Conditions: Post Traumatic Stress Disorder Alcohol Abuse
Keywords: Alcohol Use Disorder (AUD) Alcoholism Alcohol Abuse Post Traumatic Stress Disorder (PTSD)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 69
Healthy volunteers: no

Brief summary:
Objective: Evaluate the efficacy and physiological effects of sublingual buprenorphine (SL-BUP; Subutex) combined with extended-release injectable naltrexone (XR-NTX; Vivitrol) in the treatment alcohol use disorder of comorbid (AUD) and post-traumatic stress disorder (PTSD)

Detailed description:
Hypothesis: The treatment of (sublingual buprenorphine) SL-BUP + (extended release naltrexone) XR-NTX will significantly reduce both (alcohol use disorder) AUD and (post-traumatic stress disorder) PTSD symptoms.

Primary Inclusion Criteria: Treatment-seeking individuals with comorbid AUD and PTSD

Subject Completion Target: A total of 90 male and female, treatment-seeking individuals with comorbid AUD and PTSD screened, enrolled, and randomized to treatment group

Study Protocol:

Screening: Potential participants are pre-screened by phone to ensure they meet basic study criteria. During informed consent and screening processes, participants receive thorough pre-enrollment education and the commitment to and feasibility for follow-up are confirmed. Screening visit is separate (at least 2-day interval) from Baseline visit. A participant who is otherwise meeting eligibility criteria except for taking an excluded medication can undergo a medically supervised discontinuation and 5-day washout of medication(s). At any point in the screening process and based on the inclusion and exclusion criteria listed above, the participant may be deemed eligible and proceed to baseline visit or investigator may exclude a participant and refer him/her for appropriate treatment.

At baseline, participants are randomized to receive either treatment A (buprenorphine 2mg SL with naltrexone 380mg IM) or treatment B (SL placebo and IM placebo) in a double-blind fashion. The treatment allocation ratio for the treatment vs. placebo regimens is 1:1.

At Screening, Baseline and Follow-up, an independent rater at each site performs the Timeline Follow Back (TLFB), Clinician Administered PTSD Scale for DSM-5 (CAPS-5), and Columbia Suicide Severity Rating (CSSR) assessments. Safety endpoints, adverse events (AEs), vital signs, and laboratory measures are tracked for each subject to assess study drug safety.

Arms:
arm 1: 2mg Buprenex and 380mg Vivitrol

Buprenex (buprenorphine) 2mg sublingual (SL) (taken every day for 12 weeks) , with Vivitrol (naltrexone) 380mg intramuscular injection (IM) (given every 4 weeks) arm 2: Placebo (SL pill qd, IM injection q4weeks)

Placebo pill (taken sublingual every day for 12 weeks) and IM placebo (given intramuscular injection, every 4 weeks at baseline, week4 and week8)

Interventions: intervention 1: 2mg Buprenex and 380mg Vivitrol intervention 2: Placebo (SL pill qd, IM injection q4weeks)
Intervention descriptions: intervention 1: Daily 2mg SL BUP (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8 ) IM NLTRX intervention 2: Daily SL placebo (84 pills total, taken sublingual every day for 12 weeks) and Q4wks (given intramuscular, 3 injections total: at baseline, week4 and week8) IM Placebo

Protocol document:
ICF_002.pdf: 
Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 1 of 12)
INTRODUCTION
We are asking you to volunteer to take part in a research study at the Tuscaloosa Veterans Affairs 
Medical Center (TVAMC).  It is important that you read and understand the information on this form.  The 
sponsor (financial source) for this study is Pharmacotherapies for Alcohol and Substance Abuse (PASA) 
Consortium.
BACKGROUND AND PURPOSE
Currently four medications (disulfiram, oral and long-acting injectable naltrexone, and acamprosate) are 
FDA–approved to treat alcohol use disorder (AUD) and two medications (sertraline and paroxetine) FDA-
approved to treat post-traumatic stress disorder (PTSD). Despite a growing body of research in this area, 
there are no medications shown to be clearly effective when heavy drinking and PTSD co-occur. This 
study addresses the need for new and effective treatments. The purpose of this study is to evaluate how 
well the combination of sublingual buprenorphine (SL-BUP; Subutex) combined with extended-release 
injectable naltrexone (XR-NTX; Vivitrol) works in the treatment of co-occurring AUD and PTSD. In 
addition, we are also trying to learn what happens to a person’s physical responses to unexpected 
sounds, lights, images, and air puff while viewing computer images of neutral, trauma-related, and 
alcohol-related topics. You are possibly eligible for this study because you may have recent heavy 
alcohol use and symptoms of PTSD.  Your study participation will last approximately 15 weeks.  You will 
be one of approximately 90 to 135 people across three medical centers to participate in this study.
STUDY PROCEDURES 
Baseline Assessments: After signing the informed consent, you will meet with someone from the 
research team to be screened for the study (lasting several hours over 1 to 14 days), which includes 
answering questions about your mental health conditions, drinking patterns and PTSD symptoms, filling 
out pen-and-paper surveys about your alcohol use, PTSD symptoms, depression symptoms, life 
activities, and tendencies to be impulsive, and getting your blood drawn for basic laboratory tests, which 
includes a urine drug screen in the research clinic. At the screening and baseline visits, you will be 
assessed for signs and symptoms of withdrawal from alcohol. If you have signs such as unstable pulse, 
blood pressure, or sweating or symptoms such as tremor, nausea, vomiting, agitation, feeling crawling 
sensations on skin, or hallucinations, we may recommend a referral to mental health provider for alcohol 
detoxification treatment. The results of the urine drug screen remain in the research records and do not 
go into your VA records. You will also be asked to blow into a breathalyzer to test for alcohol level and 
these results will be kept in the research records, but the results will not be entered into your VA records 
unless there is a serious safety issue that requires medical intervention.  If the drug screen is positive for 
any drugs (except marijuana) and/or you have a breathalyzer level > 0.02 or positive blood alcohol level, 
the appointment will be canceled, and you will not be paid for this appointment. In addition, we are also 
trying to learn what happens to a person’s physical responses to unexpected sounds, lights, images, and 
air puff while viewing computer images of neutral, trauma-related, and alcohol-related topics.   We may 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 2 of 12)
be able to reschedule your appointment for a later date. You may continue some allowed medications 
that are prescribed for PTSD, but you cannot take other psychiatric medication or medication used to 
treat AUD during the study.
Study Medications: At the baseline visit, the research medication provider orders the study medication 
and the VA pharmacy dispenses the study medication or placebo medication according to the computer-
generated assignment to one of two treatments in a random order (i.e. like flipping a coin).  You will be 
taking the assigned treatment during the next 12 weeks (i.e. the dose will not change); however, you will 
not know which one of the three treatments you are assigned from the following list:  

SL-BUP 2mg and XR-NTX 380mg, or 

SL-placebo and XR-placebo; You have 1 in 2 chances of being on placebo.
XR-NTX or XR-placebo given by injection in your gluteal muscle (buttocks) in the research clinic by a 
trained research nurse or medical doctor on the day it is dispensed from the pharmacy and every 28-
days on week 4 and week 8 of the study. You will receive the first injection of XR-NTX or XR-placebo in 
the research clinic and remain in the clinic under the supervision of the research team for approximately 
1 hour after the 1st dose is administered. 
SL-BUP or SL-placebo is started on the next day, taken sublingually (in other words, place and hold the 
table under your tongue until it dissolves) and is taken daily at the same time every day. If you miss a 
dose, you should take the next dose as soon as possible. You will be given enough pills 
needed to allow one pill per day for each day to last until the date of your next scheduled 
visit.  It is important that you keep your appointments so that you do not run out of 
medication. Bring any remaining medication back to the next research appointment. 
Do not share your study drug with others, keep study drug secured (in your 
possession or locked up), keep study drug out of reach of children and pets. 
Bring any unused study drug back to the pharmacy when you return.
If for any reason there is study medication that will go permanently unused, the research 
coordinator will give you a Take-Away Medication Recovery System tamper-resistant 
envelope and you will place the unused medication in this envelope and put in a US postal 
service mailbox to be sent to a pharmacy destruction service.
Follow-Up Visits: You will be evaluated by phone or video telehealth at week 1, 2, 6, and 8; however, 
you return to the research clinic for in-person assessments on weeks 4, 8, and 12. If you prefer all visits 
to be conducted in person, we will honor your preference.  The research coordinator will also contact you 
by telephone (t) during the weeks between face-to-face visits to remind you of the next office visit and to 
check on adherence to the study medication and if there have been any serious adverse events. 
The investigators and a research coordinator will meet with you to provide ongoing reinforcement of your 
commitment to the study participants. The study medication provider will emphasize the need to properly 
adhere to prescribed study medication or to call to revise the treatments if side effects occur or 
therapeutic effects are lost. The face-to-face assessments will include your answering questions about 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 3 of 12)
your mental health conditions, drinking patterns and PTSD symptoms, filling out pen-and-paper surveys 
about your alcohol use, PTSD symptoms, depression symptoms, life activities, and a urine drug screen 
in the clinic. The results of the urine drug screen remain in the research records and do not go into your 
VA records. You will also be asked to blow into a breathalyzer to test for alcohol level at all research 
visits and these results will be kept in the research records, but the results will not be entered into your 
VA records unless there is a serious safety issue that requires medical intervention.  At week 8 and 12, 
you will also have your blood drawn for an alcohol-related blood lab test.
While every attempt is made to retain you in the study on medication for the full 12 weeks, you 
may discontinue medication at any point and remain in the study for assessments through week 
12. If you exit prior to week 8, all procedures for week 8 are completed.  If you exit after week 8 but prior 
to week 12, all week-12 procedures are completed. The investigator may discontinue your study 
participation without your consent for reasons of safety or your nonadherence to the study procedures.
At week 12, the study medications are discontinued, and all week 12 assessments are completed. A 
member of the research team will call you a few days later to make sure you have not had any problems 
with stopping the study medication.  At week 12, you will be referred back to your previous or newly 
assigned long-term PTSD provider for follow-up and continued treatment.  At week 14, you will be 
assessed for discontinuation or withdrawal side effects and resolution or emergence of adverse events, 
either in-person visit or by video telehealth visit. 
For women of childbearing potential: Since it is unknown whether the study drug may have bad 
effects on an unborn child and should not be taken during pregnancy, it is necessary that a pregnancy 
test be done during screening and during follow-up. If you are a woman of child-bearing potential, you 
will be asked to have a urine pregnancy test in the clinic to make sure that you are not pregnant. You 
agree to use contraceptives and take precautions against becoming pregnant during this study.  
Because this is a new combination of drugs, we do not know all side effects.  You should contact 
Dr. Pilkinton at 205-554-2000 ext. 1-2944 or Dr. Lori Davis at ext. 1-3819 if you have any side 
effects.  
We cannot guarantee that you will be able to continue receiving this medication after this study is 
over.  Naltrexone is currently on VA formularies and you may have access to this medication from your 
clinic provider. Although SL-BUP is on VA formulary, it is not currently indicated for AUD or PTSD.
While in the study, your responsibilities include:
Take the study medication as instructed and return unused study drug to the research team.
Keep your study appointments and let the investigator know if you are having problems.
If you miss an appointment, please contact the research coordinator to reschedule.
Keep your study drug in a safe place for your use only and away from children or pets.
Do not take part in any other research project without talking it over with the investigator.
Do not take additional or new medication without talking it over with the investigator.
Psychophysiological Assessments (OPTIONAL):  At baseline (two days), week 2 (one day), and 
week 8 (two days), you may choose to undergo a psychophysiological assessment that will take place 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 4 of 12)
over two days (lasting approximately 1 hour and 10 minutes on day one and 30 minutes on day two). 
You will be asked to complete several tasks where we will monitor your physical reactions to lights, 
sounds, and images. We will measure how strong your eyes blink, the amount of sweat on your hands, 
and changes in your heart rate and breathing throughout the tasks.  You will receive additional 
compensation for participating in this part of the study. 
We will measure these responses by placing electrodes (tiny metal discs with wires attached to them) on 
your skin which will send information to a computer. Before placing the electrodes, a member of the 
research team will clean the following areas with alcohol and/or a gritty gel: the left forearm, right 
collarbone, and just below your right eye. The electrodes will then be placed below your eye, arm, 
collarbone, and fingers. 
Next, a brief hearing test will be conducted. During the first task, you will be seated in a sound-proof 
booth and given instructions for the task. Next, you will hear sounds through headphones while lights in 
the booth switch between “on” and “off”. You may be startled when you hear these sounds and you may 
blink your eyes. The electrodes will allow us to measure how strongly you blink your eyes. During the 
second task, you will see a series of shapes on a computer screen and hear sounds through the 
headphones. There will be some mildly uncomfortable events, including short puffs of air pointed toward 
your neck, but these will not be painful. When each shape appears, you will be asked to press a button 
indicating what you think the shape means in the context of the task. You will also view a computer-
generated virtual reality environment that includes victim-reported contexts associated with assault (e.g. 
barracks, latrines, rear seat of a vehicle). These contexts do not recreate the traumatic events that may 
have led to the development of PTSD. You will also repeat the task while viewing images related to 
alcohol cues. During the 2nd day, we will administer another task like those described above, although 
the 2nd day is much shorter duration.
PHOTOGRAPHY, VIDEO AND/OR AUDIO RECORDING FOR RESEARCH PURPOSES 
During the assessment of your PTSD symptoms and alcohol use, the interview will be audio-recorded for 
purposes of making sure that the person conducting the interview is adhering to the questions and 
making the assessment of your symptom severity according to our study plan. This recording will be 
listened to by a study monitor and your information will be kept confidential.  This recording will not be 
shared with your providers, the public, or other members of the research team.
POSSIBLE RISKS OR DISCOMFORTS 
Any procedure has possible risks and discomforts.  The procedures in this study may cause all, some, or 
none of the risks or side effects listed.  Rare or unexpected risks also may occur. Risks of the usual 
health care you receive are not risks of the research and are not listed in this consent form.  If you have 
any questions about the risks of your usual care, you should talk with your health care providers.
Questionnaires/interview-based assessments may bring up painful emotions, such as sadness, 
worry, or increased anxiety or upsetting memories, such as trauma-related events or periods of heavy 
alcohol use. You are free to take breaks or to not answer a question. To minimize the risk, the person 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 5 of 12)
doing the interview is trained to ask the questions with respect and dignity and allow you to express how 
you feel without causing blame or shame.
Venipuncture (blood draw): It is unlikely, but for some people the blood draw(s) may cause discomfort, 
pain, bruising, and rarely, fainting, or infection. These procedures are done only by skilled and 
experienced laboratory or research personnel to reduce the risk of any negative reactions.
Sublingual buprenorphine: Sublingual buprenorphine (SL-BUP) is FDA-indicated for the treatment of 
opioid dependence. SL-BUP is a Schedule III narcotic under the Controlled Substances Act. The use of 
SL-BUP in a non-opioid dependent population has a risk of misuse or abuse. However, to essentially 
eliminate the potential for misuse, dependency, and withdrawal, SL-BUP is combined with XR-NTX, a 
medication that blocks the brain receptor involved in euphoric properties of buprenorphine. Adverse 
events most commonly observed during clinical trials and post-marketing experience for SL-BUP 
compared to placebo are headache (29% vs 22%), nausea (14% vs 11%), vomiting, hyperhidrosis, 
constipation (8% vs 3%), signs and symptoms of withdrawal (18% vs 37%, i.e. greater in placebo group), 
insomnia (21% vs 16%), and pain (18% vs 19%). The doses used in this study are lower and may yield 
fewer side effects. Since the SL-BUP dosing is low, there is only a very low risk (% unknown) of having 
symptoms of upset stomach, headache, or sweating for a few days after you discontinue the medication.  
If this happens, the doctors or nurse practitioner can give you non-controlled medication to help reduce 
symptoms.
Significant respiratory depression and death have occurred in association with buprenorphine, 
particularly when taken by the intravenous (IV) route in combination with benzodiazepines or other CNS 
depressants (including alcohol). Many, but not all post-marketing reports regarding coma and death 
associated with the concomitant use of buprenorphine and benzodiazepines involved misuse by self-
injection. To minimize these risks, you are not allowed to take benzodiazepines (i.e., Ativan, Valium, 
Xanax, Klonopin, etc.) and anti-seizure medications during the study.
Extended-release naltrexone: Side effects of XR-NTX that led to more discontinuation of treatment 
compared to placebo include the following: pain, tenderness, induration or pruritus at the site of the 
injection (3%), nausea (2%), headache (1%), and suicide-related events (0.3%). Other known non-
serious side effects that differ from placebo include nausea (29% vs 11%), vomiting (12% vs 6%), 
diarrhea (13% vs 10%), abdominal pain (11% vs 8%), injection site reactions (65% vs 50%), 
arthralgia/arthritis (9% vs 5%), muscle cramps (5% vs 1%), rash (6% vs 4%), headache (21% vs 18%) 
dizziness (13% vs 4%), somnolence/sedation (5% vs 1%), and appetite decrease (11% vs 3%). XR-NTX 
has the capacity to cause liver injury when given in excessive doses (five-fold times the recommended 
dose). Thus, XR-NTX does not appear to be a risk to the liver at the recommended doses used in this 
study. Since naltrexone gradually leaves your body over time, there is no risk of withdrawal symptoms 
after you discontinue the medication.
In a situation when analgesia (i.e. sedative for surgery) may be required, consideration should be given 
to regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid analgesics, or 
general anesthesia. If opioid analgesia is required, the amount of opioid needed may be greater than 
usual, and the resulting respiratory depression may be deeper and more prolonged. In this case, a 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 6 of 12)
rapidly-acting opioid analgesic that minimizes the duration of respiratory depression is preferred. XR-
NTX can also diminish the benefit from opioid-containing cough, cold, and antidiarrheal preparations. 
These warning are standard when treating patients with XR-NTX and a safety card will be provided to 
you for you to carry in your wallet or purse in case of emergency.
Combination of SL-BUP and XR-NTX: The occurrence of side effects may be slightly more frequent 
(22% of people taking the combination compared to 18% for XR-NTX) but the type of side effect does 
not change when the two medications are used in combination. The combination of these medications 
may reduce the desire to use more SL-BUP than otherwise prescribed.
Caution: Do not drive or operating hazardous machinery until you are reasonably certain that treatment 
does not adversely affect your ability to engage in such activities. If you experience a medical 
emergency, informed the emergency team that you may be on these medications so that they know how 
to treat you. 
The risks of complications during pregnancy or congenital problems with this drug combination is not fully 
known, although much is known about each medication separately.  There is no evidence that either 
medication affects reproductive risks after discontinuation. Similarly, there is no evidence that either 
medication affects male reproductive risks. 
There may be unknown risks or discomforts involved. Study staff will update you in a timely way on any 
new information that may affect your decision to stay in the study. 
Psychophysiology tasks: It is somewhat likely that scrubbing your skin in the places where the monitor 
pads are placed may cause redness or mild swelling. The noise level you will hear during the session 
should not result in any discomfort but may be mildly annoying. You may find the air blasts, darkness, 
small room, or virtual reality contexts somewhat annoying or uncomfortable. To reduce this risk, the tasks 
are performed at your own pace and in a private clinic office. You may ask for the session to be stopped 
immediately if you are uncomfortable or distressed. The decibel levels and duration of the auditory stimuli 
are not sufficient to cause any damage to the ear.
POTENTIAL BENEFITS  
We cannot promise that you will get any benefits from taking part in this study.  XR-NTX is FDA 
approved for the treatment of alcohol dependence, as well as for the prevention of relapse to opioid 
dependence, following opioid detoxification. Thus, XR-NTX may directly benefit you in this study and 
help you reduce or stop the use of alcohol. Reducing alcohol use may also be a factor in reduction of 
PTSD symptoms and conversely, reduced PTSD symptoms may lower your tendency to self-medicate 
with alcohol. Another benefit of the study is that knowledge to be gained can help guide treatment for 
patients with comorbid AUD and PTSD in the future. 
OTHER TREATMENT AVAILABLE 
If you do not wish to participate in this study, you may continue in your present treatment or you 
may be referred to a mental health clinic or PTSD clinic for additional treatment. 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 7 of 12)
Four medications (disulfiram, oral and long-acting injectable naltrexone, and acamprosate) are FDA–
approved to treat alcohol use disorder (AUD).  If you would like to try these medications without being in 
the study, you need to be referred to or stay in treatment for a mental health provider. There are two 
medications (sertraline and paroxetine) FDA-approved to treat post-traumatic stress disorder (PTSD). If 
you are already taking these medications, you may continue them at a steady dose during the study.
You may also seek counseling as treatment for AUD and PTSD.  During the study, you can participate in 
supportive counseling for PTSD or 12-step programs for alcohol problems.  However, you are not 
allowed to participate in cognitive behavioral or prolonged exposure therapies during the study.  If you 
want to participate in these treatments, you may do so either before or after your study participation.
CONFIDENTIALITY
Taking part in this study will involve collecting confidential information about you, including your name, 
address, phone number, and the surveys that you complete during the study. If you decide to participate, 
your identity will be protected. Individuals who participate will be assigned a study ID number, which will 
be kept on a secure network server that complies with all VA Data Security regulations. In order to 
participate in the study, you will be asked for your contact information (telephone and address) and the 
name of alternate contact if we are unable to locate you.  This information will be protected in the 
following ways: the information collected will be kept in locked files and on computers protected with 
passwords. Electronic data will be access-restricted to approved research study staff and will be stored 
on a secure network server that complies with all VA Data Security Regulations. Information collected for 
this study will be stored such that only research personnel with permission to see the data will have 
access to it.  Any hard copies will be kept in a locked file cabinet that only study staff will have access to. 
A copy of this consent form will be place in your medical record.  
To minimize breach or invasion of privacy, records that have personal identifiers (i.e., clinical records or 
source documents) are stored in a locked cabinet behind a locked door. Only the research team and 
clinical staff assigned to your care have access to non-anonymous research records. Research case 
report forms do not contain personal identifiers and are labeled with a study i.d. number. Files that link 
your name with screening and randomization numbers are maintained in a secure location either on VA 
server or in a locked file within a locked office in the research clinic. 
The study findings will be reported in the aggregate, meaning that information about you will be 
combined with information from other people taking part in the study.  Any talks or written papers about 
this study will not identify you by name, by recognizable photograph, or by any other means without your 
specific consent.  If results of this study are reported in medical journals or at meetings, you will not be 
identified by name, by recognizable photograph, or by any other means without your specific consent.  
No presentation or publication of the study results will refer to you individually. 
All study participant research data, which is for the purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the PASA Consortium Data Coordinating Center (DCC). 
This will not include your contact or directly identifying information. Rather, you and your research data 
will only be identified by a unique study identification number. The study data entry and study 
management systems used by the clinical site and PASA Consortium Management will be secured and 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 8 of 12)
password protected.  In addition, if you experience a serious adverse event, the investigators will make a 
report that does not contain your name or identity to the PASA Consortium and to Alkermes (the 
manufacturer of XR-NTX), as well as to the local IRB; however, the dates and details about the serious 
event will be provides to the PASA Consortium and to Alkermes. In addition, any pregnancy that occurs 
during the study and the outcome of the pregnancy will also be reported to PASA Consortium and to 
Alkermes.
Additionally, as this study is funded by the Department of Defense, a version of the data set will 
ultimately be made available to the research community (which includes both scientific and consumer 
advocacy communities) and to the public at large. Those datasets do not include any identifying 
information. This data will be used for other research studies in the future. If you do not agree that your 
data be used in future studies, you will NOT be able to participate in this study.
The investigators will treat your identity with professional standards of confidentiality.  Your medical 
records will be maintained according to this medical center’s confidentiality requirements.  However, 
there are times when we might have to show your records to other people who have oversight of the 
study.  For example, the Food and Drug Administration, other federal oversight agencies, representatives 
of the PASA Consortium, members of our Data and Safety Management Board, the Medical Monitor (Dr. 
Tom Kosten), members of the Government Steering Committee, and/or the VA Institutional Review 
Board (IRB) may inspect your records, particularly if there is a safety issue. The Research Compliance 
Officer (RCO) will review this form and may review your other records.  A person responsible for 
monitoring the PTSD and alcohol interview will listen to an audio recording of the interview, but you will 
not be identified by name or anything other than study i.d. number.
The investigator’s research records for this study will be maintained according to the disposition 
instructions by the National Achieves and Records Administrations and are published in VHA’ s Records 
Control Schedule (RCS) 10-1, in accordance with the new VHA’ s Records Control Schedule 10-1 (RCS) 
policies for the Office of Research and Development; section 7.6. For a study such as this one, the 
instructions state that the PI may destroy research records 6 years after the end of the fiscal year after 
completion of the research project, but the investigator may retain longer if needed.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will include a 
summary of the results.  You can search this Web site at any time. 
A federal Certificate of Confidentiality, which protects your records against subpoena, has been 
approved for this study. Exceptions to confidentiality are those required by law and include suspicion of 
child abuse, elder abuse, and threat of imminent action on suicidal or homicidal ideation.  The Certificate 
of Confidentiality cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of Federally funded projects or for information that 
must be disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
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 research. If an 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 9 of 12)
insurer, employer, or other person obtains your written consent to receive research information, then the 
researchers may not use the Certificate to withhold that information.
WITHDRAWAL FROM STUDY 
You are not required to take part in this study:  your participation is entirely voluntary.  You can refuse to 
participate at this time, or you can withdraw from the study at any time without penalty or loss of benefits 
to which you are otherwise entitled.  Regarding information already collected prior to your withdrawal, the 
investigator may continue to review the data already collected for the study but cannot collect further 
information. Results from laboratory specimens already used cannot be withdrawn.
Your treatment, payment, enrollment or eligibility for benefits will not be affected if you choose not to take 
part in the study. If you decide to withdraw from this study, you should contact Lori Davis, MD or Patricia 
Pilkinton, MD.  Discontinuation will in no way affect the quality of care you receive now, or in the future, 
at this institution or your right to participate in other studies.  The investigator or your doctor may also 
withdraw you without your consent, for medical or administrative reasons, in a study that has not ended.  
Any significant new findings that develop during the research study that, in the opinion of the 
investigator, may affect your willingness to continue to participate will be provided to you ASAP.  
COST TO YOU FOR PARTICIPATION IN RESEARCH 
There will be no costs to you for any of the treatment or testing done as part of this study.  Eligibility for 
medical care is based upon the usual VA eligibility policy and is not guaranteed by participation in a 
research study.  Depending on your veteran status, you might have to pay co-payments for medical care 
and services provided by VA.  Alkermes and Tonix has donated some of the medication used in this 
study, so there will be no cost to you for the study medication.  There is no guarantee that the medicines 
you will receive during this study will be continued after the study is completed. 
PAYMENT FOR PARTICIPATION IN THE RESEARCH 
You will be paid according to the table below to offset out of pocket expenses such as parking, travel, 
childcare, missed work, etc.  Your personal information will be provided to the Tuscaloosa Research and 
Education Advancement Corporation so that they can make a check out or give you a cash card to pay 
you within 30 days of your visit. If you live >50 miles away, you will be given a $25 gas card for each 
office visit that attend in which you (or other) drives a vehicle to the appointment. You will NOT be paid 
for the screening visit if you test positive for any drugs (except marijuana) and/or have a positive blood 
alcohol level or breathalyzer alcohol level > 0.02. You will only get paid for the visits that you attend.
If you opt in to participate in the psychophysiologic assessments, you will get paid $25 per day 
(total of $125 for all 5 days). 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
Schedule of Payments for Completed Visits
Screen
Baseline
1
2
T
4
T
6
T
8
T
10
T
12
T
14
Payments ($)
25
75
25
25
75
25
75
25
50
25
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 10 of 12)
Please note: if you receive research payments of $600 or more in each calendar year, an IRS Form 
1099 will be sent to you and you will need to report this as income when filing your income tax return.  
The Form 1099 will include your full social security number.  
INJURY COMPENSATION CLAUSE  
This research project has been approved by the Tuscaloosa VA Institutional Review Board and R&D 
Committee, and it is being supervised by one or more VA employees.  Every reasonable safety measure 
will be used to protect your well-being. If you are injured as a result of taking part in this study, the 
Tuscaloosa VA Medical Center will provide you with the necessary medical treatment at no cost to you 
unless the injury was due to your not following the study procedures. This care is governed by Federal 
regulations and VA policy.  Non-emergency, non-VA Treatment requires prior authorization.  Financial 
compensation is not available for such things as lost wages, disability or discomfort due to an injury. The 
Department of Veterans Affairs does not normally provide any other form of compensation for injury. You 
have not released this institution from liability for negligence.   
NEW FINDINGS 
You and your physician will be informed if any important discoveries are made during this study which 
may affect you, your condition, or your willingness to participate in this study.  Information obtained in this 
study which, in the opinion of the investigator(s), suggests that you may be at significant risk of harm to 
yourself or others will be reportable to a third party in the interest of protecting the rights and welfare of 
those at potential risk.  
QUESTIONS
If you have questions, concerns or complaints about your rights as a study participant, you may contact 
the Research Compliance Officer, at (205) 554-2000, ext. 3200 or the Institutional Review Board (IRB) 
Administrator who will have the IRB member subject representative contact you.  The IRB Administrator 
can be reached at (205) 554-2000, ext. 3674 (Tuscaloosa VA Patients).  If the IRB Administrator cannot 
be reached, contact the IRB Clerical Assistant at (205) 554-2000, ext. 2536 and she will direct your call 
to an IRB member. 
If you have questions regarding this study or the procedures, if you have unexpected reactions, or if you 
are injured and become ill as a result of participation in this study, please call Dr. Patricia Pilkinton at 
(205) 554-2000, ext. 2944 or 1-888-269-3045, ext. 2944 (toll free); or Dr. Lori Davis at (205) 554-3819.  
You may also call the Tuscaloosa VA operator at (205) 554-2000 or 1-888-269-3045 (toll free) and have 
the operator page Dr. Patricia Pilkinton or Dr. Lori Davis. 
If you are unable to reach Dr. Pilkinton or Dr. Davis and need immediate medical assistance for 
research-related injury, please call the Tuscaloosa VAMC hospital operator at 205-554-2000 or 1-888-
269-3045 and ask for the Triage Nurse to obtain advice or ask to speak with the psychiatrist or medical 
officer on duty.  
If for any reason, you experience suicidality, please call 911 or the Suicide Prevention Hotline at 
1-800-273-8255, or the TVAMC Suicide Prevention Coordinator at (205) 554-2000 ext. 3235.  
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 11 of 12)
AGREEMENT TO PARTICIPATE IN THE RESEARCH STUDY   
RESEARCH SUBJECTS’ RIGHTS:  You have read or have had read to you all of the above.  
One of the above listed investigators or a member of her research team has explained the study to you 
and answered all your questions.  You have been told of the risks or discomforts and possible benefits of 
the study.  You have been told of other choices of treatment available to you.  You have been given the 
chance to ask questions and obtain answers.  
You voluntarily consent to participate in this study, and your refusal to participate will involve no penalty 
or loss of rights to which you are entitled.  Your will receive contact information regarding the research 
study.  You may withdraw from this study at any time without penalty or loss of VA or other benefits to 
which you are entitled.  
The results of this study may be published but your records will not be revealed unless required by law.  
In case there are medical problems or if you have questions, you have been told that you can call Dr. 
Patricia Pilkinton at (205) 554-2000, ext. 2944 or 1-888-269-3045, ext. 2944 (toll free); or Dr. Lori Davis 
at (205) 554-3819.  You may also call the Tuscaloosa VA operator at (205) 554-2000 or 1-888-269-3045 
(toll free) and have the operator page Dr. Patricia Pilkinton or Dr. Lori Davis. 
If any medical problems occur in connection with this study, the VA will provide emergency care in 
accordance with your eligibility.  
You will receive a copy of this consent after you sign it.  A copy of this signed consent will also be put in 
your medical record if applicable.  
I prefer to opt in _______ or opt out _______ of the psychophysiologic assessments.
                             Initials                      Initials
 
