo or narcolepsy; liver enzymes aspartate aminotransferase (AST), cirrhosis, 
alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), > 8 x the upper limit of normal or total 
bilirubin >2 mg/dL (in the absence of Gilbert’s disease); allergy or previous adverse reaction to naltrexone, 
prazosin, quinazolines, or other -1 adrenergic blockers or use of other -1 adrenergic blocker; women who 
are pregnant, breastfeeding, or of childbearing potential and not using a contraceptive method judged by the 
investigator to be effective; legal involvement that could interfere with study participation including being court 
ordered for treatment; signs or symptoms of withdrawal at time of initial consent, or any participation in an 
experimental drug study or any addiction study past 30 days (See Appendix 1 for Initial Inclusion/Exclusion 
Checklist). 
 
*DSM-IV criteria are used to determine these aspects of eligibility because we did not have access to the new 
DSM-5 criteria for these disorders at the start of the study. 
 
Additional Inclusion/Exclusion Criteria:  
To proceed to randomization participant lab values will need to indicate that it is safe for them to take 
the study medications (See Appendix 1 for Additional Inclusion/Exclusion Checklist). 
 
Study Visits and Procedures 
Telephone Screen: Interested callers are provided an overview of the study procedures either immediately if 
they reach someone when they call or their call is returned in two to three business days. Those who remain 
interested undergo a 15-20 minute telephone screen to ascertain basic inclusion/exclusion criteria under a 
waiver of documentation of consent. Those who are eligible and remain interested are scheduled for an in-
person screening assessment. Please see the attached Study Flow Chart for a schematic overview of study 
activities. 
Consent, Screening Assessment, and IVR Initiation (Visit 1; Study Day 1):  
Consent Procedures: During Visit 1 (Study Day 1) the Study Clinician (Advanced Registered Nurse 
Practitioner (ARNP), Physician Assistant (PA), or physician) explains the study in detail by reviewing the study 

consent with the patient, and if the individual is interested in proceeding, written informed consent and HIPAA 
authorization is obtained.  
 Participants are then asked to complete the UCSD brief assessment consent quiz to insure adequate 
comprehension of the consent and study procedures. If any items on the consent quiz are missed, the 
information pertaining to the items in question are reviewed and those items are re-administered. This measure 
is used to ensure that the potential participant can read well enough to be able to adequately read the written 
directions regarding the medication regimen and other study activities. If the clinician determines that the 
potential participant is likely to have adequate cognitive capacity to participate safely in the study, she/he 
reviews the quiz items missed and re-administer those items. If one or more of these items are missed again, 
the person is deemed unable to adequately understand study procedures, and the interview will be terminated. 
Those who able to answer the items correctly move on to the screening assessment.  
Screening Procedures: The Study Clinician administers the substance use disorders section of the Mini 
International Neuropsychiatric Interview (MINI) to confirm DSM-V AUD and to assess for other potential 
substance use disorder diagnoses, any suicidal ideation in the past 7 days, plan or intent past 6 months, or 
suicide attempt past year, and homicidal ideation with plan and intent in the past 30 days (see Study 
Instruments Table below for an overview of assessment measures and materials). Recent drinking will be 
determined during the AUD assessment to determine whether participants meet drinking inclusion 
requirements. Presence of at least mild craving will be assessed via the self-report instrument “Pennsylvania 
Alcohol Craving Scale (PACS);” a score of at least 10 is required. Participants undergo a complete medical 
history and a physical examination with the Study Clinician. Participants who are found to be in good medical 
health from the initial exam complete the Clinician-Administered PTSD Scale for DSM-5 (CAPS) –to determine 
current PTSD diagnostic status. Participants complete a self-report demographic questionnaire that includes a 
forced choice item regarding their goals for their alcohol use over the next month (i.e., no change, reduce or 
cut down on amount of drinking, abstain completely). Those who indicate no desire to change their drinking are 
excluded from the study. 
 