I agree to participate in this research study as has been explained in this document.
_________________________
Participant’s Name
____________________________
Participant’s Signature
___________
Date
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021


Subject Name:           
 
           
 
           
 
           
 
 SSN:
 
             
 
           
 
           
 
 Date:           
 
           
 
 
Title of Study:  KOR Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD
 
 
Principal Investigator:  Lori L. Davis, MD
 
      
 
           
 
        VAMC:  Tuscaloosa
Co- Investigators:  Patricia Pilkinton, MD
 
       
 
 Version Date:    August 9, 2021
 
 
VA RESEARCH CONSENT FORM
(Page 12 of 12)
___________________________
Name of person obtaining consent
______________________________
Signature of person obtaining consent
____________
Date
 
                                                    IRB Use Only:
VA FORM
JAN 1990  10-1086
Revised:  September 28, 2015 
VA   Department of Veterans Affairs
 
Tuscaloosa VAMC IRB
Effective Date:
August 31, 2021

Prot_000.pdf: 
 
Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder  
and Comorbid PTSD 
 
Protocol Identifying Number: AS140026-A5 
Principal Investigator: Lori Davis, MD 
Co-Principal Investigator: Ismene Petrakis, MD 
 
IND/IDE Sponsor: Not applicable; Exempt from IND 
Funded by: The Pharmacotherapies for Alcohol and Substance Abuse (PASA) Consortium 
[funded through a Cooperative Agreement between the US Department of Defense 
Congressionally Director Medical Research Programs (CDRMP) and RTI International] 
 
Version Number:  7.0/July 19, 2021  
 
Section 
Substantive Changes (v6, 6/19/2020 to v7, 7/19/2021 ) 
Summary 
Expanded recruitment area for Tuscaloosa site to include Central Alabama VA Healthcare System (CAVAHS)  
Summary 
Updated to 37-month study period that includes ~32-month enrollment period. 
2.3.1, 3,  4.1, 
4.2.2, 7.1.1, 
7.3.4, 7.3.7, 
10.2,  and 10.4.3 
Restarted the psychophysiologic assessments. 
• 
Removed where protocol states “psychophysiologic assessments on HOLD due to COVID-19.” 
• 
Changed psychophysiologic assessments to highly encouraged but optional.  
o 
Procedures should not be a barrier to recruitment 
o 
Participant payments for these procedures should provide incentive for participation. 
1 and 6.1 
• 
Closed enrollment at Wayne State/Detroit site 
o 
Dr. Norrholm remains co-investigator (for purposes of the psychophysiologic assessments) 
7.3.7 
COVID-19 Safety Precautions section was updated to allow for flexibility for sites to follow local policies as both 
vaccination and infection rates evolve.   
7.5 
Updated the prohibited medications to:  
• 
Lamotrigine removed from the prohibited medication list. 
o 
There is no medical contraindication to combining lamotrigine with study medications; thus, 
removing an unnecessary barrier to enrollment. 
• 
Quetiapine removed from the prohibited medication list. 
o 
There is no medical contraindication to combining lamotrigine with study medications; thus, 
removing an unnecessary barrier to enrollment. 
• 
Atomoxetine removed from the prohibited medication list. 
o 
ADHD treatment medication, but not a stimulant; thus, removing an unnecessary barrier to 
enrollment. 
 
Since all scenarios for concomitant medication use cannot be anticipated, we have added this statement so that 
exceptions can be made without causing a protocol deviation: 
“Due to the potential drug: drug interactions (e.g., opiates) or confounding therapeutic effects (e.g., naltrexone or 
acamprosate), participants may not use the medications listed in the table below, unless authorized by PASA 
medical monitor and approved by the lead PIs.” 
5.2 
Clarified exclusion # 7  criteria wording:  
• 
Version 6: ‘….including seizures (other than childhood febrile seizures),….’ 
• 
Version 7: ‘….including seizure disorder (other than childhood febrile seizures),…..’ 


 
5.2 and 7.2.1 
Changed exclusion criteria # 8 (wording regarding ALT and AST upper limit of normal (ULN)):  
• 
Version 6: ALT or ASTs >3x ULN = exclusion criteria  
“aspartate aminotransferase and/or alanine aminotransferase > 3 times upper limit of normal” 
• 
Version 7:  ALT or AST >5x ULN = exclusion criteria  
“aspartate aminotransferase and/or alanine aminotransferase > 5 times upper limit of normal” 
 
This patient population has transiently high ALT and AST levels due to heavy alcohol use. This criterion has 
caused delay in treatment in several cases to date, due to having to wait and repeat baseline labs. Thus, the 
threshold of 3x ULN is an unnecessary barrier to randomization. 
 
Added procedure:  
• 
If baseline ALT or AST is between 3x to 5x ULN 
o 
Recheck ALT and AST at Week 4 visit:  
▪ 
If ALT or AST >4x ULN, PI may consider discontinuing the study medication if 
clinically indicated.   
o 
Recheck ALT and AST at Week 8 visit:  
▪ 
If ALT or AST >3x ULN, PI may consider discontinuing the study medication if 
clinically indicated.   
• 
The PI may consult with the medical monitor as needed. 
 
5.3 and 7.3.1 
Changed compensation per visit based on the optional psychophysiologic assessments and telehealth visits.  
 
 
 


 
 
Table of Contents 
Table of Contents ................................................................................................................................................... iv 
LIST OF ABBREVIATIONS ....................................................................................................................................... 1 
Statement of Compliance: ......................................................................................................................................... 4 
PROTOCOL SUMMARY ........................................................................................................................................... 4 
SCHEMATIC OF STUDY DESIGN .......................................................................................................................... 6 
1 
KEY ROLES .................................................................................................................................................... 6 
2  
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE ..................................................... 8 
2.1 
Background........................................................................................................................................... 8 
2.2 
Scientific Rationale .............................................................................................................................. 8 
2.3 
Potential Risks and Benefits ............................................................................................................ 10 
2.3.1 
Potential Risks ................................................................................................................ 10 
2.3.2 
Potential Benefits ........................................................................................................... 13 
3 
OBJECTIVES AND SPECIFIC AIMS ........................................................................................................ 13 
4 
STUDY DESIGN AND ENDPOINTS ......................................................................................................... 14 
4.1 
Description of the Study Design ...................................................................................................... 14 
4.2 
Endpoints ............................................................................................................................................ 15 
4.2.1 
Primary Endpoint ............................................................................................................ 15 
4.2.2 
Secondary Endpoints .................................................................................................... 15 
4.2.3 
Exploratory Endpoints ................................................................................................... 16 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................................... 16 
5.1 
Participant Inclusion Criteria ............................................................................................................ 16 
5.2 
Participant Exclusion Criteria ........................................................................................................... 17 
5.3 
Strategies for Recruitment and Retention ...................................................................................... 18 
5.4 
Participant Withdrawal or termination ............................................................................................. 19 
5.4.1 
Reasons for Withdrawal or Termination ..................................................................... 19 
5.4.2 
Handling of Participant Withdrawals or termination .................................................. 20 
5.5 
Premature Termination or Suspension of Study ........................................................................... 20 
6 
STUDY AGENTS .......................................................................................................................................... 21 
6.1 
Study Agent(s) and Control Description ......................................................................................... 21 
6.1.1 
Acquisition ....................................................................................................................... 21 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 21 
6.1.3 
Product Storage and Stability ....................................................................................... 22 
6.1.4 
Preparation ...................................................................................................................... 22 
6.1.5 
Dosing and Administration ............................................................................................ 22 
6.1.6 
Route of Administration ................................................................................................. 23 
6.1.7 
Dose 
23 
6.1.8 
Dose Adjustments/Modifications/Delays .................................................................... 23 
6.1.9 
Duration of Therapy ....................................................................................................... 23 
6.1.10 
Tracking of Dose ............................................................................................................ 23 
6.1.11 
Device Specific Considerations ................................................................................... 24 
6.2 
Study agent Accountability Procedures .......................................................................................... 24 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................................................. 24 
7.1 
Study Procedures/Evaluations ......................................................................................................... 24 
7.1.1 
Study specific procedures ............................................................................................. 24 


 
7.1.2 
Standard of care study procedures ............................................................................. 27 
7.1.3 
Medical management .................................................................................................... 27 
7.2 
Laboratory Procedures/Evaluations ................................................................................................ 28 
7.2.1 
Clinical Laboratory Evaluations .................................................................................... 28 
7.2.2 
Other Assays or Procedures ........................................................................................ 29 
7.2.3 
Specimen Preparation, Handling, and Storage ......................................................... 29 
7.2.4 
Specimen Shipment ....................................................................................................... 30 
7.3 
Study Schedule .................................................................................................................................. 31 
7.3.1 
Schedule of Assessments ............................................................................................ 31 
7.3.2 
Screening ........................................................................................................................ 32 
7.3.3 
Baseline and randomization visits ............................................................................... 33 
7.3.4 
Follow-up VISITS ........................................................................................................... 34 
7.3.5 
Final Study VisitS ........................................................................................................... 34 
7.3.6 
Early Termination Visit .................................................................................................. 34 
7.3.7 COVID-19 Safety Precautions .............................................................................................................. 34 
7.4 
Justification for Sensitive Procedures ............................................................................................. 35 
7.5 
Prohibited Medications, Treatments, and Procedures ................................................................. 36 
7.6 
Allowable Concomittant Medications and Treatments ................................................................. 38 
7.7 
Allowable Rescue Medications ........................................................................................................ 39 
7.8 
Participant Access to Study Agent At Study EXIT ........................................................................ 39 
8 
ASSESSMENTS OF SAFETY AND ADVERSE EVENTS ..................................................................... 40 
8.1 
Specification of Safety Parameters ................................................................................................. 40 
8.1.1 
Definition of Adverse Events (AE) ............................................................................... 40 
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 40 
8.1.3 
Definition of Unanticipated Problems (UP) ................................................................. 41 
8.2 
Classification of an Adverse Event ................................................................................................. 41 
8.2.1 
Severity of Event ............................................................................................................ 41 
8.2.2 
Relationship to Study Agent ......................................................................................... 44 
8.2.3 
Expected And ANticipated Adverse Events ............................................................... 44 
8.3 
Adverse Event Assessment and Follow-Up................................................................................... 44 
8.4 
Reporting Procedures ....................................................................................................................... 45 
8.4.1 
Adverse Event Reporting .............................................................................................. 45 
8.4.2 
Serious Adverse Event Reporting ............................................................................... 45 
8.4.3 
Unanticipated Problem Reporting ................................................................................ 46 
8.4.4 
Reporting of Pregnancy ................................................................................................ 47 
8.5 
Study Halting Rules ........................................................................................................................... 47 
8.6 
Safety Oversight ................................................................................................................................ 48 
8.7 
Risks MINIMIZATION ........................................................................................................................ 48 
9 
CLINICAL MONITORING ............................................................................................................................ 51 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 51 
10.1 
Statistical and Analytical Plans ........................................................................................................ 51 
10.2 
Statistical Hypotheses ....................................................................................................................... 51 
10.3 
Analysis Datasets .............................................................................................................................. 52 
10.4 
Description of Statistical Methods ................................................................................................... 52 
10.4.1 
General Approach .......................................................................................................... 52 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 53 


 
10.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 53 
10.4.4 
Safety Analyses .............................................................................................................. 54 
10.4.5 
Adherence and Retention Analyses ............................................................................ 54 
10.4.6 Baseline Descriptive Statistics ............................................................................................................ 54 
10.4.7 
Planned Safety and Interim Analyses ......................................................................... 54 
10.4.9 
 Multiple Comparison/Multiplicity ................................................................................. 55 
10.4.10 Tabulation of Individual Response Data ......................................................................................... 55 
10.4.11 Exploratory Analyses ......................................................................................................................... 55 
10.5 
Sample Size ....................................................................................................................................... 55 
10.6 
Measures to Minimize Bias .............................................................................................................. 58 
10.6.1 Enrollment/ Randomization/ Masking Procedures ........................................................................... 58 
10.6.2 
 Evaluation of Success of Masking .............................................................................. 58 
10.6.3 
 Breaking the Study MASK/Participant Code ............................................................. 58 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 59 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 59 
13 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS........................................................................... 59 
13.1 
Ethical Standard ................................................................................................................................. 60 
13.2 
Institutional Review Board ................................................................................................................ 60 
13.3 
Informed Consent Process ............................................................................................................... 60 
13.4 
Participant and data Confidentiality ................................................................................................ 61 
13.4.1 
Research Use of Stored Human SAMPLES, SPECIMENS or Data ...................... 62 
13.5 
Future Use of Stored Specimens .................................................................................................... 62 
14 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 62 
14.1 
Data Collection and Management Responsibilities ...................................................................... 62 
14.2 
Study Records Retention .................................................................................................................. 63 
14.3 
Protocol Deviations............................................................................................................................ 63 
14.4 
Publication and Data Sharing Policy ............................................................................................... 63 
15 
AMENDMENTS ............................................................................................................................................ 64 
16 
CONFLICT OF INTEREST POLICY .......................................................................................................... 64 
17 
LITERATURE REFERENCES.................................................................................................................... 65 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 1  
 
LIST OF ABBREVIATIONS 
 
ADS 
Alcohol Dependence Scale 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AOD 
Accounting of Disclosure  
APN 
Advanced Practice Nurse 
ASP 
Acoustic Startle Pulse 
AST 
Aspartate Aminotransferase 
AUD 
Alcohol Use Disorder 
BrAC 
Breathalyzed alcohol concentration 
BIS 
Barratt Impulsivity Scale 
BMP 
Basic metabolic panel 
BVAMC 
Birmingham VA Medical Center 
BUN 
Blood urea nitrogen 
BUP 
Buprenorphine 
CAPS-5 
Clinician Administered PTSD Scale for DSM-5 
CBC 
Complete Blood Count 
CDMRP 
Congressionally Directed Medical Research Program   
CFR 
Code of Federal Regulations 
CGI-S/CGI-I 
Clinical Global Impression-Severity & Clinical Global Impression-Improvement 
CIWA-Ar 
Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CoC 
Certificate of Confidentially 
Co-I 
Co-Investigator 
CO2 
Carbon dioxide 
COWS 
Clinical Opiate Withdrawal Scale 
CPRS 
Computerized Patient Record System 
CREEF 
Connecticut Research & Education Foundation  
CRC 
Clinical Research Coordinator  
CS 
Conditioned Stimulus  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DAQ 
Desire of Alcohol Questionnaire 
DCC 
Data Coordinating Center 
D/C 
Discontinued 
dL 
Deciliter 
DoD 
Department of Defense 
DSM-5 
Diagnostic and Statistical Manual-5th Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EMG 
Electromyography 
FDA 
Food and Drug Administration 
FPS 
Fear-Potentiated Startle 
FU 
Follow-Up 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 2  
 
FY 
Fiscal Year 
g 
Grams 
GABA 
Gamma-Aminobutyric Acid 
GCP 
Good Clinical Practice 
GGT 
gamma-GTP  
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GOR 
Grants Officer Representative 
GSC 
Government Steering Committee 
GSR 
Galvanic skin response 
H&P 
History and Physical  
HCT 
Hematocrit 
HGB 
Hemoglobin 
HIPPA 
Health Insurance Portability and Accountability Act of 1996 
HR 
Heart rate 
hr 
Hour 
Hz 
Hertz 
IATA 
International Air Transport Association (IATA) 
ICH 
International Council for Harmonization  
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IOM 
Institute of Medicine 
IRB 
Institutional Review Board 
KOR 
Kappa opioid receptor 
kg 
Kilograms 
LFTs 
Liver function tests 
LEC-5 
Life Events Checklist for DSM-5 
LOC 
Loss of Consciousness 
LSI 
Local Site Investigator 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MD 
Doctor of Medicine 
mEq 
Milliequivalent 
mg 
Milligrams 
MINI-5 
Mini-International Neuropsychiatric Interview for DSM-5 
ml 
Milliliters 
MM 
Medical management 
MMRM 
Mixed-Effect Model of Repeated Measure 
MOP 
Manual of Procedures 
msec 
Millisecond 
NA 
Noise alone 
NDA 
New Drug Application 
N/A 
Not Applicable 
NIAAA 
National Institute on Alcohol Abuse and Alcoholism 
NIH 
National Institute of Health 
NIMH 
National Institute of Mental Health 
NTX 
Naltrexone 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 3  
 
OCDS 
Obsessive Compulsive Drinking Scale 
OSU-TBI 
Ohio State University Traumatic Brain Injury Identification Method (Short Form) 
PASA 
Pharmacotherapies for Alcohol and Substance Abuse Consortium 
PCL-5 
PTSD Checklist for DSM-5 
PEth 
Phosphatidyl ethanol 
PharmD 
Pharmacist with a Doctorate Degree 
PHQ-9 
Patient Health Questionnaire 
PI 
Principal Investigator 
PLC 
Placebo 
PO4 
Phosphate 
PSI 
Pounds per square inch 
PTSD 
Post-Traumatic Stress Disorder 
RCS 
Records Control Schedule 
RBC 
Red blood cell count 
RCT 
Randomized Controlled Trial  
RN 
Registered Nurse 
RSA 
Respiratory sinus arrhythmia 
SAE 
Serious adverse event 
SCL 
Skin conductance level 
SCR 
Skin conductance response 
SIP 
Short Inventory of Problems 
SL 
 
Sublingual 
SNRI 
Serotonin and norepinephrine reuptake inhibitors 
SSRI 
Selective serotonin reuptake inhibitors 
T 
Telephone visit 
TLFB 
Timeline Follow Back 
TRD 
Treatment Resistant Depression 
TREAC 
Tuscaloosa Research & Education Advancement Corporation 
TSH 
Thyroid Stimulating Hormone 
TVAMC 
Tuscaloosa VA Medical Center 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
USPS 
United States Postal Service 
VA 
Veteran’s Administration 
VACT 
VA Connecticut Healthcare System 
VR 
Virtual reality 
VR-12 
Veterans RAND 12-item Health Survey 
WBC 
White blood cell count 
WHO 
World Health Organization 
XR 
Extended release 
XR-NTX 
Extended-release injectable naltrexone 
 
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 4  
 
STATEMENT OF COMPLIANCE:  
All key personnel, defined as all individuals responsible for the design and conduct of this 
trial, will complete Human Subjects Protection Training. The trial will be carried out in 
accordance with Good Clinical Practice (GCP) as required by the following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21CFR Part 11, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312)  
• 
ICH E2, E3, E6, E8 and E9 
 
PROTOCOL SUMMARY 
 
Title: 
 
Kappa Opioid Receptor Antagonism for the Treatment of Alcohol 
Use Disorder and Comorbid PTSD  
 
Objectives: 
 
Evaluate the efficacy and physiological effects of sublingual 
buprenorphine (SL-BUP; Subutex) combined with extended-release 
injectable naltrexone (XR-NTX; Vivitrol) in the treatment of comorbid 
alcohol use disorder (AUD) and post-traumatic stress disorder 
(PTSD) 
 
Endpoint 
Primary endpoint is improved AUD+PTSD outcomes at 8 weeks, in 
patients with comorbid AUD and PTSD  
 
Population: 
Treatment-seeking veterans, non-veterans, and service members 
with comorbid AUD and PTSD screened, enrolled, and randomized 
to the two treatment groups. With respect to sample size, the goal is 
to obtain at least 90 participants randomized to either of the two 
retained arms (XR-NTX/2mgBUP arm or PLACEBO arm).  
Recruitment will occur over a 32-month enrollment period. If this goal 
is met with time left in the enrollment period, sites will be allowed to 
randomize additional participants but will not exceed the original 
planned sample size of 135 randomized participants. 
 
Phase: 
Phase II Randomized Controlled Trial (RCT) 
Number of Sites 
enrolling participants: 
2 sites: 
1. Tuscaloosa: Tuscaloosa Research & Education 
Advancement Corporation (TREAC)/Tuscaloosa VA Medical 
Center (TVAMC)  
a. Recruitment area to include catchment area for 
Tuscaloosa, Birmingham, and Central Alabama VA 
Healthcare System (CAVHS) 
2. West Haven: Connecticut Research & Education Foundation 
(CREEF) / VA Connecticut Healthcare System (VACT) 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 5  
 
Description of Study 
Agent: 
Sublingual buprenorphine, which acts as an antagonist at kappa and 
partial agonist of the mu receptors, combined with extended-release 
injectable naltrexone, which blocks the mu receptor, yields a 
pharmacologically net effect of kappa opioid receptor (KOR) 
antagonism. Concurrent use of naltrexone diminishes the potential of 
buprenorphine misuse. 
 
Study Duration: 
37-month study period that includes ~32-month enrollment period 
Participant Duration: 
14 weeks from the time of randomization 
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 6  
 
SCHEMATIC OF STUDY DESIGN 
 
*Psychophysiologic assessments are optional to not be a barrier to enrollment or randomization. 
1 
KEY ROLES 
 
• 
Lori L. Davis, MD (Co-Principal Investigator); Tuscaloosa Research & Education 
Advancement Corporation (TREAC)/Tuscaloosa VA Medical Center (TVAMC)  
Dr. Davis is a Clinical Professor of Psychiatry at the University of Alabama School of Medicine 
and the Associate Chief of Staff for Research at the TVAMC. As a PTSD clinical researcher and 
Study Chair of the VA Cooperative Study Program #589, she is well-suited for the role of Co-
Principal Investigator for this multisite randomized controlled trial. She has 24 years of VA 
clinical research experience under continuous peer-reviewed funding, including pivotal work in 
psychopharmacologic and vocational rehabilitation treatments Veterans with posttraumatic 
stress disorder (PTSD). Dr. Davis is currently collaborating with Dr. Kathleen Brady as the local 
site investigator for a study on mindfulness-based relapse prevention in Veterans with 
addictions. Her work on the NIMH-funded STAR*D study focused on secondary analysis of the 
comorbidity of depression and substance use disorders, predictors of treatment response, and 
outcomes. Dr. Davis has led several multisite placebo-controlled drug studies for the treatment 
of PTSD and is highly regarded by the field for her leadership in PTSD clinical trials. For this 
reason, she was a member of the 2017 VA-DoD Clinical Practice Guidelines for the Treatment 
of PTSD workgroup.   
 
• 
Ismene Petrakis, MD (Co-Principal Investigator); VA Connecticut Research & 
Education Foundation (VACREEF) / VA Connecticut Healthcare System (VACT) 
N= 180  
N= ~90 Randomized  
SL-buprenorphine 2mg 
XR-naltrexone 380mg  
n= 45 
Baseline      1 
    2         4         
6 
8 
10     
12  
14 (Weeks) 
SL-placebo 
XR-placebo  
n= 45 
Consented  
and 
Screened 
Study Design: RCT of KOR Antagonist in the treatment of Comorbid AUD and PTSD 
Baseline (2-day) 
Psychophysiology*  
Week 2 (1-day) 
Psychophysiology*  
Week 8 (2-day) 
Psychophysiology*  
Week 12 
Med D/C   
Week 14 
COWS 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 7  
 
Dr. Petrakis is a Professor of Psychiatry at Yale school of Medicine, and the Chief of Psychiatry 
at VACT Healthcare System. She serves as co-PI and is instrumental in the design of the 
methods, implementation, clinical management, integration and interpretation of the findings 
based on her past research and clinical experience. Over the past 20 years, her research focus 
has been on understanding and developing treatments for alcohol dependence particularly in 
those with psychiatric comorbidity, and in understanding the underlying neurobiology of alcohol 
use disorders. This work informed the randomized clinical trials that she has conducted in 
patients with alcohol dependence and comorbid mental illness. This work includes the first study 
to evaluate naltrexone in individuals with schizophrenia and studies evaluating other 
medications approved to treat alcohol dependence by the Food and Drug Administration (FDA) 
in patients with psychiatric comorbidity. More recently, Dr. Petrakis has also explored different 
pharmacologic options for veterans with alcohol dependence with comorbid PTSD. This 
includes the largest study to date of prazosin in Veterans with alcohol dependence and 
comorbid PTSD.  
• 
Seth Norrholm, PhD (Co-investigator/Subject Matter Expert, Wayne State 
University); fear-potentiated startle testing   
Dr. Norrholm is a translational neuroscientist who studies trauma-, stressor-, and anxiety-related 
disorders in combat and civilian populations. The primary objective of his work is to develop 
“bench-to-bedside” clinical research methods to inform therapeutic interventions for PTSD and 
the disorders with which it is co-morbid. The most effective treatments for PTSD involve 
exposure therapy, a clinical analog to laboratory fear extinction, and as such there is a 
compelling need to further study these processes. Dr. Norrholm has developed a conditioned 
fear extinction paradigm using fear-potentiated startle (FPS); a methodology that has the 
potential to be an effective outcome measure for PTSD treatment as well as an index of fear 
recovery. His work is and has been supported by funding from the VA Clinical Science R&D, 
NATO, the Brain and Behavior Foundation (formerly NARSAD), the Congressionally Directed 
Medical Research Program through the Department of Defense (CDMRP/DoD), and the Emory 
University Research Committee. Dr. Norrholm and his collaborators have recently established a 
Human Psychophysiology of Emotion Laboratory that brings together cutting-edge 
psychophysiological techniques to study the neurobiology of fear, anxiety, and depression. 
These collaborations are focused on the interaction between genetic and environmental risk 
factors that mediate vulnerability to developing PTSD, PTSD symptom severity, and treatment 
outcome, with a focus on the identification of intermediate phenotypes.  
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 8  
 
2  
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE  
 
2.1 
BACKGROUND  
Alcohol use disorder (AUD) affects 18 million Americans and is highly prevalent in U.S. service 
members and among military Veterans.  AUD has a large detrimental impact on society.1,2 One 
important comorbid condition for individuals with AUD is PTSD. PTSD has a past year and 
lifetime prevalence of 4.7% and 6.1%, respectively.3 The odds of having PTSD are 30% greater 
for those with a lifetime AUD than those with no lifetime AUD.4 Taken from the other direction, 
those with lifetime PTSD are at greater risk of having an AUD (20% increased risk) compared to 
those without PTSD.12 Comorbidity is associated with many detrimental outcomes including 
significant social instability, disability, and more severe symptoms, higher rates of relapse, 
suicidal behaviors, and medical complications.5, 6 Currently, there are only four FDA–approved 
medications (disulfiram, oral and long-acting injectable naltrexone, and acamprosate) to treat 
AUD and two FDA-approved medications (sertraline and paroxetine) to treat PTSD. Despite a 
growing body of research in this area,7 there is no medication with clear evidence of efficacy in 
AUD-PTSD comorbidity and there are no FDA-approved medications to treat these disorders 
when they co-occur.15 New treatment strategies are urgently needed. This study addresses the 
substantial deficit in pharmacologic treatments for comorbid AUD and PTSD.  
2.2 
SCIENTIFIC RATIONALE  
The use of medication that result in kappa opioid receptor (KOR) antagonism represents a novel 
potential treatment for Veterans and Service Members with comorbid AUD and PTSD. 
Endogenous opioid systems in the brain are involved in regulation of mood, stress modulation, 
and cravings.1 Kappa opioid receptors are densely localized in limbic and cortical areas 
comprising the brain reward system, which play a role in modulating stress and in promoting 
addictive behaviors.2,3 Endogenous dynorphins, called k-selective opioid peptides, are released 
during the stress response and contribute to the anxiogenic and dysphoric responses to the 
stressful experience.4 Further, the KOR dynorphin system impacts stress-induced drug and 
alcohol seeking behavior.8 In animal models of alcohol dependence, KORs are implicated in the 
excessive alcohol consumption, particularly during withdrawal. KOR antagonists block the 
actions of endogenous dynorphins and block the stress-induced reinstatement of extinguished 
cocaine- and ethanol-seeking behaviors in animals. Studies for animal models of cocaine 
dependence have shown promise for using a combination of buprenorphine and naltrexone, 
without producing opioid dependence.9  
KOR antagonists may be beneficial in the treatment of addictions,5 PTSD,6 and major 
depressive disorder.6-8 An example includes a short-acting potent KOR antagonist with 
selectivity over other opioid receptors (CERC-501) which has demonstrated antidepressant-like 
effects in animal models of depression and been shown to reduce ethanol self-administration in 
alcohol-preferring rats.10 CERC-501 is currently unavailable for additional studies due to its 
being purchased by another pharmaceutical company that is pursuing its use in major 
depression as the first approved indication.  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 9  
 
Another medication that acts as a net KOR antagonist is ALKS-5461, which is a combination 
drug formulation of buprenorphine and samidorphan.  Buprenorphine acts as an antagonist at 
kappa and partial agonist of the mu receptors and samidorphan is a mu opioid receptor 
antagonist, resulting in a pharmacologically net effect of kappa-opioid receptor antagonism (i.e., 
the same mechanism of action as the combination approach proposed in this application). The 
combination drug binds with high affinity to opioid receptors with low net intrinsic signaling 
activity.  ALKS-5461 is intended to support opioid tone in the brain regions with impaired 
endogenous activity and dampen opioid tone in upregulated regions. In a recent study, 
adjunctive ALKS-5461 significantly reduced depression scores compared to placebo in patients 
with treatment resistant depression.11  Following a positive phase II trial, ALKS-5461 was 
granted Fast Track Designation by the FDA for treatment resistant depression (TRD) in October 
2013.12 In 2014, two of three core phase II trials showed that ALKS-5461 at daily doses of 
0.5mg/0.5mg and 2mg/2mg were safe and well-tolerated but, disappointingly, the trials failed to 
meet their primary efficacy endpoints, due in part to an unusually strong placebo effect. 
However, some endpoints trended towards efficacy for 2mg/2mg/d and a statistically significant 
signal on the depression endpoint. In a sequential parallel comparison design study (stage 1 
double-mask placebo-controlled parallel comparison with higher proportion of patients 
randomized to placebo than to active drug and those patients who meet placebo nonresponse 
are re-randomized in stage 2 to drug or placebo), the 2mg/2mg and 8mg/8mg doses of ALKS 
5461 were tested in patients with TRD.20 The 2/2 dose was significantly better that placebo 
across the three depression outcomes.  Although there was significant improvement in the 
8mg/8mg dosage, it did not achieve statistical significance. The medication was well tolerated 
and there was no evidence of opioid withdrawal on treatment discontinuation. Three additional 
Phase 3 studies showed efficacy ALKS-5461 2mg/2mg in participants with TRD maintained on 
their selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake 
inhibitors (SNRI) or bupropion.  
Alkermes is currently seeking approval of ALKS-5461 as adjunctive treatment of TRD, 
which makes the timing for assessing this compound in AUD+PTSD studies potentially 
problematic. While initially interested in partnering with us, Alkermes leadership decided 
to forego testing ALKS 5461 in AUD+PTSD at this time due to priorities related in their 
current FDA new drug application (NDA). Alkermes is willing to continue to partner with 
us by providing the long-acting injectable naltrexone and placebo for this proposal. 
The combination of buprenorphine, which acts as an antagonist at kappa and partial agonist of 
the mu receptors, and naltrexone, which blocks the mu receptor, yields a pharmacological net 
effect of a KOR antagonist, and thus, is an excellent alternative study medication to ALKS-5461 
and CERC-501. Several clinical trials have been conducted safely and effectively using 
buprenorphine combined with naltrexone, including one in patients with comorbid cocaine and 
opioid use disorders.13 Buprenorphine alone has been evaluated for antidepressant effects in 41 
studies, most of which were conducted in comorbid opioid dependence, but several were not.14 
There is clinical evidence that buprenorphine is effective in attenuating some PTSD symptoms 
among those with opioid use disorder.15 The use of buprenorphine in a non-opioid dependent 
population has ethical implications given its risk of addiction, which has led to the idea to 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 10  
 
combine it with naltrexone in order mitigate the potential for misuse. Further, preclinical studies 
suggest KOR antagonism is important for drinking behavior, stress induced reinstatement of 
drug and alcohol consumption.   For these reasons, there is substantial interest in the 
development of KOR antagonists for indications such as AUD and PTSD and the combination of 
buprenorphine and naltrexone allows for a proof-of-concept study until a formulated KOR-
antagonist becomes commercially available. 
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 POTENTIAL RISKS  
Naltrexone for extended-release injectable suspension (XR-NTX; Vivitrol) is FDA-indicated for 
the treatment of alcohol dependence, so participants in this study may have direct benefit from 
this treatment. XR-NTX is not a controlled substance.  
Sublingual buprenorphine (SL-BUP) is FDA-indicated for the treatment of opioid dependence. 
SL-BUP is a Schedule III narcotic under the Controlled Substances Act. The use of SL-BUP in a 
non-opioid dependent population has a risk of misuse or abuse. Buprenorphine is a partial 
agonist at the mu-opioid receptor and chronic administration produces physical dependence of 
the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or 
rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be 
delayed in onset. However, to mitigate the potential for misuse, dependency, and withdrawal, 
buprenorphine can be combined with XR-NTX, a medication that blocks the mu receptor 
involved in psychogenic properties of buprenorphine.  
XR-NTX can antagonize the effects of opioids via competitive inhibition of opioid receptors, 
which raises the concern that the combination of SL-BUP and XR-NTX will make SL-BUP less 
effective. This would be a risk for individuals who are using opiates or SL-BUP on a regular 
basis prior to starting XR-NTX, (i.e., the addition of XR-NTX may precipitate opioid withdrawal 
symptoms). For this reason, this study excludes patients who have recent opioid use or opioid 
use disorders, and opiates are not allowed to be concurrently taken during the study. XR-NTX is 
contraindicated in patients receiving opioid analgesics and in patients with current physiologic 
opioid dependence, acute opiate withdrawal, acute hepatitis or liver failure, and previous 
hypersensitivity reaction to XR-NTX.  Patients with these contraindications are not eligible to 
participant in this study.  
The CURB study16 evaluated low dose and high dose SL-BUP added to XR-NTX in participants 
recovering from current cocaine use disorder and past year (not recent) opioid use or 
dependence and whom did not necessarily have a diagnosis of PTSD.  In the publication of its 
results, Ling et al (2016) provide an extensive table of the reported and related adverse events, 
with a breakdown of causal relationship and type of adverse events comparing placebo, low 
dose and high dose SL-BUP added to XR-NTX. The study found no significant differences in 
numbers of adverse events or serious adverse events by treatment arm and there were no 
significant adverse events related to induction onto XR-NTX. None of the serious adverse 
events were deemed by the medical monitor as study-related16.  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 11  
 