Those who are found to be initially eligible are asked to complete a short battery of self-report 
measures regarding craving, PTSD symptom severity, and characteristics that may moderate response to 
prazosin and naltrexone.  
Data Capture: The interview data are recorded on paper or entered directly into an ACCESS database 
and self-report measures are entered online into a Survey Monkey form. Research staff remain in the room 
with participants while they complete the self-report measures to ensure that they do not leave the Survey 
Monkey website. Note: there are paper forms available in the event there is a problem with either the ACCESS 
or Survey Monkey systems or if a participant prefers to complete measures off-line. 
Laboratory Procedures: Women of childbearing potential provide urine for a pregnancy test at screening and 
again at weeks 4 and 8. Laboratory evaluation of blood samples includes CBC, routine liver function tests, and 
routine serum chemistries. Specimens are also sent to a lab in Minnesota, MedTox, for assessment of the 
alcohol biomarker phosphatidylethanol – Peth. The lab procedure differs slightly by site as follows: 
Seattle VA: The Clinical Research Unit (CRU) draws the blood samples and ship the specimens to MedTox. 
Either the Clinical Research Unit (CRU) or study staff deliver the remaining vial(s) to the Seattle VA lab for 
processing. Study participants are escorted by study staff to the CRU at the end of the initial study visit. 
American Lake VA:  Clinical Studies Unit staff (CSU) draws the blood samples and ships the specimens to 
MedTox. A member of the Clinical Studies Unit (CSU) or study staff delivers the remaining vial(s) to the lab for 
processing. Study participants are escorted by study staff to a room in the CSU at the end of the initial study 
visit.  
Mt. Vernon CBOC VA:Blood specimens are drawn by lab personnel in the on-site lab. Specimens are then 
transported to the Seattle VA via a courier service. Mt Vernon CBOC VA specimens for MedTox are held at an 
identified location in the Seattle VA lab and then picked up by Clinical Research Unit (CRU) staff to be shipped 
to MedTox. 
 
Safety and Comfort Call by Study RA (Safety and & Comfort Call #1): The RC calls the participant the next 
business day following the initial screen to assess any symptom exacerbation stemming from the visit, to 
provide support. 
 