In the current study, XR-NTX is administered as a long-acting injectable, the protective 
pharmacologic properties are present for the full duration of treatment with SL-BUP, thereby 
eliminating the risk that the participant will become psychologically or physically addicted to SL-
BUP. In addition, we are using low dose SL-BUP (Note: the dose is lower than 16mg dose used 
in CURB study).  At the end of the study XR-NTX is gradually eliminated from the body.  Thus, a 
pharmacologic taper is not needed for either XR-NTX or SL-BUP.  Participants should not 
experience withdrawal symptoms, but to be conservative, they are followed by the investigators 
for an additional two weeks to monitor the participants for any adverse events related to 
discontinuation. To be cautious and thorough, the investigators assess for signs and symptoms 
of opioid withdrawal at the end of the study. 
The study uses low dose of buprenorphine (2mg daily) which is usually the target of a taper 
when stopping treatment in a patient on medication-assisted therapy for opioid use disorders.  
Withdrawal is highly unlikely with these low doses after 12 weeks of treatment, especially when 
used in combination with naltrexone. The potential for withdrawal is mitigated by naltrexone.  
Withdrawal from low dose buprenorphine in patients with non-opioid use disorders is not 
described in the literature. Case reports of discontinuation of higher dose (12mg to 20 mg daily) 
buprenorphine indicate that mild opiate withdrawal symptoms last 1 to 2 days and did not 
require opioid medication or other medication. Psychosocial intervention is recommended, and 
the lengthy withdrawal regimens might prolong withdrawal symptoms unnecessarily.   
The investigators have designed the study to include two weeks (from Week 12 to Week 14) to 
monitor the patient for drug discontinuation or withdrawal symptoms. The investigators will treat 
emergent psychological symptoms with psychosocial support and physical symptoms with the 
appropriate treatments, such as metoclopramide for nausea, NSAIDs for pain, clonidine for 
opioid-like withdrawal symptoms, and loperamide for diarrhea. Three to five days after Week 12 
discontinuation of medication, the research nurse will call participant to check on emergent 
adverse symptoms 
A caution that is included in the informed consent stating that in a situation when analgesia may 
be required in a patient who has received full blocking doses of XR-NTX, consideration should 
be given to regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid 
analgesics, or general anesthesia. If opioid analgesia is required, the amount of opioid needed 
may be greater than usual, and the resulting respiratory depression may be deeper and more 
prolonged. In this case, a rapidly acting opioid analgesic that minimizes the duration of 
respiratory depression is preferred. XR-NTX can also diminish the benefit from opioid-containing 
cough, cold, and antidiarrheal preparations, which is listed as a warning in the informed 
consent. These warning are standard when treating patients with XR-NTX. 
Side effects of XR-NTX that led to more discontinuation of treatment compared to placebo 
include the following: pain, tenderness, induration or pruritus at the site of the injection (3%), 
nausea (2%), headache (1%), and suicide-related events (0.3%). Other known non-serious side 
effects that differ from placebo include nausea (29% vs 11%), vomiting (12% vs 6%), diarrhea 
(13% vs 10%), abdominal pain (11% vs 8%), injection site reactions (65% vs 50%), 
arthralgia/arthritis (9% vs 5%), muscle cramps (5% vs 1%), rash (6% vs 4%), headache (21% vs 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 12  
 
18%) dizziness (13% vs 4%), somnolence/sedation (5% vs 1%), and appetite decrease (11% vs 
3%). XR-NTX has the capacity to cause hepatocellular injury when given in excessive doses 
(the margin of separation between the apparently safe dose of naltrexone and the dose causing 
hepatic injury appears to be five-fold. XR-NTX does not appear to be a hepatoxin at the 
recommended doses used in this study. 
SL-BUP is contraindicated in patients who have had prior hypersensitivity to any formulation of 
buprenorphine. Significant respiratory depression and death have occurred in association with 
buprenorphine, particularly when taken by the intravenous (IV) route in combination with 
benzodiazepines or other CNS depressants (including alcohol). Buprenorphine, particularly 
when taken by the IV route, in combination with benzodiazepines or other CNS depressants 
(including alcohol), has been associated with significant respiratory depression and death. 
Many, but not all post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. 
Deaths have also been reported in association with concomitant administration of 
buprenorphine with other depressants such as alcohol or other CNS depressant drugs. For 
these reasons, participants are not allowed to take concomitant benzodiazepines or CNS 
depressant drugs (i.e., neuroleptics or sedating anticonvulsants) during the study. In the case of 
overdose, the primary management should be the re-establishment of adequate ventilation with 
mechanical assistance of respiration, if required. Naloxone may be of value for the management 
of buprenorphine overdose. Higher than normal doses and repeated administration may be 
necessary. Patients should be warned of the potential danger of self-administration of 
benzodiazepines or other depressants while under treatment with SL-BUP. SL-BUP should be 
used with caution in patients with compromised respiratory function (e.g., chronic obstructive 
pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or 
pre-existing respiratory depression). Cases of cytolytic hepatitis and hepatitis with jaundice have 
been observed in individuals receiving buprenorphine in clinical trials and through post-
marketing adverse event reports. For this reason, patients with severe liver disease or liver 
failure are excluded, and liver enzymes are measured at baseline and endpoint. SL-BUP may 
impair the mental or physical abilities required for the performance of potentially dangerous 
tasks such as driving a car or operating machinery, especially during treatment induction and 
dose adjustment. Patients should be cautioned about driving or operating hazardous machinery 
until they are reasonably certain that buprenorphine therapy does not adversely affect his or her 
ability to engage in such activities. SL-BUP is metabolized to norbuprenorphine primarily by 
cytochrome CYP3A4; therefore, potential interactions may occur when SL-BUP sublingual tablet 
is given concurrently with agents that affect CYP3A4 activity. The concomitant use of SL-BUP 
sublingual tablet with CYP3A4 inhibitors (e.g., azole antifungals such as ketoconazole, 
macrolide antibiotics such as erythromycin, and HIV protease inhibitors) should be monitored 
and may require dose-reduction of one or both agents. 
Adverse events most commonly observed during clinical trials and post-marketing experience 
for SL-BUP compared to placebo are headache (29% vs 22%), nausea (14% vs 11%), vomiting, 
hyperhidrosis, constipation (8% vs 3%), signs and symptoms of withdrawal (18% vs 37%, i.e., 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 13  
 
greater in placebo group), insomnia (21% vs 16%), and pain (18% vs 19%). The dose used in 
this study is lower and may yield fewer side effects. 
Although the virtual reality exposure may evoke physiologic reactivity (increased heart rate and 
skin conductance; alcohol craving), it is not at the level of overt PTSD symptom provocation.  
The psychophysiological studies* are well tolerated. This protocol has been utilized in previously 
published studies in both active service member and veteran populations. The virtual reality 
environments have been reported by military personnel, past and present, as capable of 
evoking trauma-related memories and physiological responses but not to be re-traumatizing. 
*Psychophysiologic assessments are optional so as to not be a barrier to enrollment or 
randomization.  
2.3.2 POTENTIAL BENEFITS  
Extended-release naltrexone is FDA approved for the treatment of alcohol dependence, as well 
as for the prevention of relapse to opioid dependence, following opioid detoxification. Thus, 
naltrexone may directly benefit the participants in this study and help them to reduce or stop the 
use of alcohol.  As described in a report of outcomes from the Vivitrol’s Cost and Treatment 
Outcomes Registry, XR-NTX has been used effectively and safely.17 
As described in the section above, SL-BUP has antidepressant effects and may help attenuate 
the symptoms of PTSD.  
When added to XR-NTX, SL-BUP may further potentiate the anti-craving effects and reduce 
alcohol use and this combination may reduce symptoms of PTSD.  Reducing alcohol use may 
also be a factor in reduction of PTSD symptoms and conversely, reduced PTSD symptoms may 
lower the participants’ tendency to self-medicate with alcohol. 
Another benefit of the study is that knowledge to be gained can help guide treatment for patients 
with comorbid AUD and PTSD in the future.  
3 
OBJECTIVES AND SPECIFIC AIMS 
The objective of this study is to evaluate the efficacy and physiological effects of sublingual 
buprenorphine (SL-BUP; Subutex) combined with extended-release injectable naltrexone (XR-
NTX; Vivitrol) in the treatment of comorbid AUD and PTSD. 
Aim 1: To evaluate the efficacy of SL-BUP + XR-NTX in the treatment of comorbid moderate-to-
severe AUD and PTSD based on a response in both AUD and PTSD outcomes.  
Aim 2a: Examine the baseline association between fear extinction and PTSD symptom severity 
in participants with comorbid AUD and PTSD. 
Aim 2b: Examine the baseline association between Psychophysiological Reactivity to a 
Trauma-Relevant Stimuli and PTSD symptom severity. 
Aim 2c: Examine the baseline association between Psychophysiological Reactivity to Alcohol-
Cues Stimuli and measures of alcohol craving. 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 14  
 
Aim 3: Examine the association of baseline fear extinction*, stress reactivity*, and treatment 
outcomes. 
Aim 4: Examine whether the degree of change from baseline to 2-week psychophysiological 
measures are associated with AUD and PTSD outcomes at Week 8. An early indication of 
signal detection can be used in the future to enhance precision medicine treatment decisions. 
*Psychophysiologic assessments are optional so as to not be a barrier to enrollment or 
randomization. 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This randomized, double-mask, placebo-controlled, multi-site study evaluates the efficacy of SL-
BUP combined with XR-NTX in the treatment of comorbid AUD and PTSD. In addition to the 
primary clinical outcomes for AUD and PTSD, pre- and post-treatment psychophysiological 
correlates of fear and alcohol craving include 1) measures of the extinction of fear-potentiated 
startle and 2) measures of psychophysiological reactivity to trauma stimuli and alcohol cues. 
Recruitment is based on convenience sampling of treatment-seeking veterans, nonveterans, 
and active duty service members. Upon contact with a potential participant, the study team 
member describes the study and reviews initial eligibility criteria (prescreening under an 
approved HIPAA waiver).  Persons meeting initial criteria are given a consent form to read and 
discuss with research team members, family and/or providers. Persons who provide written 
informed consent are scheduled for an initial screening and baseline visit.  
Following screening and baseline visits, eligible patients are randomization to receive one of two 
treatments in a double-mask fashion for 12 weeks. 
• 
Treatment A (SL-BUP 2mg and XR-NTX 380mg) or  
• 
Treatment B (SL-PLC and XR-PLC).  
 
The treatment allocation ratio for the treatment vs. placebo (PLC) regimens is 1:1 and is stratified 
by site, presence of concomitant antidepressants, and gender using a random permuted block 
scheme with variable block size. 
The optional psychophysiological studies are conducted at baseline (2-day testing), Week 2 (1-
day testing), and Week 8 (2-day testing). The participants are assessed for outcomes on Weeks 
1, 2, 4, 6, 8, 10, and 12. Primary and secondary efficacy endpoints are at Week 8. At Week 8, 
participants remain on the assigned drug or placebo for an additional 4 weeks to allow for a 12-
week endpoint. Study medication is discontinued at Week 12 and participants return at Week 14 
for evaluation of withdrawal side effects.  
All Adverse Events occurring during the clinical trial are collected at each visit, documented, and 
reported by the PI according to the specific procedures detailed in Section 8.  
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 15  
 
4.2 
ENDPOINTS 
 
4.2.1 PRIMARY ENDPOINT 
Primary Hypothesis: Compared to the PLC group, a proportionally higher number of 
participants will respond to treatment with SL-BUP + XR-NTX, as defined as decrease > 8 
points on the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) and reduction >1-shift in 
World Health Organization (WHO) risk levels of alcohol use disorder, as assessed on the 
Timeline Follow-Back (TLFB)18 from baseline to Week 8. The primary efficacy endpoint is a 
reduction of both AUD and PTSD symptoms, such that lowering both will be coded success and 
any other outcome will be failure. All group comparisons will be made. 
As a complement to the primary hypothesis, we will also examine each of the components 
individually. Compared to PLC group, SL-BUP + XR-NTX will significantly reduce PTSD 
symptoms, as measured by the change in CAPS-5 over an 8-week treatment period. Compared 
to PLC group, SL-BUP + XR-NTX will be more effective in decreasing heavy alcohol use at 8 
weeks.  This outcome is the percent of heavy drinking days (defined as >4 standard 
drinks/sessions for men and >3 standard drinks/sessions for women) as assessed by the TLFB.  
4.2.2 SECONDARY ENDPOINTS 
Secondary outcomes examined both between group and over time include: 
• 
Examine association between baseline psychophysiological measures, severity of PTSD 
and AUD, and treatment outcomes.  
• 
Examine whether SL-BUP + XR-NTX improves psychophysiology measures at Week 8.  
• 
Examine whether the degree of change from baseline to 2-week psychophysiological 
measures* are associated with AUD and PTSD outcomes at Week 8. 
*Psychophysiologic assessments are optional so as to not be a barrier to enrollment or 
randomization. 
Aim 2a Hypotheses: PTSD symptom severity in participants with comorbid AUD and PTSD will 
be positively associated with an elevated level of fear (“fear load”) during the acquisition and 
extinction of fear.  Participants with comorbid AUD and PTSD will show increased spontaneous 
recovery of fear as compared to archival data from research participants with no diagnosis of 
AUD and PTSD. 
Aim 2b Hypotheses: Given recently published evidence showing individuals with PTSD 
characterized by severe, repeated trauma display a hyper-reactive, elevated physiological 
responses,19,20 we hypothesize greater PTSD symptoms will be associated with a hyper-reactive 
stress reactivity, evidenced by an increased skin conductance and trauma-potentiated startle 
difference scores (max response– baseline).  
Aim 2c Hypothesis: Greater AUD craving will be associated with hyper-reactive stress 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 16  
 
reactivity, evidenced by increased skin conductance and trauma-potentiated startle difference 
scores (max response– baseline).  
Aim 3 Hypotheses: Compared to PLC group, 2mg SL-BUP + XR-NTX will reduce 
psychophysiological responses at 8 weeks in patients with comorbid AUD and PTSD. Deficits in 
fear extinction at pre-treatment baseline will be associated with poorer treatment outcome. 
Increased physiological responding during trauma-relevant and alcohol cue stimulus at baseline 
will be associated with poorer treatment outcomes.   
Aim 4 Hypotheses:  Change from baseline to Week 2 in the psychophysiological reactivity* to 
trauma-related stimuli will predict the AUD and PTSD outcomes. 
4.2.3 EXPLORATORY ENDPOINTS 
Exploratory Endpoints: Examine all AUD and PTSD outcomes over time between the SL-BUP 
+ XR-NTX and PLC groups at Week 12. As suggested by the Government Steering Committee, 
some AUD and PTSD measures were added to the study to harmonize with the Simpson-Saxon 
study. Changes in these exploratory outcome measures from baseline to Week 8 will be 
compared against the SL-BUP+XR-NTX and PLC groups.  
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
To be enrolled in this study, participants must meet the following criteria. 
1. Male or female, 18 to 70 years of age, capable of reading and understanding English, 
and able to provide written informed consent (i.e., no surrogate). 
2. Current moderate to severe AUD as determined by MINI International Neuropsychiatric 
Interview for DSM-5 (MINI-5). 
3. At least two recent episodes of heavy drinking (>5 standard drinks/sessions for men and 
>4 standard drinks/sessions for women) over the past 30 days, and heavy drinking 
pattern defined as 14 drinks per week for women and 21 drinks per week for men for at 
least 2 of a 4-week interval within the 90 days prior to baseline (i.e., at least Moderate 
Risk level on WHO category). 
4. PTSD diagnosis defined by MINI-5 at screening. 
5. Clinician Administered PTSD Scale for DSM-5 (CAPS-5) total score ≥26 for the past 
week at baseline. 
6. Females of child-bearing potential must be using medically acceptable birth control (e.g., 
oral, implantable, injectable, or transdermal contraceptives; intrauterine device; double-
barrier method) AND not be pregnant OR have plans for pregnancy or breastfeeding 
during the study.  
7. Must have a CIWA-Ar score of < 8 prior to randomization. 
8. Willing and able to refrain from medications thought to influence alcohol consumption 
(other formulations of naltrexone, disulfiram, acamprosate, topiramate, ondansatron, and 
baclofen).  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 17  
 
9. Willing and able to refrain from psychotropic medications listed in the prohibited 
medication list (7.5) that includes opioids, stimulants, Alzheimer’s medications, most 
antipsychotics, benzodiazepines/other sedatives and most mood stabilizers.  
Notes:  
• 
Participants may continue stable dose of antidepressants, prazosin, and non-
benzodiazepine hypnotics and non-benzodiazepine anxiolytics to treat PTSD or 
insomnia.   
• 
Stable dose is defined as taken for ≥2 months prior to randomization and current dose 
has been stable for ≥3 weeks prior to randomization and held constant during 12 weeks 
of study medication.) 
 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
To be enrolled in this study, participants must not meet the following criteria. 
1. Current diagnosis of DSM-5 bipolar I, schizophrenia, schizoaffective, and/or major 
depressive disorder with psychotic features (defined by MINI-5 at screening). 
2. Increased risk of suicide that necessitates inpatient treatment or warrants therapy 
excluded by the protocol, and/or current suicidal plan, per investigator clinical 
judgement, based on interview and defined on the Columbia Suicidality Severity Rating 
Scale (C-SSRS). 
3. Treatment with trauma-focused therapy for PTSD (e.g., Cognitive Processing Therapy, 
Prolonged Exposure, or EMDR) within two weeks of baseline study visit.  Note: 
Supportive psychotherapy in process for PTSD at time of Screening may be continued. 
4. Current diagnosis of severe non-alcohol substance use disorder (except for caffeine and 
nicotine) during the preceding 1 month, based on participant screening interview.  
5. Use of opioids within 2 weeks of baseline or opioid use disorder in the previous 90 days. 
6. History of severe traumatic brain injury (TBI) per Ohio State University TBI Identification 
Method. Note: history of mild or moderate TBI is allowed. 
7. Any clinically significant, uncontrolled, or medical/surgical condition that would 
contraindicate use of SL-BUP + XR-NTX, or limit ability to complete study assessments, 
including seizure disorders (other than childhood febrile seizures), severe renal 
insufficiency, significant arrhythmia or heart block, heart failure, or myocardial infarction 
within the past 2 years, severe thrombocytopenia or hemophilia, severe hepatic failure, 
complete hearing loss, and/or need for surgery that might interfere with ability to 
participate.  
8. Clinically significant laboratory abnormalities, including a thyroid stimulating hormone 
(TSH) >1.5 times upper limit of normal, hyperthyroidism, cardiovascular findings QTcF 
≥500 msec on electrocardiogram (ECG) or blood pressure >190/110, and aspartate 
aminotransferase and/or alanine aminotransferase > 5 times upper limit of normal.   
9. History of allergic reaction, bronchospasm or hypersensitivity to a naltrexone or 
buprenorphine. 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 18  
 