Randomization, Baseline Assessment, and Initial Medication Administration (Visit 2; Study Day 8):  
Randomization: In this double-blind, double-dummy design participants are randomized to one of four 
study conditions: prazosin + naltrexone; prazosin + naltrexone placebo; naltrexone + prazosin placebo, and 
double placebo. Randomization is blocked by gender, PTSD status, and alcohol consumption goal (abstention 
vs. reduction). Random assignment to study condition is conducted by the VAPSHCS Research Pharmacist 
with randomization tables supplied by the study PIs. The Research Pharmacist distributes study medications 
appropriate to the randomization condition. The Research Pharmacist will have no contact with participants. 
Study medications will have been prepared ahead of time and will be available at Study Visit 2. 
Baseline Assessment: Approximately one week after the screening visit (Study Day 8) the RC or Study 
Clinician contacts each participant to inform her/him as to whether she/he continues to fit the study inclusion 
criteria. Note: If issues arise while attempting to contact participant, there may be up to an additional week 
between the initial screen and the baseline appointment. At the outset of this visit, blood pressure and 
suicidality are rescreened to ensure that participants are safe to start the study medications. Those that are 
eligible and wish to continue are asked to complete the Form-90 to evaluate drinking history over the past 
three months. They also complete the Script Preparation Form to provide details for the craving induction 
paradigm (see below). They also complete a battery of self-report measures as well as complete the two 
craving measures (Desire for Alcohol Questionnaire and Obsessive Compulsive Drinking Scale) again.  
Form-90 Details. The RC or Study Clinician administers the Form-90 to ascertain drinking history over 
the last three months as well as involvement in various types of health care and mental health treatment. 
Script Preparation Details. Participants complete the Script Preparation Form to provide details 
regarding two different recent situations that led to alcohol craving or actual use, including physiological and 
emotional reactions and specific information on the type of alcohol craved or consumed. One situation will 
have evoked anxiety, concern, or worry that led to craving or consumption, and the other will have involved 
craving or consumption meant to lead to or enhance positive emotional reactions in a situation or that pertain 
to desired effects of alcohol (e.g., feeling high, intoxicated, “good,” etc.). These materials are used by study 
staff to write brief, personalized, imaginal craving inductions using a standard format that portrays each 
experience in the second person, present tense, and incorporates between five and seven different visceral 
and muscular reactions. The imaginal scene leads the person through the situation up to the acquisition of the 
alcohol and bringing the drink to her/his lips (but not consuming it). Each induction is 1 minute long 
(approximately 214 words) and is recorded in a neutral tone by someone other than the Study Clinician or RC 
for replay during the induction procedures at session 8 
Self-report Details. In addition, participants complete self-report measures on craving, drinking motives, 
and social networks. In addition, potential phenotypic moderators of interest will be examined, including family 
history of AUD, age of onset of drinking and AUD, drinking motives, depression, PTSD severity, anxiety 
sensitivity, emotional reactivity, disinhibition/impulsivity, and sensitivity to reward and punishment. They also 
complete the Stroop, another measure of impulsivity, which is administered by the RC or Study Clinician. 
Medication Administration: Upon completion of the questionnaires the Study Clinician meets with the 
participant and orients him/her to the medication regimen. A two-week supply of the study medications loaded 
into a 14-day, 3-compartment Mediset is provided along with written instructions with visuals (i.e., pictures of 
the capsules) regarding dosing. Safety precautions regarding the medications are reviewed and participants 
are reminded to call the study telephone number should they experience any concerning side-effects or have 
any questions. The two-week prazosin titration schedule detailed in Table 1 is followed. Naltrexone does not 
require a titration period; participants are instructed to take the naltrexone/matched placebo capsule at the 9pm 
dosing time. Participants are given a pre-printed index-size card with study contact information and an alert 
that they could be taking naltrexone should they need emergency medical care involving pain medication (i.e., 
opiates). 
Titration Schedule. 
Prazosin 
Dosing: 
9 AM 
3 PM 
9 PM 
Naltrexone 9 PM 
Dosing: 
Days 1-2 
 
 
1 mg 
50mg 
Days 3-4 
1 mg 
1 mg 
1 mg 
50mg 
Days 5-7 
2 mg 
2 mg 
2 mg 
50mg 
Day 8-10 
2 mg 
2 mg 
8 mg  
50mg 
Day 11-14 
4 mg 
4 mg 
8 mg  
50mg 
Day 15-42 
4 mg 
4 mg 
8 mg 
50mg 