10. Unable or unwilling to refrain from medications thought to influence alcohol consumption 
(see inclusion criteria above.)  
11. Unable or unwilling to refrain from psychotropic medications on the prohibited 
medication list; with the exception of stable doses of psychotropics listed on the allowed 
psychotropic medications list.   
12. Persons who are imprisoned, of minor age, diagnosed with dementia, diagnosed with a 
terminal illness, or otherwise require a surrogate to provide informed consent.  
Note: Allowance for elevated liver function enzymes, with close medical monitoring, upon 
enrollment into this study protocol due to the expected impact of heavy drinking in this study 
population causing transiently high liver function enzymes.  
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Multipronged Recruitment Strategy: The recruitment strategies include direct recruitment 
from the investigator’s clinics, social media and news advertisement, self-referral through word-
of-mouth interactions with others, and integrated outreach to mental health and primary care 
outpatient clinics, substance rehabilitation programs, community, and inpatient units. The 
investigators may use social media, advertisements, and commercial services to advertise the 
study and outreach to potential participants. Under a HIPAA waiver, IRB-approved letters of 
invitation can be mailed to prospective participants with a past diagnosis of AUD or PTSD who 
otherwise might meet eligibility criteria. Rate of enrollment at each site is monitored monthly to 
make sure sites remain on track, and if enrollment is less than 80% of target, for two or more 
consecutive months, an action plan is developed and implemented. Sites provide cumulative 
de-identified pre-screening data to the DCC on a monthly basis.  This data will allow for the 
DCC/PASA Consortium to check both site performance metrics as well as help identify any 
trends in eligibility criteria that could be causing difficulties in enrolling participants into the 
study.     
Retention Strategies: Adherence and attendance is vital to the success of both treatment and 
the study. Patient education on study procedures and treatment approaches in the study is the 
cornerstone. As a primary way to minimize drop-out from the study, the investigators and/or 
Clinical Research Coordinators (CRC) provide thorough pre-enrollment education for all 
prospective participants during the informed consent process and confirm the participant’s 
commitment to and feasibility for follow-up.  Screening and baseline visits are separate from day 
of randomization so that any ambivalence can manifest, and participants can back-out prior to 
randomization. The investigators and CRCs also provide ongoing support and education during 
the study to reinforce the participants’ commitment and resolve logistical barriers to keeping the 
appointments. Participant burden is kept to a minimum (i.e., small number of assessments and 
low frequency).  
To maximize participant retention, CRCs are trained to have a substantial focus, especially in 
the first several meetings with participants, on developing a strong alliance, educating them 
about the study, understanding the importance of adhering to treatment, what is expected of 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 19  
 
them as a study participant, and eliciting commitment. The investigators also provide ongoing 
reinforcement of the patients’ commitment to long-term follow-up and medication adherence.  
The study medication and visits are provided at no cost. The study medication providers 
emphasize the need to properly adhere to prescribed treatments or to call to revise the 
treatments if side effects occur or therapeutic effects are lost. 
The participant receives a modest payment for each attended visit to offset the inconvenience of 
the follow-up appointments and transportation costs. The site IRBs have approved similar 
payments in the past and have not viewed the amount as coercive. Service members cannot be 
paid while on active duty but may be reimbursed for travel costs. Participants are paid more on 
the days of the psychophysiological testing since these visits require more time. Participants 
exiting early are encouraged to undergo Week 12 assessments and are paid Week 12 amount. 
After consenting to participate, a urine drug screen and breathalyzer will be conducted at each 
visit.  If the drug screen is positive for opiates at screening or baseline visit and/or if the 
participant has a breathalyzer level > 0.02 at any visit, the appointment will be canceled and 
rescheduled, and the participant will not be paid for the canceled appointment.  The CRC may 
reschedule the appointment for a later date. If the urine drug screen is positive for opiates at 
follow-up visits, the investigator must assess the safety of continuing the participant on study 
medication, but the visit does not need to be canceled. 
 
The above payment schedule offers maximum for study participation of $425 for medication 
outcomes without psychophysiologic assessments and $525 with psychophysiologic 
assessments.  (Note: There is flexibility for sites to adjust their participation payment amounts, 
for instance West Haven has a minimum payment amount of $25) 
Also, sites can pay for transportation or provide a $25 gas/gift card to offset transportation costs 
if needed, at the discretion of investigator and TREAC Executive Director. 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Participants may discontinue study treatment or withdraw from participation in the study at any 
time without cause or reason. Participants may stop study medication but are encouraged to 
Schedule of Participation Payments 
 
Screening, Baseline, Week (#) or Telephone (T) Visit 
Screen 
Base-
line 
1 
2 
T 
4 
T 
6 
T 
8 
T 
10 T 12 
T 
14 
Outcome 
Visits  
25 
75 
25 
25 
 
75 
 
25 
 
75 
 
25 
 
50 
 
25 
Psychophy
siology 
testing 
 
50  
2d 
 
 
 
 
 
 
 
50 
2d 
 
 
 
 
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 20  
 
remain in the study for follow-up assessments. The investigator may discontinue study 
treatment for a participant or withdraw a participant from the study for one or more of the 
following reasons:  
• 
The participant’s expressed desire to end his/her participation in the study.  
o Note: The participant may choose to stop the study drug but continue in the study 
for data collection and is thus not withdrawn from the study. 
• 
A clinically significant adverse event (AE), laboratory abnormality, or other medical 
condition or situation that makes continued participation in the study to be not in the best 
interest of the participant  
• 
The participant demonstrates an inability to comply with the verbal and written study 
instructions and/or procedures, (i.e., loses the capacity to provide informed consent) 
• 
The participant exhibits unsafe behaviors (e.g., abusive, aggressive) or becomes 
suicidal, homicidal, or psychotic, (i.e., at significant risk of harming self or others). 
• 
The participant has an intolerable adverse reaction to a study medication. 
• 
The participant’s underlying condition is worsening and needs alternative treatment(s) 
• 
The study is canceled by the PASA Consortium, DoD, or investigators.   
• 
The study is closed by the Data Safety and Monitoring Board (DSMB), Institutional 
Review Board (IRB), or other oversight committee. 
• 
New information regarding the safety of a study medication emerges that changes the 
risk benefit profile for a sub-group of participants 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
If an early exit occurs, the reason(s) for early termination is documented and all Week 12 
procedures are conducted. A post-study phone call or visit is scheduled with the research 
team to ensure that the participant has made or scheduled the appropriate follow-up 
appointments and to address any clinical problems or AEs that may have occurred.  
Participants may stop study medication but are encouraged to remain in the study for follow-up 
assessments. In this case, the participant may attend assessments for data collection or 
consent to allow for continued follow-up through chart review. If a participant withdraws from the 
interventional portion of a study and does not consent to continued follow-up of associated 
clinical outcome information, then the investigators will not access the participant's medical 
record or make future contact with the participant. If a study participant withdraws consent for 
study participation, then the participant is excluded from all future study procedures and 
treatments. No additional study data is collected from the participant after consent has been 
withdrawn. 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be suspended or prematurely terminated if there is reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by 
the suspending or terminating party to the investigator, DoD Grants Officer Representative 
(GOR) for further distribution to the Government Steering Committee (GSC), PASA 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 21  
 
Consortium PI (or designee), DSMB, and regulatory authorities. If the study is prematurely 
terminated or suspended, the PI will promptly inform the IRB and will provide the reason(s) for 
the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to:  
❖ A pattern of AEs indicating that the selected dose of SL-BUP + XR-NTX is inappropriate 
or unsafe 
❖ Determination of unexpected, significant, or unacceptable risk to participants  
❖ New information emerges that suggests the risks are increased beyond an acceptable 
limit and outweigh benefits 
❖ Significant and recurring protocol violations that threaten the integrity of the study data 
❖ Data that are not sufficiently complete and/or evaluable  
❖ Continuing and ongoing serious noncompliance with human research protections and 
regulations that warrants study closure 
❖ Determination of futility. While there are no formal assessments of futility for efficacy, the 
study may be terminated if operationally futile, (e.g., there is an inability to enroll or retain 
study participants). The study may resume once concerns about safety, protocol 
compliance, data quality is addressed and satisfy the PASA Consortium, IRB and/or 
other regulatory agencies.   
❖ Generally, any study suspension that could occur will be based upon review of the study 
and recommendations made by the DSMB. Details of safety oversight and associated  
study halting rules are provided in Sections 8.6 and 8.5, respectively. 
❖ A local site that is not performing for one of the reasons above, may be selectively 
terminated and replaced with a new site. 
 
6 
STUDY AGENTS 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
XR-NTX and XR-PLC are donated by Alkermes, Inc; and will be sent by Alkermes to the local 
site pharmacies.   
SL-BUP is purchased by each local site’s pharmacy from a manufacturer of generic formulation. 
SL-PLC is donated to the study by TONIX Pharmaceuticals; and will be distributed through 
Tuscaloosa VA pharmacy to the West Haven VA.  
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
XR-NTX (naltrexone for extended-release injectable suspension, VIVITROL) is supplied as a 
single use kit containing one 380 mg vial of VIVITROL microspheres, one vial of diluent, one 5-
mL syringe, one ½-inch 20-gauge preparation needle, and two 1½-inch 20-gauge administration 
needles with safety device. VIVITROL microspheres consist of a sterile, off-white to light-tan 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 22  
 
powder that is available in a dosage strength of 380-mg naltrexone per vial. Naltrexone is 
incorporated in 75:25 polylactide-co-glycolide (PLG) at a concentration of 337 mg of naltrexone 
per gram of microspheres. The diluent is a clear, colorless solution. The composition of the 
diluent includes carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water 
for injection.  
SL-BUP (sublingual buprenorphine tablet; SUBUTEX) is supplied as an uncoated oval white 
tablet in counts of 30 tablets per bottle in 2mg/sublingual tablet dosage. SL-BUP contains no 
naloxone. 
SL-PLC is supplied in 40 tablets per bottle that contains 1-gram Sorb-it canister desiccant and 
polyester coil. The pill is yellow, T debossed on one side, plain on the other side, 4mm diameter 
x 2.5mm thick. 
6.1.3 PRODUCT STORAGE AND STABILITY 
Investigational products are for investigational use only and are to be used only within the 
context of this study. The study drug supplied for this study must be maintained under adequate 
security and stored under conditions specified on the label until dispensed for participant use or 
destroyed per instructions from PASA Consortium Leadership and according to local 
regulations. Product is stored in a limited-access location in the local site VA pharmacies. 
The entire dose pack of XR-NTX should be stored in the refrigerator (2 - 8°C, 36 - 46°F). 
Unrefrigerated, XR-NTX can be stored at temperatures not exceeding 25°C (77°F) for no more 
than 7 days prior to administration. Do not expose the product to temperatures above 25°C 
(77°F). XR-NTX should not be frozen.   
The SL-BUP and SL-PLC should be stored at 25°C (77°F) and excursions are permitted to 15°-
30°C (59°-86°F). 
6.1.4 PREPARATION 
The XR-NTX microspheres must be suspended in the diluent prior to injection. Parenteral 
products should be visually inspected for particulate matter and discoloration prior to 
administration whenever solution and container permit. A properly mixed suspension is milky 
white, does not contain clumps, and moves freely down the wall of the vial. 
SL-BUP has no preparation requirements. 
6.1.5 DOSING AND ADMINISTRATION 
The dose of XR-NTX is 380 mg delivered intramuscularly [gluteal; alternating buttocks for each 
subsequent injection and documentation of injection site and date in the Computerized Patient 
Record System (CPRS) source notes] every 4 weeks or once a month by research MD, APN or 
RN. XR-NTX and XR-PLC must be suspended only in the diluent supplied in the dose kit and 
must be administered with the needle supplied in the dose kit. All components (i.e., the 
microspheres, diluent, preparation needle, and an administration needle with safety device) are 
required for administration. A spare administration needle is provided in case of clogging. Do 
not substitute any other components for the components of the dose kit. 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 23  
 
SL-BUP or SL-PLC will be ordered by an investigator/co-investigator with prescribing privileges 
in the quantity of pills (one per day) needed for the exact number of days until the next 
scheduled visit (may vary according to patient needs and location, (i.e., can dispense a four-
week supply with number of tablets needed until next scheduled visit for the injection).  The 
local pharmacy or research pharmacist dispenses the medication. The medication management 
provider and/or the research coordinator reviews the medication instructions with the participant. 
The participant is informed that he/she must bring any unused portion of the study medication to 
subsequent visits so that the prescriber can issue the correct number of pills to allow for enough 
supply to last until the next scheduled visit.  Also, the participant is informed that if she/he 
misses a dose, she/he should take the next dose as soon as possible.  
If for any reason there is SL-BUP or SL-PLC study medication that will go unused, the 
participant will place the unused medication in a Take-Away Medication Recovery System 
tamper-resistant envelope and place in a US postal service mailbox to be sent to a pharmacy 
destruction service.  This can vary by site and may be done at each visit and/or at the end of the 
study. 
6.1.6 ROUTE OF ADMINISTRATION 
XR-NTX or XR-PLC should be administered by a health care professional as an intramuscular 
(IM) gluteal injection, alternating buttocks, using the manufacturer’s kits provided.  
SL-BUP or SL-PLC is taken sublingually by the participant, (i.e., placed and held under the 
tongue until it is dissolved); swallowing the tablet reduces the bioavailability of the drug. 
6.1.7 DOSE  
Pretreatment with oral naltrexone is not required before using XR-NTX.  XR-NTX starting dose 
is 380mg IM every four weeks. The dose is held constant for the duration of the study treatment 
period. 
SL-BUP is started at 2mg daily and the dose is held constant for the duration of the study 
treatment period. 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
If a participant misses a dose, he/she should be instructed to receive the next dose ASAP. 
6.1.9 DURATION OF THERAPY 
The duration of therapy is 12 weeks. 
6.1.10 TRACKING OF DOSE 
XR-NTX or XR-PLC is dispensed by the local site pharmacy and administered by a health care 
professional in the research clinic.  The local site pharmacy keeps record of the electronic order 
for dispensing the medication and the research clinic provider tracks the administration at time 
of injection in a research note. 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 24  
 
SL-BUP or SL-PLC is dispensed by the local site pharmacy. The local site pharmacy keeps 
record of the electronic order for dispensing the medication and the clinical research assistant 
tracks the pill count at the return visits. The participant is instructed to bring any unused 
medication back to the research clinic at each visit. 
6.1.11 DEVICE SPECIFIC CONSIDERATIONS 
Not applicable. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
Each local site Pharmacy is responsible for study medication receipt, storage, dispensing, 
accounting for inventory, and destruction of unused medication.  Each local site Pharmacy has 
standard operational procedures for the handling of research medications and controlled 
medications that are required to be adhered to for this study. 
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
 
7.1.1 STUDY SPECIFIC PROCEDURES  
Rater Training and CAPS-5 Fidelity Monitoring:  An independent rater at each site performs 
the Timeline Follow Back (TLFB), Clinician Administered PTSD Scale for DSM-5 (CAPS-5), and 
Columbia Suicide Severity Rating (C-SSR) assessments. The independent rater is kept masked 
to the treatment assignment and does not assess adverse events (to avoid accidental un-
masking) and remains therapeutically neutral (to avoid an inflated placebo response). In 
consultation with Frank Weathers, Ph.D., all independent raters undergo training and 
certification by Dr. Davis and Dr. Petrakis prior to assessing study participants. CAPS-5 inter-
rater reliability coefficients in the range of 0.90 to 0.95 will be established and repeated 
annually. The audio-recordings of TLFB and CAPS-5 assessments are sent to the Tuscaloosa 
research team via a secure data transmission method (shared VA server access) and 
Tuscaloosa research team sends the recordings on an encrypted disc to Dr. Weathers via chain 
of custody mail. Dr. Weathers or a trained designee listens to at least 25% of the recordings for 
consensus scoring and give personalized written feedback to the independent raters. If there is 
rater-drift, the rater receives additional training from Dr. Davis, Dr. Weathers, and/or Dr. 
Petrakis. To the extent possible, participants are evaluated by the same independent rater 
throughout their duration in the study. Back-up raters are trained and certified. 
Table below provides a brief description of the study instruments that will be utilized during the 
course of this study.   
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 25  
 
Description of Study Instruments 
SCREENING or BASELINE (Administered by trained investigator or CRC) 
MINI International Neuropsychiatric Interview for DSM-5 (MINI-5)21 is an updated semi-structured clinician-
administered interview for DSM-5 diagnoses. To reduce participant burden, modules B (Suicidality), L (anorexia 
nervosa), M (bulimia), N (generalized anxiety), P (antisocial) and optional assessment measures will not be 
collected. Purpose: To document current and past psychiatric diagnoses and confirm eligibility criteria for AUD, 
PTSD and excluded diagnoses; administered by trained local site investigator (LSI), assessor, or CRC. 
Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)22 is an interviewer-driven 
measure of alcohol withdrawal used to identify withdrawal symptoms requiring medical treatment. 
Alcohol Dependence Scale (ADS)23 is a self-report measure of alcohol dependence that is used as a measure for 
group differences in severity of alcohol dependence at baseline. 
Clinical Opiate Withdrawal Scale (COWS)24 is an 11-item clinician-administered scale used to rate common signs 
and symptoms of opiate withdrawal, to make sure participants meet baseline eligibility. 
Ohio State University Traumatic Brain Injury Identification Method – Short Form (OSU-TBI)25,26 is an 
interviewer-administered questionnaire of history and severity of TBI to characterize sample and determine eligibility. 
Barratt Impulsivity Scale (BIS)27 is a 30-item self-report instrument that uses a 4-point scale for declarative “I” 
statements meant to be answered quickly that is used to assess the behavioral construct of impulsiveness. 
Life Events Checklist for DSM-5 (LEC-5)28,29 is a self-report that assesses exposure to 16 traumatic events, as a 
preface to the CAPS-5, to provide an anchor of the index trauma and document category of trauma.  
SCREENING, BASELINE, AND FOLLOW-UP  
(Administered by certified independent assessor) 
Timeline Follow Back (TLFB)30 is a calendar-based method of assessing drinking patterns used to document the 
frequency and amount of daily alcohol consumption and to categorize the World Health Organization Risk Levels 
of Alcohol Use. 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)31  is a 30-item structured interview to assess PTSD  
severity for baseline eligibility (total score ≤2632) and outcome of treatment. 
Columbia-Suicide Severity Rating Scale (C-SSRS)33 is clinician-administered interview to measure suicidality and 
document suicidal behavior used to evaluate recent suicidality, ideation, and suicidal behavior for eligibility at 
baseline (past two months) and to track emergent suicidality at Week 8. 
BASELINE AND FOLLOW-UP INSTRUMENTS 
PTSD Checklist for DSM-5 (PCL-5)34,35 is a 20-item self-report measure that assesses the DSM-5 symptoms of 
PTSD and is used in confirmatory analysis of change in PTSD symptoms. 
Short Inventory of Problems (SIP)36 measures adverse consequences of alcohol abuse in five areas: 
Interpersonal, Physical, Social, Impulsive, and Intrapersonal total adverse consequences.  
Obsessive Compulsive Drinking Scale (OCDS)37 measures obsessive and compulsive thoughts related to drinking 
alcohol and is used as a measure craving for alcohol.  
Desire of Alcohol Questionnaire (DAQ)38 is a self-report measure the assesses (a) desires/intentions to drink, (b) 
negative reinforcement, and (c) positive reinforcement and ability to control drinking. DAQ scores have been found to 
increase during cue exposure and after alcohol administration in the laboratory and is used to measure 
desire/intentions, negative and positive reinforcements for alcohol during the stress reactivity paradigm. 
Clinical Global Impression-Severity & Clinical Global Impression-Improvement (CGI-S/CGI-I) 39  are two single-
item 7-point clinician-rated scales used to measure global change in severity of illness and status of improvement. 
Patient Health Questionnaire (PHQ-9)40 is a validated 9-item self-report measure of depressive symptoms used to 
measure change in depression and has one item that is used to monitor suicidality (safety measure). 
Veterans RAND 12-Item Health Survey (VR-12)41 is used to assess functioning domains: physical functioning, role 
limitations due to physical problems, bodily pain, general health perceptions, energy/vitality, social functioning, role 
limitations due to emotional problems, and mental health.  
Adverse Events (AE) are assessed by a research team member at each assessment using Food and Drug 
Administration (FDA) standards for AE reporting.  AEs, SAE are reported to the DSMB, and local IRB.   
 
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 26  
 
Psychophysiological Studies*: Local site research personnel are trained by Dr. Norrholm.  
*Psychophysiologic assessments are optional to not be a barrier to enrollment or randomization. 
Fear Conditioning and Extinction Paradigm (Assessment Time: Preparation 15 min, 
Acquisition phase 20 min, and Extinction phase: 20 min.) The participant undergoes the two-day 
psychophysiological assessments, prior to beginning the study medication.   
Fear Acquisition: The following method has been used successfully in Dr. Norrholm’s previous 
studies to generate a robust fear response.  The unconditioned stimulus (US) is a 250-
millisecond blast of air with an intensity of 140 psi directed to the larynx. The conditioned stimuli 
(CS’s) are different colored shapes presented on a computer monitor in front of the participant. 
The startle probe is presented after six seconds and is followed by the US 500 milliseconds 
seconds later. The CS+ is paired with the air blast, while the CS- is not. The acquisition session 
consists of a habituation phase and a conditioning phase with three blocks of four trials of each 
type (noise alone, (NA), CS+, CS-) in each block.  
Fear-potentiated startle is defined as the increase in the magnitude of the acoustic startle 
response in the presence of a cue that has been paired with an aversive US. Startle responses 
to a CS stimulus are compared to startle responses to the noise alone. Fear-potentiated startle 
is calculated by subtracting the startle magnitude to the noise probe alone (termed noise alone 
or NA trials) from startle in the presence of the CS stimuli and expressed as a difference score. 
For this reason, trial types are termed NA, CS+ (paired to airblast US), and CS- (not paired to 
an airblast US). Successful fear conditioning is observed by an increase in startle to the CS+ 
(paired with an airblast US) as compared to noise alone and a significant difference to the CS+ 
as compared to the CS- (this is termed CS discrimination).  
Fear Extinction: The following method allows us to assess fear extinction and has been used 
successfully in our previous studies.49 The extinction session occurs ten minutes after 
acquisition. Neither the CS+ nor the CS- are paired with the US. The extinction session consists 
of six blocks of four trials of each type (NA, CS+ (unreinforced), and CS-) in each block.  
Extinction Recall: The test of spontaneous recovery of fear occurs 24 hours after fear 
conditioning and consists of one block of four trials of each type (NA, CS+ (unreinforced), and 
CS-). This paradigm has been used successfully in healthy volunteers as well as combat 
Veterans seeking treatment in the Trauma Recovery Program. After completing this test, three 
unpaired air blasts are delivered during a subsequent session to measure reinstatement effects. 
Psychophysiological Reactivity to Trauma-Evoking and Alcohol-Related Stimuli using 
Virtual Reality (VR) Exposure: (Assessment time: Trauma related reactivity: 8 min and Alcohol 
cues reactivity: 8 min.)  
Participants view a computer-generated VR environment that includes combat-related contexts 
associated with deployment (e.g., Middle Eastern city, combat scenes, barracks, military 
vehicles). A second paradigm using computer-generate VR environment for alcohol-related 
stimuli is subsequently conducted.  If the participant is a someone who experienced sexual 
trauma as the cause of his/her PTSD, he/she will view a high definition video that contains 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 27  
 
images or sounds associated with assault in locations such as barracks, latrines, rear seat of a 
vehicle instead of combat scenes. These contexts do not recreate the assault. A third paradigm 
for non-combat, non-sexual trauma will be used for civilian participants with non-sexual trauma. 
Acoustic Startle Assessment: As described in our prior work, the eye-blink component of the 
acoustic startle response is measured by electromyography (EMG) recordings of the right 
orbicularis oculi muscle with two 5-mm Ag/AgCl electrodes filled with electrolyte gel. This is 
done by scrubbing on the cheek below the eye with a special cleanser and attaching two 
electrodes to the skin just below the eye.  The startle probe is a 108-dB (A) SPL, 40 ms burst of 
broadband noise with near instantaneous rise time, delivered binaurally through headphones 
(Model TDH 39, Maico, Inc.). The startle response data is acquired using Biopac MP150 for 
Windows (Biopac Systems, Inc.). All data are sampled at 1000 Hz and amplified with a gain of 
5000 using the EMG module of the Biopac system. The acquired data are filtered, rectified, and 
smoothed using MindWare software (MindWare Technologies, Ltd.) and exported for statistical 
analyses. The maximum amplitude of muscle contraction 20–200 ms after the startle probe is 
used as a measure of the startle response.   
Galvanic Skin Response (GSR, Skin Conductance Level): We measure skin conductance 
reactivity based upon the amount of perspiration on the skin. Two 5-mm Ag/AgCl disposable 
electrodes filled with isotonic paste are attached to middle phalanges of the second and fourth 
finger of the non-dominant hand. We assess tonic skin conductance and skin conductance 
change from baseline during the above-mentioned psychophysiological tasks. The skin 
conductance level and skin resistance data are acquired at a sampling rate of 1 kHz using the 
GSR module of the Biopac system. Additionally, skin conductance level (SCL) and skin 
conductance response (SCR) data are acquired at a sampling rate of 10 Hz using the eSense 
system connected to a secure, study designated iPad. Two 5 mm Ag/AgCl electrodes filled with 
isotonic paste are attached to middle phalanges of the second and fourth finger of the non-
dominant hand during the Stress Reactivity to Trauma Evoking Stimuli portion of the study. The 
acquired data are exported for further analyses.  
Heart Rate (HR) and Respiration: Heart rate is measured throughout the psychophysiological 
assessment by attaching two Ag/AgCl electrodes, one below the right clavicle and the other on 
the left forearm. High frequency heart-rate variability is quantified from spectral analysis of HR in 
the 0.12 to 0.40 Hz frequency band. Heart rate is recorded at a sampling rate of 1 kHz using the 
ECG module of the Biopac system. The dependent variables are HR, respiratory sinus 
arrhythmia (RSA), and HR reactivity as previously performed by members of our research 
group. Respiration (breathing rate) is measured throughout the psychophysiological assessment 
by attaching an elastic band around the participant’s chest.   
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
No procedures or assessments for this study are considered standard of care. 
7.1.3 MEDICAL MANAGEMENT 
At each visit, the participant meets with the medication provider (MD, PharmD, RN, or APN) 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 28  
 
who is qualified to provide Medical Management42 (MM).  MM includes instructions on the study 
medication, adjust the dosing, and evaluate side effects. The initial visit focuses on educating 
the patient on medication regiment and adherence, negative consequences of drinking, and 
other health issues. Follow-up visits focus on medication adherence, evaluating and managing 
side effects, and psychoeducation. The MM provider remains masked to the treatment 
assignment and is not involved in the outcome assessments. The CRC is responsible for the pill 
count and gives the pill count information to the MM provider for use in counseling the 
participant on the importance of adherence to the treatment and dosing. Adverse events might 
be identified during MM and subsequently documented and reported according to instructions in 
Section 8. 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Laboratory studies (complete blood count, comprehensive chemistry which includes liver and 
kidney function tests) are performed at screening and end of treatment (Week 12) or early 
termination visit. *Additional labs may need to be drawn at Week 4 and Week 8 depending on 
ALT and AST values at screening and study enrollment.   
➢ Laboratory tests (except for pregnancy tests and urine drug screens) performed within 
90 days of screening are acceptable for study screening purposes.  
➢ All laboratory test results are reviewed by the investigator or qualified designee and 
acknowledged.  
➢ Any value outside of the normal range is flagged and the investigator determines 
whether it is clinically significant.   
➢ If a test is questionable, the test(s) may be repeated, or additional testing done to 
provide clarification.   
➢ Unscheduled laboratory testing may be done at the discretion of the investigator for 
appropriate medical care.   
 
• 
Hematology – White blood cell count (WBC), Red blood cell count (RBC), hemoglobin 
(Hgb), hematocrit (Hct), mean corpuscular volume (MCV), platelet count (PLT) 
• 
Thyroid Function – Thyroid Stimulating Hormone (TSH) at screening only to confirm 
participant eligibility.  
• 
Serum Chemistry – basic metabolic panel (BMP); must include liver (ALT, AST, GGT) and 
kidney function labs (BUN and Creatinine). However, GGT is collected at baseline, Week 8 
and Week 12. 
Added procedures with v7:  
• 
If baseline ALT or AST is between 3x to 5x ULN 
o Recheck ALT and AST at Week 4 visit:  
▪ 
If ALT or AST >4x ULN, PI may consider discontinuing the study 
medication if clinically indicated.   
o Recheck ALT and AST at Week 8 visit:  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 29  
 
▪ 
If ALT or AST >3x ULN , PI may consider discontinuing the study 
medication if clinically indicated.   
• 
The PI may consult with the medical monitor as needed. 
A history and physical (H&P) and ECG within the prior 90-days is acceptable for the study 
screening purposes; otherwise, it should be repeated.   
Pregnancy Testing: Urine pregnancy dip tests for women of childbearing potential are 
processed in the research clinic by a member of the study team at screening, Week 4, Week 8, 
and Week 12 (or end of study/early study termination), as well as any time that pregnancy is 
suspected.   
Urine Drug Screening: Urine samples are collected using a CLIA waived 10 panel drug test. 
Urine drug screens are conducted in the research clinic by a member of the study team at 
screening, baseline, and each study visit. The results are retained in the participant’s research 
files. Urine drug screen results are not entered into the participant’s medical record. 
Buprenorphine is not included in the urine drug screen to avoid accidental un-masking of the 
study team members to the treatment arm.   Osmolality, temperature, pH, and adulterants will 
be assessed at collection time to ensure sample validity.  
Alcohol Breathalyzer Test: Breathalyzer tests are conducted at each research visit in the 
research clinic by a trained clinical research coordinator and used to measure participants’ 
breathalyzed alcohol concentration (BrAC).  Samples >0.01 g/dl are considered positive. 
Results are kept in research records and not entered in medical records.  
(Note: this test may not be conducted if restricted by local COVID protocols). 
7.2.2 OTHER ASSAYS OR PROCEDURES 
Not applicable. 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Phosphatidyl ethanol (PEth) Testing by Dried Blood Spot Collection 
Phosphatidyl ethanols (PEth) are a series of abnormal phospholipids located in the cell 
membrane and formed in the presence of ethanol and phospholipase D. PEth serves as a 
biomarker of alcohol ingestion in the past 2-3 weeks using liquid chromatography tandem mass 
spectrometric assessment of human blood (whole or dried spots). PEth is not significantly 
affected by age, gender, or medical disease.  
Dried blood spots offer numerous advantages over venipuncture including reduced costs, 
invasiveness and discomfort. Five dried blood spots are obtained from a finger puncture onto a 
lab provided collection card.  The collection is performed by the participant under the 
observation of the study team staff.    Sample results are available to the study team via the 
commercial lab’s portal using a study specific username/password combination and the unique 
non-PHI identifier on the blood spot collection card.   NOTE: For this study, only the unique 
study participant number is used to identify the sample. The chain of custody process as 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 30  
 
described in the instruction sheet and video (participant signature, picture identification card, 
participant name, etc.) is not applicable to this protocol.    
 
 
Serum Buprenorphine 
Buprenorphine and its metabolite norbuprenorphine are assayed using liquid chromatography 
tandem mass spectrometry by a commercial laboratory. Approximately 2.5 to 10 mL of blood 
will be collected by a trained phlebotomist into a red-top tube.  The sample is allowed to clot and 
then centrifuged to separate the serum from the cells before transferring the serum into a 
standard transport tube labeled with a unique study participant code.  Sample results are 
available via the commercial laboratory portal using a study specific username/password 
combination and the unique participant code/requisition number.   
7.2.4 SPECIMEN SHIPMENT 
The PEth collection card is placed in the box provided and shipped in a standard cardboard 
(non-plastic) envelope along with the laboratory requisition form to the commercial lab using 
tracked carrier such as FedEx or UPS.  Biohazard shipping labels are not required for this type 
of specimen.   The dried blood specimens are stable, without refrigeration, thus they do not 
require overnight shipping, ice packs, or dry ice for shipping.  
Buprenorphine sample(s) and lab requisition form are transported to the commercial lab using 
tracked carrier such as FedEx/UPS or by direct pick-up by a commercial lab courier (available at 
some sites).  Samples should be shipped overnight, at ambient temperature (no dry ice 
required) using IATA guidelines in a UN 3373 Overpack (Biological Substance Category B) 
envelope. 
So that local sites remained masked from serum BUP levels, lab results will be securely 
provided to the DCC.  Samples and subsequent results will be identified only by the unique 
participant ID and the visit week.   
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 31  
 
7.3 
STUDY SCHEDULE 
7.3.1 SCHEDULE OF ASSESSMENTS  
*Smoking: Will include both tobacco and marijuana at baseline, and marijuana only at Weeks 8 and 12.  **H&P, laboratory tests, and ECG 
within previous 90 days is acceptable at screening visit. (At Week 12: The H&P, thyroid test, and ECG do not need to be repeated.)  If baseline 
level was between 3x-5x ULN, ALT and AST needs to be repeated at week 4 and week 8 visit. At Week 8,GGT needs to be repeated. &Vital 
signs and breathalyzer on Week 2, 6, 10 may be omitted due to COVID-19 reduction of in-person visits.  +Psychophysiologic assessments are 
optional so as to not be a barrier to enrollment or randomization.***Day of Randomization is on Baseline. The schedule of follow-up visits is 
anchored to Baseline. ****CAPS-5 and C-SSRS can be administered prior to day of baseline so long as it is within one week of day of 
randomization and scores are entered as baseline. *****C-SSRS can be done either at screening or baseline visit, as well as Week 8.  $ 
Baseline and week 8 drug dispensing will occur on day 1 if not participating in psychophysiology testing and on day 2 if participating in testing  
Assessments  
Schedule of Assessments: Screening, Baseline, Week (#) or Telephone (T) Visit 
Screen 
Baseline 
Baseline 
(Day 2) 
Week 1 
Week 2 
T 
Week 4 
T 
Week 6 
T 
Week 8 
Week  8 
(Day 2) 
T 
Week 10 
T 
Week 12 
T 
Week 14 
Assessments to Qualify for Study and Characterize Population 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking Status* 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
MINI-5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H&P** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VS, BMI, BrAC 
X 
X 
 
X& 
X& 
 
X 
 
X& 
 
X 
 
 
X& 
 
X 
 
X 
Labs/ECG** 
X 
 
 
 
 
 
X** 
 
 
 
X** 
 
 
 
 
X 
 
 
Pregnancy 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
CIWA-Ar 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
COWS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
ADS  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OSU-TBI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychophysiology Study 
Fear Conditioning 
 
X+ 
 
 
 
 
 
 
 
 
X+ 
 
 
 
 
 
 
 
Psychophys. Tests 
 
 
X+ 
 
X+ 
 
 
 
 
 
X+ 
X+ 
 
 
 
 
 
 
Alcohol Related Outcomes  
TLFB 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
OCDS 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
Peth 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Serum BUP 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
SIP 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
DAQ  
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
PTSD Related Outcomes 
LEC-5 Checklist 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCL-5 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
CAPS-5**** 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Psychological Symptoms and Quality of Life 
C-SSRS***** 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
PHQ-9 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
VR-12 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
CGI-S 
 
X 
 
 
 
 
X 
 
 
 
X  
 
 
 
 
X 
 
 
CGI-I 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Adverse Events and Concomitant Medications 
Con-Meds 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug*** 
Dispense Drug 
 
X 
 
 
 
 
X 
 
 
 
X$ 
 
 
 
 
 
 
 
Pill Counts 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
Study Drug Knowledge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 32  
 
7.3.2 SCREENING 
During the process of informed consent and screening, the investigators and CRCs provide 
thorough pre-enrollment education for all prospective participants and confirm the participant’s 
commitment to and feasibility for follow-up.  Screening and baseline visits are separate from day 
of randomization so that any ambivalence can manifest, and participants can back-out prior to 
randomization.  
Screening takes place over 1 to 14 days and includes the study instruments listed in table 
above and laboratory tests described in section 7.2. A history and physical (H&P) and ECG 
within the prior 90-days is acceptable for the study screening purposes; otherwise, it should be 
repeated. Laboratory tests (except for pregnancy tests and urine drug screens) performed within 
90 days of screening are acceptable for study screening purposes. All laboratory test results are 
reviewed by the investigator or qualified designee and acknowledged. Any value outside of the 
normal range is flagged and the investigator determines whether it is clinically significant.  If a 
test is questionable, the test(s) may be repeated, or additional testing done to provide 
clarification.  Unscheduled laboratory testing may be done at the discretion of the investigator 
for appropriate medical care.   
At any point in the screening process and based on the inclusion and exclusion criteria listed 
above, the participant may be deemed eligible and proceed to baseline visit or investigator may 
exclude a participant and refer him/her for appropriate treatment. 
Participants should not be taken off psychotropic or disallowed medications for purposes of 
entering the study. However, he/she can work with their provider to discontinue and washout 
excluded medication(s) that are not clinically indicated or effective and subsequently be referred 
to the study. A participant who is otherwise meeting eligibility criteria except for taking an 
excluded medication can undergo a medically supervised discontinuation and 5-day (or longer if 
indicated) washout of medication(s), if representative of the clinical plan regardless of study 
participation, (i.e., psychotropic medications are only be discontinued for washout if the 
consenting participant is not tolerating or not responding to the medication). 
At screening and baseline, the investigators will evaluate the participant for signs and symptoms 
of acute withdrawal from alcohol.  In addition to vital signs and participant verbal history, the 
Clinical Institute Withdrawal Assessment (CIWA-Ar) will be used to facilitate assessment of 
withdrawal, and decisions regarding appropriateness for study entry and continuation with 
respect to physical dependence will be made by the investigators based on the judgment of 
study physicians. We will use a CIWA-Ar score of < 8 for an approximate cutoff level for 
inclusion into the study. A CIWA-Ar score of 10 – 15 indicates a need for medical treatment, 
which may include chlordiazepoxide (Librium), benzodiazepines, or anticonvulsants (in addition 
to thiamine and folate). All our study physicians have extensive experience in assessing and 
triaging patients who may be experiencing alcohol withdrawal. Participants that show signs or 
symptoms of alcohol withdrawal and who need detoxification will be referred for detoxification at 
the local outpatient clinic or an inpatient unit (depending on the level of care needed) and 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 33  
 
managed according to local VA Center Memorandum or policies for managing alcohol 
withdrawal.  
If it is in the best interest of the patient, the investigators may begin standard treatment for 
alcohol withdrawal without delay for a referral or outpatient MD or APN in mental health or 
primary care (i.e., not research activity).  After detoxification, the participant may be eligible for 
the study at a later time under re-consent and re-screening.  In addition, at any time during the 
course of the study, if relapse into heavy drinking has occurred, the investigators may repeat the 
CIWA-Ar as needed to evaluate need for exit from the study and medical detoxification. The 
CIWA-Ar is repeated at the conclusion of the 12-week medication treatment period and at the 
week-14 follow-up visit to confirm that the patient is medically stable and can be referred to 
usual care treatment without the need for treatment for withdrawal.   
7.3.3 BASELINE AND RANDOMIZATION VISITS 
The investigators and CRCs provide ongoing support and education during the study to 
reinforce the participants’ commitment and resolve logistical barriers to keeping the 
appointments. Participant burden is kept to a minimum (i.e., small number of assessments and 
low frequency). Adherence and attendance are vital to the success of both treatment and the 
study. Patient education on study procedures and the treatment approach in the study is the 
cornerstone to promote adherence. To maximize participant retention, study coordinators are 
trained to have a substantial focus, especially in the first several meetings with participants, on 
developing a strong alliance, educating them about the study, understanding the importance of 
adhering to treatment, what is expected of them as a study participant, and eliciting 
commitment.  
At the baseline visit, the research team evaluates the participant per the study instruments listed 
in the Schedule of Assessments table in 7.3.1.  Participants undergoing the optional two-day 
psychophysiological assessments, as described above, will complete both days of the 
psychophysiological testing prior to beginning the study medication. 
The research medication provider enters the medication orders (one for XR-NTX and one for 
SL-BUP) and the local site pharmacy dispenses the study medication according to the 
randomized assignment to one of two treatments:  
• 
Treatment A (SL-BUP 2mg + XR-NTX 380mg) or  
• 
Treatment B (SL-PLC and XR-PLC).  
SL-BUP is taken daily and XR-NTX is given every 4 weeks. All medications are dispensed by 
local site pharmacies with clearly labeled instructions. 
The participant receives the first dose of XR-NTX injectable in the research clinic and remains in 
the clinic under the supervision of the research team for approximately 1 hour after the 1st dose 
is administered.  
The medication provider or trained CRC reviews the medication instructions with the participant 
(how to administer sublingual, keeping up with medication dosing, and need to return any 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 34  
 
unused medication to the research medication provider at the next visit). The participant initiates 
SL-BUP on the following day.  
7.3.4 FOLLOW-UP VISITS 
Assessments occur at screening, baseline, and post-randomization Weeks 1, 2, 4, 6, 8, 10, and 
12.  There is a visit window of +/- 7 days for follow-up visits.  
The investigators and CRCs provide ongoing reinforcement of the patients’ commitment to long-
term follow-up.  The study medication providers emphasize the need to properly adhere to 
prescribed treatments or to call to revise the treatments if side effects occur or therapeutic 
effects are lost.  
Adherence to SL-BUP medication is confirmed by pill count. Concomitant medications are 
updated at each of these visits.  
If participants experience side effects that cannot be managed by adjustments in the timing of 
the medication (i.e., taking at bedtime, etc.), they may have their medication titration either held 
or the medication dosing may be decreased (i.e., less frequent).  
The CRC makes a telephone (t) contact with the participant between face-to-face visits to 
remind the participant of the next office visit and to check on adherence to the study medication 
and if there have been any serious adverse events.  
*Psychophysiologic assessments are optional to not be a barrier to enrollment or randomization. 
The one-day psychophysiological assessment is repeated at Week 2. 
The two-day psychophysiological assessment is repeated at Week 8. 
At Week 8, the participant remains on the assigned treatment and dose from Week 8 to Week 
12. 
While every attempt is made to retain the participant in the study on medication for the 
full 12 weeks, the participant may discontinue medication at any point and remain in the 
study for assessments through Week 12. 
7.3.5 FINAL STUDY VISITS 
At Week 12, the study medication is discontinued, and all Week 12 assessments are completed. 
At Week 12, the participant is referred back to his/her previous or newly assigned long-term 
PTSD provider for follow-up and continued treatment.  At Week 14, the participant is assessed 
for discontinuation or withdrawal side effects and resolution or emergence of adverse events. 
The participant’s ongoing clinical treatment plan is confirmed. 
7.3.6 EARLY TERMINATION VISIT 
If a participant exits prior to Week 8, all procedures for Week 8 are completed.  If the participant 
exits after Week 8 but prior to Week 12, all Week-12 procedures are completed. 
7.3.7 COVID-19 SAFETY PRECAUTIONS 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 35  
 