 
Study Clinician Safety and Comfort Call (Safety and Comfort Call #2): The Study Clinician calls each 
participant the day immediately following the initial dose of study medications to assess whether any 
concerning side effects were experienced, including any suicidal ideation.  
Vital Signs and Adverse Events Checks (Visits 3-7; Safety Calls # 3 & 4):  
In-person Visits: To assure that participants are tolerating the study medications they are scheduled for 
five brief visits after the initial medication administration visit and before the final visit. Study days 12, 19, 29, 
36, and 42 are the target (+ 3 days) days for these in-person visits. At each of the in-person visits, sitting and 
orthostatic BP and HR are obtained. Participants are queried for adverse events using the open-ended 
question “How have you been feeling since you were last here?” Any elicited adverse events are recorded and 
rated for severity, duration, action taken, and relatedness to study medication. 20 mmHg drop in systolic BP 
accompanied by dizziness, lightheadedness or syncope at time of measurement or blood pressure systolic 
reading <100 with reported dizziness, lightheadedness or syncope at the time of measurement or between 
visits are considered unacceptable side effects and the titration is slowed or decreased to the last tolerated 
dosage or medication discontinued and study participation terminated as clinically appropriate. When the 
titration is adjusted, new study medications are requested from the pharmacy immediately and dispensed 
before the participant leaves.  
In addition, participants complete a brief battery of measures to assess depression, anxiety, pain, and 
sleep and wake disturbance at each in-person visit. Participants are administered the PHQ-9 to screen for 
depression and suicidal ideation; the PHQ-9 was adapted for a one week timeframe.  
Safety Calls: Study days 16 and 22 will be the target (+ 3 days) days for the telephone calls 2 and 3. 
Participants are queried for adverse events using the open-ended question “How have you been feeling since 
we last saw you in the research clinic?” If safety concerns are apparent, participants are either be told to 
discontinue study medications or to adjust their dosing. An in-person study visit is scheduled as soon as 
possible in either case. The PHQ-9 suicide screen question is asked during each call with the timeframe 
adapted to cover since the participant last had contact with study staff. 
Final Assessment and Craving Induction (Visit 8; Study day 42):  
Final Visit Timing: Participants are scheduled to come back for their final visit approximately 7 weeks 
after their screening visit (Note: if scheduling difficulties arise there may be up to a two-week delay following 
the target end of the medication period in completing the final visit).  
Final Assessment: Participants will complete the CAPS, PHQ-9, PROMIS measures, Form-90 (adapted 
for the 7-week time interval), and the Stroop with the study RC or Study Clinician, as well as the same paper-
and-pencil measures collected at Visit 2 and during the weekly visits. They then undergo the two craving 
inductions in counterbalanced order (see below). At the conclusion of the craving induction procedures, the 
Study Clinician checks the participants’ vital signs and adverse events as per Visits 3-7, and questions will be 
answered about medication discontinuation. Level of craving is reassessed and if the participant indicates a 
strong desire to actually drink, the Study Clinician will work with him/her to identify alternatives or ways of 
drinking moderately. Laboratory evaluation of blood samples is repeated and again includes CBC, routine liver 
function tests, and routine serum chemistries. Specimens are sent to a lab in Minnesota, MedTox, for 
assessment of the alcohol biomarker phosphatidylethanol – Peth. The same blood draw procedures indicated 
above for Visit 1 are repeated at the final visit. 
The portion of the visit with the Study Clinician may take place before the craving induction depending 
on scheduling and room availability. At the end of the appointment participants are thoroughly debriefed, and 
provided community or VA referrals for alcohol treatment. This portion of the visit may be conducted by either 
the RC or the Study Clinician. 
Craving Induction Procedures: At approximately 1pm or later participants are oriented to the craving 
induction procedures by the study RC or Study Clinician. Participants are seated in a comfortable chair in a 
quiet, undecorated room and fitted with headphones. The craving inductions are presented in counterbalanced 
order. Immediately prior to the first induction participants rate their current craving using the abbreviated Desire 
for Alcohol Questionnaire (DAQ). Current positive and negative affect are also assessed with the PANAS. 
Participants are then be instructed to close their eyes and imagine that they are in the situation they are about 
to hear. Their personalized reward oriented or relief oriented craving scene is played over the headphones. At 
the end of the scene the participants imagine the scene for an additional three minutes following which they 
are asked to complete the same ratings as before. Participants then relax for 30 minutes with engaging but not 

provocative reading material and puzzle books prior to completing the second induction, the procedures of 
which parallels the first.  
 
Study Medications 
Prazosin: Prazosin HCl or identical matched placebo capsules are dispensed as 1, 2, and 4 mg 
capsules prepared by Kelley-Ross Pharmacy, a compounding pharmacy in Seattle. A 25mg riboflavin trace will 
be added to each capsule to evaluate medication compliance. 
 
Naltrexone: 50 mg naltrexone or identical matched placebo capsules prepared by Kelley-Ross 
Pharmacy (tablets are ground and then compounded with the 25mg riboflavin trace).  
 