COVID-19 Safety Precautions:   
1. 
Adhere to local VA or University policies or mandates, for example:   
a. Screening before entering the facility, which may include a ‘no touch’ method 
to check temperature and COVID-19 screening questions.   
b. Participants encouraged or required to wear facial covering/mask while in the 
buildings, as mandated by the facility.  
c. Anyone who screens positive for COVID-19 (exposure or symptoms) and/or 
has a fever will be rescheduled (and possibly tested for COVID-19 as 
deemed clinically appropriate).   
2. 
Study staff:  
a. The research team will monitor scheduling of participants in order to allow for 
social distancing and cleaning procedures between participant visits.   
b. Research staff members will sanitize high-touch surfaces before and after 
each in-person visit with disinfectant wipes or sprays.  
c. Staff members will adhere to local policies regarding wearing protective facial 
masks, frequent handwashing/use of alcohol-based hand sanitizer, and social 
distancing.  
d. Visits will take place in a large enough space so that study staff and the 
participant can practice social distancing.  
e. As much as possible, self-assessment forms should be completed via 
telehealth or phone; and can be given directly to or mailed to the participant 
in advance of any appointment.   
f. If the patient desires to complete in-person visit forms on site, staff will honor 
that request, but maintain social distancing. 
g. Participants will receive compensation for visits. As needed, study staff will 
verify their current address in order to be able to mail compensation to the 
participant.   
3. 
    In-Person visits:  
a. The in-person research visits will be restricted to those that are clinically 
essential (screening, baseline, Week 4, Week 8, Week 12, and Week 14; due 
to required labs and/or medication injections).  
4. 
Telehealth/Phone visits: 
a.  Week 1, 2, 6, & 10 visits may be conducted over the phone or telehealth to 
limit the participants contact (study staff and time in the clinic).  
5. 
Week 14  Visit:  
a. Week 14 is highly preferred to be conducted in-person or by telehealth due to 
need for safety check and treatment planning (not as easy to assess over 
phone without video component).  
b. At this visit, participant has been off study medications for 2 weeks. 
Investigators would like to visually assess participants for withdrawal 
symptoms.   
c. All safety precautions will be followed during these visits to protect participant 
and study staff members. 
 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not applicable. 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 36  
 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Due to the potential drug: drug interactions (e.g., opiates) or confounding therapeutic effects 
(e.g., naltrexone or acamprosate), participants may not use the medications listed in the table 
below, unless authorized by PASA medical monitor and approved by the lead PIs. 
PROHIBITED MEDICATIONS 
Opioids 
Abstral, Actiq, Duragesic, 
Fentora, Onsolis (fentanyl) 
Exalgo (hydromorphone 
hydrochloride) 
Oxycet, Percocet, Roxicet, 
Xartemis XR (oxycodone/ 
acetaminophen) 
Anexsia, Co-Gesic, Hycet, 
Lorcet, Lortab, Liquicet, 
Maxidone, Norco, Vicodin, 
Xodol, Zolvit, Zydone 
(hydrocodone/ acetaminophen) 
Hycodan, Hydromet 
(hydrocodone/ homatropine) 
Percodan (oxycodone/ aspirin) 
Avinza, Kadian (morphine 
sulfate) 
Hysingla (hyrocodone) 
Rezira  (hydrocodone/ 
pseudoephedrine) 
Butrans (buprenorphine) 
Ibudone, Reprexain, Vicoprofen  Targiniq ER (oxycodone/ 
naloxone) 
Demerol (meperidine) 
Morphabond, Oramorph, 
Roxanol-T, Sublimaze 
(morphine) 
TussiCaps and Tussionex, Vituz 
(hydrocodone/ 
chlorpheniramine) 
Dilaudid, Zohydro ER 
(hydromorphone) 
Nucynta ER (tapentadol) 
Tylenol #3 and #4 (codeine/ 
acetaminophen) 
Dolophine, Methadose 
(methadone) 
Oxaydo, Xtampza ER 
(oxycodone) 
Zutripro (hydrocodone/ 
chlorpheniramine/ 
pseudoephedrine) 
Embeda (morphine/ naltrexone) 
OxyContin, Palladone 
(oxycodone hydrochloride) 
 
Medications Used to Treat AUD 
Antabuse (disulfiram) 
Revia (naltrexone 
hydrochloride) 
 
Campral (acamprosate) 
Vivitrol (extended-release 
naltrexone as a non-study drug)  
 
Medications Thought to Effect ETOH Consumption 
Gablofen, Lioresal (baclofen, 
muscle relaxant) 
Topamax (topiramate; also 
listed under mood stabilizer) 
 
Zofran (ondansatron; prevents 
nausea and vomiting) 
 
 
Stimulants and/or ADHD Treatment 
Adderall (amphetamine, 
dextroamphetamine) 
Dexedrine 
(dextroamphetamine) 
Vyvanse (lisdexamfetamine) 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 37  
 
PROHIBITED MEDICATIONS 
Desoxyn (methamphetamine) 
Ritalin, Concerta 
(methylphenidate) 
 
Antipsychotics (except for quetiapine that may be used for insomnia) 
Benperidol (benperidol) 
Mellaril (thioridazine)  
Saphris or Sycrest (asenapine) 
Clozaril, FazaClo, Versacloz 
(clozapine) 
Moban (molindone) 
Serentil (mesoridazine) 
Geodon (ziprasidone) 
Navane (thiothixene)  
Stelazine (trifluoperazine) 
Haldol (haloperidol) 
Orap (pimozide) 
Trilafon (perphenazine) 
Invega (paliperidone) 
Prolixin (fluphenazine) 
Vraylar (cariprazine) 
Latuda (lurasidone)  
Risperdal (risperidone) 
Zyprexa, Zydis (olanzapine)  
Loxitane (loxapine)  
Ruxulti (brexpiprazole)  
 
Alzheimer’s Medications 
Aricept (donepezil) 
Reminyl (galantamine) 
 
Benzodiazepine/ Other Sedatives 
Ativan (lorazepam)  
Luminal (phenobarbital) 
Thorazine (chlorpromazine) 
Belsomra (suvorexant)  
Novo-Clopate, Tranxene 
(clorazepate) 
Tranxene (clorazepate) 
Diastat, Valium (diazepam) 
Prosom, Eurodin (estazolam) 
Valium (diazepam) 
Frisium, Onfi, Tapclob, Urbanol 
(clobazam) 
Restoril (temazepam) 
Vistaril (hydroxyzine) 
Gabitril (tiagabine) 
Rozerem (ramelteon)  
Xanax (alprazolam) 
Klonopin (clonazepam)  
Novo-Clopate, Tranxene 
(clorazepate) 
 
Librium (chlordiazepoxide) 
Serax (oxazepam) 
 
Mood Stabilizers (except for lamotrigine that may be used in this population) 
Depakote, Depakene (valproic 
acid/sodium valproate, 
divalproex) 
Keppra (levetiracetam) 
Tegretol (carbamazepine) 
Eskalith, Lithobid (lithium)  
Trileptal (oxcarbazepine) 
Topamax (topiramate) 
Due to the potential confounding therapeutic effects of psychotherapy,43 concurrent evidence-
based psychotherapy for PTSD (EMDR, Cognitive Processing Therapy, Prolonged Exposure, 
and cognitive behavioral therapy) are not allowed during the study. Participants who want this 
type of treatment may enroll in a course of treatment and complete it prior to the study 
participation.  
If a participant develops suicidal, homicidal, or psychotic symptoms or a significant exacerbation 
of depression or anxiety, that clinically requires non-protocol allowed psychotropic medications, 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 38  
 
the individual is withdrawn from the study and treated by a mental health provider in the 
appropriate setting.  
7.6 
ALLOWABLE CONCOMITTANT MEDICATIONS AND TREATMENTS  
Concomitant psychotropic medication use for the 60 days prior to baseline and during the study 
is documented at each office visit.  Non-psychotropic medications are reviewed by the 
medication management provider at each visit and the list is retained in source documents (i.e., 
the local site pharmacy profile from the participant’s medical records). 
Participants may be maintained on a stable dose of psychotropic medications listed in 
table below, which has been prescribed for ≥ 2 months and current dose being stable for 
≥3 weeks prior to randomization and held constant during the trial.  
ALLOWED PSYCHOTROPIC MEDICATIONS 
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRI) 
Celexa (citalopram) 
Luvox (fluvoxamine)  
Prozac (fluoxetine)  
Lexapro (escitalopram)  
Paxil (paroxetine) 
Zoloft (sertraline) 
Antidepressants: Serotonin–norepinephrine reuptake inhibitors (SNRI) 
Cymbalta (duloxetine) 
Fetzima (levomilnacipran) 
Pristiq (desvenlafaxine) 
Effexor (venlafaxine)  
Ixel, Savella, Dalcipran, Toledomin 
(milnacipran) 
 
Antidepressants: Serotonin Modulator and Stimulator (SMS) 
Brintellix, Trintellix 
(vortioxetine)  
Desyrel, Oleptro, Trittico 
(trazodone) 
Viibryd (vilazodone) 
Antidepressants: Atypical 
Remeron (mirtazapine) 
Serzone (nefazodone) 
Wellbutrin (bupropion) 
Antidepressants: Tricyclic 
Allegron, Aventyl, Noritren, 
Nortrilen, and Pamelor 
(nortriptyline) 
Elavil (amitriptyline)  
Tofranil (imipramine)  
Anafranil (clomipramine) 
Norpramin (desipramine) 
Vivactil (protriptyline) 
Aponal, Quitaxon, Sinequan 
(doxepin)  
Pamelor (nortriptyline) 
 
Asendin (amoxapine) 
Surmontil (trimipramine) 
 
Antidepressants: Monoamine oxidase inhibitors (MAOI) 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 39  
 
ALLOWED PSYCHOTROPIC MEDICATIONS 
Emsam (selegiline)  
Marplan (isocarboxazid)  
Nardil (phenelzine) 
Parnate (tranylcypromine) 
 
 
Alpha-1-adrenergic Antagonist 
Minipress (prazosin) 
 
 
Non-benzodiazepine Hypnotics 
Ambien (zolpidem) 
Imovane (zopiclone)  
Lunesta (eszopiclone) 
Sonata (zaleplon) 
 
 
Non-benzodiazepine Anxiolytic 
BuSpar, Vanspar (buspirone) 
 
 
Other 
Neurontin (gabapentin) 
Seroquel (quetiapine) 
Lamictal (lamotrigine) 
Melatonin 
Clonidine 
If not listed on prohibited 
medication list, consult with PI 
or medical monitor for approval. 
Participants may attend PTSD support and educational groups and continue with supportive 
psychotherapy that was initiated prior to study entry. 
7.7 
ALLOWABLE RESCUE MEDICATIONS 
As a provision to support participants who might be in distress during the trial, a medication for 
severe insomnia and severe agitation is allowed on a case by case basis.  From screening to 
Week 12 and excluding the week prior to CAPS-5 assessments, diphenhydramine or 
hydroxyzine may be used sparingly, defined as up to 50 mg twice per day not to exceed three 
days per week), for severe insomnia (described as sleeping less than 4 hours per night) or 
severe agitation (described as persistent and unmanageable), based on the participant’s self-
report and the Investigator’s clinical judgment. Benzodiazepines are not allowed.  
7.8 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY EXIT  
Naltrexone is currently on VA formularies and the participant may have access to this 
medication from his/her clinic provider. Although SL-BUP is on VA formulary, it is not currently 
indicated for AUD or PTSD. 
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 40  
 
 
8 
ASSESSMENTS OF SAFETY AND ADVERSE EVENTS 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
At each visit participants are asked by the CRC and/or investigator if they are experiencing any 
discomfort or symptoms that might indicate potential side effects of the study drug. Any reported 
complaints are documented by the CRC or investigator and, if serious, are reported to the IRB 
(per local IRB reporting requirements) and the DSMB (in regularly scheduled DSMB reports).  
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
An Adverse Event (AE) is any untoward medical occurrence temporally related with the use of a 
drug in humans, whether or not considered drug related per 21 CFR Part 312.32(a). An adverse 
event (also referred to as an adverse experience) can be unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a 
drug and does not imply any judgment about causality. An AE can arise with any use of the drug 
(e.g., off-label use, use in combination with another drug) and with any route or administration, 
formulation, or dose, including an overdose. For purposes of this study, a laboratory abnormality 
(i.e., out of the normal range) that is considered not clinically significant is not considered an AE.  
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
Serious Adverse Events (SAEs) are defined as any adverse event that in the view of the 
investigator, results in any of the following outcomes:  
• 
death 
• 
life-threatening  
• 
inpatient hospitalization or prolongation of hospitalization  
• 
persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect  
This category includes any other important medical event that an LSI judges to be serious 
because it may jeopardize the participant or require intervention to prevent one of the above 
reportable outcomes, or which would suggest a significant hazard, contraindication, side effect, 
or precaution. Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed above (e.g., allergic bronchospasm requiring intensive 
treatment in an emergency room or home, blood dyscrasia or convulsions that do not result in 
hospitalization, or the development of drug dependency of drug abuse). 
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 41  
 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The US Department of Health and Human Services Office for Human Research Protections 
(OHRP) considers unanticipated problems involving risks to participants or others to include any 
incident, experience, or outcome that meets all the following criteria: 
• 
Unexpected in terms of whether the event exceeds the nature, severity, or frequency 
given (a) the research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the participant population being studied 
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
Only a small subset of adverse events occurring in participants are likely to meet these three 
criteria for an unanticipated problem. Furthermore, there are other types of incidents, 
experiences, and outcomes that occur during the conduct of human participants’ research that 
represent unanticipated problems but are not considered adverse events. For example, some 
unanticipated problems involve social or economic harm instead of the physical or psychological 
harm associated with adverse events. In other cases, unanticipated problems place participants 
or others at increased risk of harm, but no harm occurs.  
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 SEVERITY OF EVENT 
Severity of AEs is determined by the LSI or designee using FDA’s Guidance for Industry 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, as a guide. General parameters for each grade are as listed in table 
below.   
General Parameters for Grading an Adverse Event 
Vital Signs* 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Fever (°F) ** 
100.4 – 101.1 
101.2 – 102.0 
102.1 – 104 > 104 
Tachycardia - 
beats per minute 
101 – 115 
116 – 130 
> 130 
ER visit or hospitalization for arrhythmia 
Bradycardia - 
beats per minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or hospitalization for arrhythmia 
Hypertension 
(systolic) - mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or hospitalization for malignant 
hypertension 
Hypertension 
(diastolic) - mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or hospitalization for malignant 
hypertension 
Hypotension 
(systolic) – mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or hospitalization for hypotensive shock 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 42  
 
Respiratory Rate – 
breaths per minute 
17 – 20 
21 – 25 
> 25 
Intubation 
* Participant should be at rest for all vital sign measurements.  
** Oral temperature; no recent hot or cold beverages or smoking.  
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgement when characterizing 
bradycardia among some healthy participant populations, for example, conditioned athletes. 
 
Systemic 
(General) 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Nausea or 
vomiting 
No interference 
with activity or 1 
– 2 episodes/24 
hours 
Some interference with activity or 
> 2 episodes/24 hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or hospitalization 
for hypotensive shock 
Diarrhea 
2 – 3 loose 
stools or < 400 
g/24 hours 
4 – 5 stools or 400 – 800 g/24 
hours 
6 or more watery 
stools or > 800 g/24 
hours or requires 
outpatient IV 
hydration 
ER visit or hospitalization 
Headache 
No interference 
with activity 
Repeated use of nonnarcotic pain 
med >24 hrs. or some 
interference with activity 
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity 
ER visit or hospitalization 
Fatigue 
No interference 
with activity 
Some interference with activity 
Significant; 
prevents daily 
activity 
ER visit or hospitalization 
Myalgia 
No interference 
with activity 
Some interference with activity 
Significant; 
prevents daily 
activity 
ER visit or hospitalization 
 
Systemic 
Illness 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Illness or 
clinical 
adverse event  
No interference 
with activity  
Some interference with activity 
not requiring medical intervention 
Prevents daily 
activity; requires 
medical intervention 
ER visit or hospitalization  
 
Serum Laboratory* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) ** 
Sodium; Hyponatremia mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium; Hypernatremia mEq/L  
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium; Hyperkalemia mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium; Hypokalemia mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose; Hypoglycemia mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose; Hyperglycemia Fasting 
– mg/random – mg/dL 
100 – 110 
110 – 125 
111 – 125 
126 – 200 
>125 
>200 
Insulin requirements or 
hyperosmolar coma 
Blood Urea Nitrogen BUN mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine; mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires dialysis 
Calcium; hypocalcemia mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium; hypercalcemia mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Magnesium; hypomagnesemia 
mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous (K); 
hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK; mg/dL 
1.25 – 1.5 x 
ULN*** 
1.6 – 3.0 x ULN 
3.1 –10 x ULN 
> 10 x ULN 
Albumin; Hypoalbuminemia g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein; Hypoproteinemia 
g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 43  
 
Alkaline phosphate; increase by 
factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x 
ULN 
> 10 x ULN 
 ALT, AST; increase by factor 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x 
ULN 
> 10 x ULN 
Bilirubin; when accompanied by 
any increase in LFT; increase by 
factor 
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x 
ULN 
> 1.75 x ULN 
Bilirubin; when LFT normal; 
increase by factor 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.0 – 3.0 x 
ULN 
> 3.0 x ULN 
Cholesterol 
201 – 210 
211 – 225 
> 226 
-- 
Pancreatic enzymes; amylase, 
lipase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x 
ULN 
> 5.0 x ULN 
 
Hematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin (Female) - gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) change 
from baseline value - gm/dL 
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) change from 
baseline value – gm/d 
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm3 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25, 
000 
> 25,000 
WBC Decrease - cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Neutrophils Decrease - cell/mm3 
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils - cell/mm3 
650 – 1500 
1501 - 5000 
> 5000 
Hyper-eosinophilic 
Platelets Decreased - cell/mm3 
125,000 – 
140,000 
100,000 – 124,000 
25,000 – 
99,000 
< 25,000 
PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 x 
ULN** 
1.11 – 1.20 x ULN 
1.21 – 1.25 x 
ULN 
> 1.25 ULN 
PTT – increase by factor (partial 
thromboplastin time) 
1.0 – 1.2 x ULN 
1.21 – 1.4 x ULN 
1.41 – 1.5 x 
ULN 
> 1.5 x ULN 
Fibrinogen increase - mg/dL 
400 – 500 
501 – 600 
> 600 
-- 
Fibrinogen decrease - mg/dL 
150 – 200 
125 – 149 
100 – 124 
<100; bleeding; 
disseminated intravascular 
coagulation 
 
 
 
Urine* 
 
Mild 
(Grade 1) 
 
Moderate 
(Grade 2) 
 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia 
Blood (microscopic); red blood 
cells per high power field 
(rbc/hpf) 
1 - 10 
11 – 50 
> 50 and/or gross 
blood 
Hospitalization or packed 
red blood cells (PRBC) 
transfusion 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. ** The clinical signs or symptoms associated with laboratory abnormalities might result in 
characterization of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium 
value that falls within a grade-3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if the 
participant had a new seizure associated with the low sodium value.  
***ULN” is the upper limit of the normal range. 
 