Procedures for Maximizing Research Integrity 
 
Maintaining the Study Blind: Only the VAPSHCS research pharmacist will have access to the 
randomization schedule, and she will have no contact with study participants. The blind may be broken by the 
PIs in case of safety concerns and for the purposes of interim analyses, but the information will not be shared 
with study staff except in the event of clinically significant safety concerns. 
 
Maximizing Retention: We update contact information at each clinical and assessment visit.  
Participants will be paid $15 for each of the two blood draws.  
 
Study Instruments 
Study Construct/ Variables 
Study Phase 
Purpose 
Inclusion/Exclusion Criteria and Blocking Factors 
Demographic information 
V1 
sample description, blocking (gender) 
Medical history interview  
V1 
exclusion 
Medical Exam 
V1, V8  
exclusion; safety 
Lab values 
V1, V8 
exclusion; safety 
MINI International Psychiatric Interview (DSM-V AUD 
& SUD onset of drinking and alcohol problems as well 
as recent drinking; DSM-IV Psychosis; suicidality, 
homicidality) 
V1 
inclusion and exclusion 
Alcohol use goal (embedded in MINI AUD) 
V1 
inclusion, blocking, treatment moderator  
Desires for Alcohol Questionnaire (DAQ) 
 V2, V8 
, outcome 
Life Events Checklist 
V1, V8 
blocking 
Penn Alcohol Craving Scale 
V1, V2, V8 
inclusion 
Clinician-Administered PTSD Scale For DSM-5 
(CAPS) 
V1, V8 
blocking, treatment moderator (Aim 3) 
Tracking 
Contact form 
V1-V7 
retention 
Primary Outcomes 
Alcohol Biomarker (Peth) 
V1, V8 
outcome 
Alcohol Craving (DAQ) 
V8 
outcome (Aim 2) 
Alcohol use 
V8 
outcome (Aim 2) 
Reward Craving for Craving Inductions from DAQ 
V8 
outcome (Aim 1) 
Relief Craving for Craving Inductions from DAQ 
V8 
outcome (Aim 1) 
Hypothesized Moderators 
State Trait Anxiety  
V1, V8 
moderation (Aim 3) 
Anxiety Sensitivity Inventory 
V1, V8 
moderation (Aim 3) 
Sensitivity to Reward/Punishment Scale 
V1, V8 
moderation (Aim 3) 
PHQ-9 Depression  
V1-V8 
moderation (Aim 3); safety 
Family History of AUD 
V2 
moderation (Aim 3) 
Drinking Motives (Card Sort) 
V2, V8 
moderation (Aim 1) 
Secondary Measures (Descriptive and/or Exploratory) 

AUDIT 
V1 
sample description 
Drinking Motives Questionnaire 
V1, V8 
sample description 
Obsessive Compulsive Drinking Scale 
V1, V2, V8 
sample description 
Form-90 (alcohol)  
V2, V8 
sample description and outcome 
 
 
 
 
 
 
Positive and Negative Mood States 
IVR, V8 
sample description 
Barrett Impulsivity Scale 
V2, V8 
sample description 
Stroop 
V2, V8 
sample description 
PROMIS Pain Impact 
V2 – V8 
sample description 
PROMIS Sleep quality 
V2 – V8  
sample description 
PROMIS Wake Disturbance 
V2 – V8 
sample description 
PROMIS General Distress; Anxiety 
V2 – V8 
sample description 
Important People Inventory 
V2, V8 
sample description and possible moderator 
Craving Induction Preparation 
Script Preparation Form 
V2 
provide details for craving inductions 
Medication Management / Safety Checks 
Adverse Events Checklist and Vital Signs 
All 
clinical data for medication management 
PHQ-9 Suicide item (#9) 
All Phone Calls 
safety 
 
 
 
Data Safety Monitor/Research Monitor 
In accordance with DODI 3216.02, the research monitor, Joseph Reoux, MD, has the authority to stop 
this research protocol in progress, remove individual human subjects from the research protocol, and take 
whatever steps are necessary to protect the safety and well-being of human subjects until the IRB can assess 
his report. Dr. Reoux is responsible for promptly report his observations and findings to the IRB or other 
designated official. He may also have direct contact with study participants should it be necessary to evaluate 
their safety and to make recommendations for any needed care or actions.  
 
Data Management  
Jane Shofer, M.S., a biostatistician from the University of Washington, will analyze the study data. 
Because Ms. Shofer is not a VA employee, the study data will be temporarily transferred to her laptop for 
analysis. Ms. Shofer will have the study data for one year. After one year, Ms. Shofer will delete them from her 
laptop. All data transfers will be made using methods approved by the VA Privacy Office and Information 
Security Office. 
The transferred data will not have any identifying information connected with them. They will be raw 
data numbers only identified by a study code number. Inadvertent disclosure of any of these data will not have 
any impact on participants, as a third party would not be able to discern what the data are. The study 
crosswalk, the bridge between the study code and participant’s name, will be kept in the project folder in the 
VA secure network (\\R01PUGHSM03.R01.MED.VA.GOV\Research\Simpson\IVR_Studies\00623 (AA-PaN 
Study)\11 - Tracking & Databases) and will not be shared with Ms. Shofer. 
 
Statistical Analysis Plan 
Statistical analysis will focus on three primary outcomes and a secondary outcome (average drinks per 
drinking day). The three primary outcomes are Percent Drinking Days (PDD), Percent Heavy Drinking Days 
(PHDD), and craving scores from PACS. The Form-90 will be used to gather drinking data for the three months 
prior to receipt of study medication as well as the six-weeks of study medication. This information will be used 
to compute PDD, PHDD, and average drinks per drinking day. Heavy drinking is defined as five or more drinks 
or four or more drinks in a day for men and women, respectively. 

Hypotheses will be tested using intent-to-treat (ITT) linear mixed effect analyses. Specifically, 
differences in outcome measures from pre-treatment through the study medication phase will be estimated 
using linear mixed effects regression of outcome (the dependent variable) on treatment by study visit 
interaction (the independent fixed effects). Study visit will be modeled as categorical (post- vs. pre-treatment). 
Study participant will be modeled as a random effect. Model results will be summarized with estimated 
marginal means at pre- and post-treatment for each treatment group, within-group mean change from pre-
treatment and mean difference in change by group. The latter set of means will also be presented as 
standardized effect sizes calculated using the standard deviation of the outcome at baseline as the 
denominator. Hypothesis testing for the overall difference in change in outcome by treatment will be carried out 
using the likelihood ratio test for the significance of the study visit by treatment interaction term. All means will 
be accompanied by standard errors, and all mean differences will also be presented with 95% confidence 
intervals (CIs), which will be adjusted for the four sets of differences estimated corresponding to the four 
treatment groups using the single-step method. 
Exploratory analyses will be carried out to separate the effect of the treatment from the effect of the pre-
treatment levels of each outcome on the estimates of post-treatment change in outcomes by adding a pre-
treatment outcome by visit interaction term to the model. Descriptive analyses will be carried out to summarize 
clinical outcomes at the last week of study. Lower risk drinking will be defined using NIAAA guidelines; for men 
this means exceeding neither 14 drinks per week nor 4 drinks per day and for women this means exceeding 
neither 7 drinks per week nor 3 drinks per day. The number of abstinent drinking days and the number of 
participants who are completely abstinent during the last week will also be computed. Additionally, both the raw 
mean PDDs and PHDDs will be computed for each week of study medication and plotted by group to illustrate 
changes over time in these outcomes. Type 1 error will be set at .05 for each outcome. Analyses will be carried 
out using R 3.6.2, and the packages lme4, emmeans and tidyverse. 
Descriptive information pertaining to study visit attendance, medication adherence, participant safety, 
adverse events, and medication adjustments will be provided by medication treatment condition.