 
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 44  
 
8.2.2 RELATIONSHIP TO STUDY AGENT 
Relationship of AE to study agent is recorded by the LSI or designee and identified as: 
Definitely related – the AE can be fully explained by administration of the study drug. 
Probably related – the study drug is more likely the cause of the AE than other factors. 
Possibly related – there is a reasonable possibility that the study drug is the cause of the AE, 
including that the study drug and other factor(s) are equally likely as causes of the AE. 
Unlikely related – the AE is not a previously known or suspected effect of the test drug, does 
not follow a sequence of time from drug administration for which the event could be attributed to 
the administration, and/or cannot be readily explained by the characteristics of the population 
under study but for which another incontrovertible cause is not immediately identified. 
Definitely not related – another factor is clearly (incontrovertibly) the cause of the AE. 
8.2.3 EXPECTED AND ANTICIPATED ADVERSE EVENTS 
An unexpected AE experience is any AE in which the frequency, specificity or severity is not 
consistent with the risk information described in the investigator brochure (e.g., product labeling) 
or as anticipated from the pharmacological properties of the medication class of the study 
medication(s).   This includes events that are new or greater than previously known in terms of 
nature, severity, or frequency per the pharmacological properties of the study medications.   
Anticipated events, related to both AUD and PTSD, are expected to occur in the study 
population independent of study medication exposure.  
8.3 
ADVERSE EVENT ASSESSMENT AND FOLLOW-UP 
AEs are collected from time of first dose taken after randomization through Week 14 follow-up 
visit. Study investigators follow all SAEs clinically until resolved or clinically stable. The 
occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care, or upon review by a study 
monitor. At each study visit, the LSI or trained designee asks the participant about the 
occurrence of AE/SAEs since the last visit. All AEs are captured on the appropriate CRF.  
Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study product (assessed only by those with the training and authority to 
make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship.  
Any medical condition that is present at the time that the participant is screened is considered 
as a baseline condition and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it is recorded as an AE.  
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 45  
 
8.4 
REPORTING PROCEDURES 
 
8.4.1 ADVERSE EVENT REPORTING  
All AEs and SAEs occurring during the clinical trial are collected, documented, and reported by 
the Principal Investigator according to the specific procedures detailed below. Study staff also 
review the previous Adverse Event Case Report Form and inquire whether any of those events 
are continuing. Each new or unresolved adverse event is recorded on the Adverse Event Case 
Report Form using a brief verbatim term, a severity ranking, and any additional description, 
according to the procedures. If an adverse event is reported that requires medical attention, it is 
reported to the study physician immediately. The LSI reviews each AE to assess their possible 
relationship to study medications and expectedness.  
All AE are entered into the data management system. Timely mandatory reporting is required 
for AEs that are serious; unexpected; unanticipated, and definitely, probably, or possibly related 
to study drug. Section 8.4.2 details reporting of serious events. For all other events, sites follow 
institutional policy for reporting to the IRB. Reporting to the DSMB occurs via study reviews 
occurring on a prescheduled frequency as detailed in Section 8.6.  
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
Each AE is classified by the LSI or designee as serious or non-serious. SAEs are reported by 
the LSI to their local IRB, according to that site’s local IRB reporting requirements.   
The study PI will notify Alkermes (the manufacturer and supplier of XR-NTX and XR-NTX 
Placebo) of SAEs, that are possibly, probably, or definitely related to study treatment, as quickly 
as feasible (with a goal of within 24 hours of identification by site personnel).   
Initial reports should include as much information as possible but at a minimum should include 
the event term, onset date, severity, serious criterion, relationship to study drug, date of 
resolution or continuing (if known), action taken with study drug because of the reported event, 
and an event outcome (if known). 
Initial reporting is followed up with reporting all missing adverse event characteristics and a 
description of the event. The description provides relevant screening measures, medical history 
& physical, treatment compliance, reports of other relevant AEs and any other information the 
LSI deems appropriate. If the participant experiences additional events deemed serious, then 
these should be reported separately. However, if the participant experiences non-serious AEs 
during the same period, these are detailed in the SAE description and are reported separately 
as part of AE collection in the EDC system.    
Determination of whether the event may be unexpected and at least possibly temporally related 
to study drug is made by the LSI in collaboration with the PASA Consortium medical monitor. 
Any SAE that are deemed at least possibly related and unexpected or unanticipated is 
submitted by PASA Consortium Leadership, in conjunction with the study team, via study 
DSMB reviews occurring on a prescheduled frequency.  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 46  
 
The medical and research Monitor for this study is:  
 
Thomas R. Kosten, MD, Medical Monitor and Research Monitor  
Vice-Chair of Psychiatry for Research  
Houston/Michael E. DeBakey VAMC  
 
The Research Monitor role is a role independent of the research team and is achieved through 
study oversight as part of the PASA DCC CLT through regular attendance and participation in 
DSMB meetings, and through ongoing review of SAEs.  
  
The Research Monitor:  
• 
may discuss the research protocol with the investigators, interview human subjects, and 
consult with others outside of the study about the research, if needed. 
• 
shall have authority to stop a research protocol in progress, remove individual human 
subjects from a research protocol, and take whatever steps are necessary to protect the 
safety and well-being of human subjects until the IRB can assess the monitor’s report. 
• 
shall have the responsibility to promptly report their observations and findings to the IRB 
or other designated official and the United States Army Medical Research and Material 
Command’s Human Research Protection Office (HRPO), and other relevant 
regulatory bodies. 
 
In collaboration with the PASA Consortium Leadership, the medical monitor, and DSMB; the LSI 
determines whether there is a need to redesign or amend the protocol, and/or to inform current 
and future participants of a change in description of risk; either in the consent form and protocol, 
or by other written or verbal communication. 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
Unanticipated problems that may involve risk to the participant or study staff, but do not 
necessarily result in an adverse event (i.e., harm) are reported separately from adverse events. 
An example of an unanticipated problem that may not result in an adverse event (i.e., harm) is 
misplacement of a participant’s research record containing identifiable private information such 
that the risk of loss of confidentiality is introduced. This event is reportable regardless of 
whether the confidentiality is breached or not breached.  
Any unanticipated problem that involves substantive harm (or genuine risk of substantive harm) 
to the safety, rights, or welfare of the site’s research participants, research staff, or others is 
reported by the LSI or designee to the IRB and PASA Consortium Management within 48 hours 
of identification. Otherwise, the site LSI reports the event(s) to the local IRB on an annual basis 
at the time of continuing review and to the PASA Consortium Management as part of usual data 
collection for the participant.  
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 47  
 
8.4.4 REPORTING OF PREGNANCY  
All pregnancies are reported by the LSI to the PASA Consortium Management and Alkermes 
within 48 hours of detection. A pregnancy is not considered an AE. 
8.5 
STUDY HALTING RULES  
Study halting rules are determined by the study team and submitted to the PASA Consortium 
Management. The DSMB will review the halting rules, as part of their protocol review.   
A ‘study halting rule’ typically specifies the outcome differences detected between groups during 
an interim analysis that can stop a clinical trial or study. Since the sample size for this study is at 
a minimum to determine a difference between groups, an interim analysis is not planned.  Thus, 
our halting rules reflect guidelines to be considered for temporarily halting or permanently 
stopping the study.  
New Information - There may be new information available to cause the DSMB to halt or stop 
the study, such as the following: 
• 
The results of other trials indicate that the benefits far outweigh the risks or vice 
versa,  
• 
A change in the understanding of the underlying biology of the disorders that indicate 
this pharmacological approach is ineffective or poses a substantial risk to 
participants,  
• 
A change in the understanding of the pharmacology or interaction of the study drugs, 
such that the combination poses a substantial risk to participants, or, 
• 
Outside evidence of unacceptable adverse effects from the study drug(s) and/or their 
interactions.  
Safety Reporting - There may be serious adverse reactions reported in which unmasked 
information would trigger the DSMB to review the study in advance of regularly scheduled 
meetings and the DSMB may halt enrollment of new participants, such as the following: 
• 
Three (3) Serious Adverse Events in a single organ system or related 
pathophysiology that are possibly, probably, or definitely related to the drug(s);  
• 
A single occurrence of an unexpected serious and severe, life-threatening adverse 
event that is uncommon or previously not reported and determined to be strongly 
associated with drug exposure (e.g., angioedema, aplastic anemia, Stevens-Johnson 
Syndrome);  
• 
Occurrences of an adverse event determined to be strongly associated with drug 
exposure that are not commonly associated with drug exposure and otherwise 
uncommon in the population exposed to the drug.  
After review, the DSMB will recommend whether to permanently halt the study, modify the 
protocol, or continue the protocol. Based on the type of uncommon or previously not reported 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 48  
 
adverse events and relatedness to the drug(s), the DSMB may determine that these types of 
events from safety reports may lead to a modification of the informed consent rather than study 
halting. 
8.6 
SAFETY OVERSIGHT 
The PASA Consortium Management has established a DSMB to oversee this study. Members 
of the DSMB are independent of the study investigators and include representatives with 
substance abuse, pharmacology and psychology/psychiatry expertise, a biostatistician and an 
ethicist. None will have financial, scientific, or conflicts of interest which might interfere with their 
unbiased assessment of the progress of the trial. The DSMB meets at least once every four 
months as specified in the DSMB charter to review the study, although may be convened 
between planned meetings to discuss study issues related to adverse events/safety. This 
protocol should be approved by the DSMB prior to initiation of recruitment. The DSMB monitors 
study progress and has the ability to recommend that the trial be stopped for safety or futility. No 
formal interim assessments of efficacy are planned for this protocol and thus, the DSMB makes 
no recommendations related to stopping the study for efficacy.  
During their reviews, the DSMB is responsible for a) reviewing research protocols, informed 
consent documents, and plans for data safety and monitoring; b) evaluating the progress of the 
study, including periodic assessments of data quality and timelines, participant recruitment, 
accrual and retention, participant risk versus benefit, and other factors that can affect study 
outcome; c) considering factors external to the study, when relevant, such as scientific or 
therapeutic developments that may have an impact on the safety of the participants or the ethics 
of the trial; protecting the safety of the study participants; d) reporting on the safety and scientific 
progress of the trial; e) ensuring the confidentiality of the data and the results of monitoring; and 
f) assisting the investigators by commenting on any problems with study conduct, enrollment, 
sample size and/or data collection. 
The DSMB provides recommendations to the DoD Grants Officer Representative (GOR) for 
further distribution to the GSC, and to the PASA Consortium PI (or designee) for archiving and 
further distribution to the Study PIs and all sites for IRB submission. Recommendations are also 
reported to the U.S. Army Office of Research Protections (HRPO) via annual reports for the 
study. While study halting rules described in Section 8.5 are to be considered by the DSMB in 
their deliberations about study safety and futility, final stopping recommendation criteria will be 
established by the DSMB. 
8.7 
RISKS MINIMIZATION 
To mitigate the potential for misuse, dependency, and withdrawal, SL-BUP is combined with 
XR-NTX, a medication that blocks the mu receptor involved in psychogenic properties of 
buprenorphine. As stated earlier, XR-NTX can antagonize the effects of opioids via competitive 
inhibition of opioid receptors, which raises the concern that the combination of SL-BUP and XR-
NTX will make SL-BUP less effective. This would be a risk for individuals who are using opiates 
or SL-BUP on a regular basis prior to starting XR-NTX, (i.e., the addition of XR-NTX may 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 49  
 
precipitate opioid withdrawal symptoms). For this reason, this study excludes patients who have 
recent opioid use or opioid use disorders, and opiates are not allowed to be concurrently taken 
during the study. XR-NTX is contraindicated in patients receiving opioid analgesics and in 
patients with current physiologic opioid dependence, acute opiate withdrawal, acute hepatitis or 
liver failure, and previous hypersensitivity reaction to XR-NTX. Patients with these 
contraindications are not eligible to participant in this study.  
In the current study, XR-NTX is administered as a long-acting injectable, the protective 
pharmacologic properties are present for the full duration of treatment with SL-BUP, thereby 
eliminating the risk that the participant will get psychologically or physically addicted to SL-BUP. 
In addition, we are using low dose SL-BUP (Note: the dose is lower than 16mg dose used in 
CURB study).  At the end of the study XR-NTX gradually eliminates from the body. Thus, a 
pharmacologic taper is not needed for either XR-NTX or SL-BUP.  Participants should not 
experience withdrawal symptoms, but to be conservative, they are followed by the investigators 
for an additional two weeks to monitor the participants for any adverse events related to 
discontinuation. To be cautious and thorough, the investigators assess for signs and symptoms 
of opioid withdrawal at the end of the study. 
A caution that included in the informed consent states that in a situation when analgesia may be 
required in a patient who has received full blocking doses of XR-NTX, consideration should be 
given to regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid 
analgesics, or general anesthesia. If opioid analgesia is required, the amount of opioid needed 
may be greater than usual, and the resulting respiratory depression may be deeper and more 
prolonged. In this case, a rapidly acting opioid analgesic that minimizes the duration of 
respiratory depression is preferred. XR-NTX can also diminish the benefit from opioid-containing 
cough, cold, and antidiarrheal preparations, which is listed as a warning in the informed 
consent. These warning are standard when treating patients with XR-NTX. 
SL-BUP is contraindicated in patients who have had prior hypersensitivity to any formulation of 
buprenorphine. Significant respiratory depression and death have occurred in association with 
buprenorphine, particularly when taken by the intravenous (IV) route in combination with 
benzodiazepines or other CNS depressants (including alcohol). Buprenorphine, particularly 
when taken by the IV route, in combination with benzodiazepines or other CNS depressants 
(including alcohol), has been associated with significant respiratory depression and death. 
Many, but not all post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection.  
Deaths have also been reported in association with concomitant administration of 
buprenorphine with other depressants such as alcohol or other CNS depressant drugs. For 
these reasons, participants are not allowed to take concomitant benzodiazepines or CNS 
depressant drugs (i.e., neuroleptics or sedating anticonvulsants) during the study. In the case 
of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required. Naloxone may be of 
value for the management of buprenorphine overdose. Higher than normal doses and 
repeated administration may be necessary. Patients should be warned of the potential 
danger of self-administration of benzodiazepines or other depressants while under treatment 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 50  
 
with SL-BUP. SL-BUP should be used with caution in patients with compromised respiratory 
function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory 
reserve, hypoxia, hypercapnia, or pre-existing respiratory depression). Cases of cytolytic 
hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine 
in clinical trials and through post-marketing adverse event reports. For this reason, patients with 
severe liver disease or liver failure are excluded, and liver enzymes are measured at baseline 
and endpoint. SL-BUP may impair the mental or physical abilities required for the performance 
of potentially dangerous tasks such as driving a car or operating machinery, especially during 
treatment induction and dose adjustment. Patients should be cautioned about driving or 
operating hazardous machinery until they are reasonably certain that buprenorphine therapy 
does not adversely affect his or her ability to engage in such activities. SL-BUP is metabolized 
to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may 
occur when SL-BUP sublingual tablet is given concurrently with agents that affect CYP3A4 
activity. The concomitant use of SL-BUP sublingual tablet with CYP3A4 inhibitors (e.g., azole 
antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease 
inhibitors) should be monitored and may require dose-reduction of one or both agents. 
The LSI or designee instruct participants (in the consent form and verbally) to immediately 
report any adverse experiences that may arise and/or any changes in concurrent medications, 
whether prescription, over-the-counter medications, or herbal supplements.  
In the unlikely event that a participant experiences a medical emergency, the local site has 
access to a medical Center that is fully prepared to respond to any medical event that may 
arise. Physicians and nurses are fully trained to respond to all types of medical and psychiatric 
emergencies. A fully equipped crash cart is available near the research clinic. 
The risks of complications during pregnancy or congenital problems with this drug combination 
is not fully known, although much is known about each medication separately.  As a 
conservative measure, we are asking that women use contraception and have not found that 
this requirement negatively impacts recruitment rates for women.  There is no evidence that 
either medication affects reproductive risks after discontinuation. Similarly, there is no evidence 
that either medication affects male reproductive risks. Thus, women of child-bearing potential 
are informed of this unknown risk and are tested at baseline, as needed during follow-up, and at 
study endpoint. 
During the psychophysiological assessments, participants may experience minor discomfort 
associated with delivery of the air blasts for the fear conditioning task. The air blast is described 
by participants as “annoying” but not painful. The decibel levels and duration of the auditory 
stimuli are not enough to cause any damage to the ear. If any part of the psychophysiological 
procedures or assessments are uncomfortable or distressing, the participant can take breaks or 
stop the procedures at any time. 
To minimize breach or invasion of privacy, records that have personal identifiers (i.e., clinical 
records or source documents) are stored in a locked cabinet behind a locked door. Only the 
research team and clinical staff assigned to the care of the participants have access to non-
anonymous research records. In addition, the study monitors, trained in Good Clinical Practice 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 51  
 
(GCP), will have access to source documents while auditing the local site. Research case report 
forms do not contain personal identifiers and are labeled with a study i.d. number. Files that link 
participants’ names with screening and randomization numbers are maintained in a secure 
location either on VA server or in a locked file within a locked office in the research clinic.  
No presentation or publication of the study results will refer to participants individually. 
Manuscripts published regarding this work will be based on the accumulated database.  
A federal Certificate of Confidentiality, which protects participants’ records against subpoena will 
be acquired prior to study start. Exceptions to confidentiality for participants are those required 
by law and include suspicion of child abuse, elder abuse, and threat of imminent action on 
suicidal or homicidal ideation. Participants are informed of these exceptions in the informed 
consent process. In addition, representatives from PASA and the IRB will have limited access to 
the research record (e.g., in the event of a SAE, the IRB may request a review of the chart to 
assess adequacy of care during the trial). 
9 
CLINICAL MONITORING 
Clinical monitoring is conducted by PASA Consortium representatives. Monitoring occurs after 
the start of study enrollment; and at interim visits at time intervals that are determined by the 
PASA Consortium. For additional information on clinical monitoring practices and procedures, 
including the Clinical Monitoring Plan, please refer to the PASA Manual of Operations. 
10 
STATISTICAL CONSIDERATIONS  
 
10.1 STATISTICAL AND ANALYTICAL PLANS 
Analysis will be guided by the Statistical Analysis Plan (SAP) specified in accordance with the 
RTI PASA statistical quality plan: PASA Stats Quality Plan. The study-specific SAP will be 
finalized prior to locking the study data and unmasking the data.   
10.2 STATISTICAL HYPOTHESES 
To test the therapeutic actions of kappa-opioid receptor antagonism, we propose a proof-of-
concept study to evaluate the effects of sublingual buprenorphine (SL-BUP; Subutex) combined 
with extended-release injectable naltrexone (XR-NTX; Vivitrol) in the treatment of comorbid 
AUD and PTSD. In addition to the primary clinical outcomes for AUD and PTSD we plan to 
measure pre- and post-treatment psychophysiological correlates of fear and alcohol craving that 
include 1) measure of the extinction of fear-potentiated startle and 2) stress reactivity to trauma 
stimuli and alcohol cues.  The overarching hypothesis is that KOR antagonism achieved by the 
combination SL-BUP and XR-NTX will be effective in the treatment of comorbid AUD and PTSD 
and that these effects will be associated with psychophysiological changes.  There will be two 
groups: XR-NTX + 2mg SL-BUP group and a PLACEBO group.  With respect to sample size, 
the goal is to obtain at least 90 participants randomized to either of the two retained arms.  
Recruitment will occur over a 24-month enrollment period. If this goal is met with time left in the 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 52  
 
enrollment period, sites will be allowed to randomize additional participants but will not exceed 
the original planned sample size of 135 randomized participants across all study arms. 
 The primary efficacy endpoint is a reduction of both AUD and PTSD symptoms, such that 
lowering both will be coded success and any other outcome will be failure. As a complement to 
the primary outcome, the AUD and PTSD components of the composite will be evaluated 
individually. 
Secondary outcomes will also be examined both between group and over time (where 
applicable). These outcomes include: 
• 
Examine differences in baseline psychophysiological measures, severity of AUD and 
PTSD, and treatment outcomes.  
• 
Examine whether SL-BUP/XR-NTX improve psychophysiology measures at Week 8 
(primary endpoint).  
• 
Examine whether the degree of change from baseline to 2-week psychophysiological 
measures are associated with AUD and PTSD outcomes at Week 8. 
*Psychophysiologic assessments are optional to not be a barrier to enrollment or randomization.  
10.3 ANALYSIS DATASETS 
The safety population will include all randomized participants that receive any study drug 
defined by treatment they actually received (either of the SL-BUP or XR-NTX treatments or 
placebo).  
Analyses of efficacy outcome measures will be done using an intention to treat (ITT) population 
defined by the randomization irrespective of whether any study drug/placebo was actually 
received. 
10.4 DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
All statistical computations will be performed by biostatisticians at the PASA Consortium data 
coordinating center [part of the Research Triangle Institute (RTI)]. For summaries of study data, 
categorical measures will be summarized in tables listing the frequency and the percentage of 
participants; continuous data will be summarized by presenting mean, standard deviation, 
median and range; and ordinal data will be summarized by only presenting median and range. 
P-values presented will be based on two-sided tests unless otherwise specified and generally 
adjusted for randomization factors. For continuous outcomes, checks of normality will be 
performed and if required, transformations or non-parametric tests will be employed. Additional 
details for potential covariate adjustments in secondary analyses or handling violations of 
analytic method assumptions will be detailed in the statistical analysis plan.  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 53  
 
The analyses will include all available observations (i.e., from the various assessment times) 
from each participant. The Mixed-Effects Model of Repeated Measures (MMRM) provides valid 
inference under the assumption of ignorable missingness. No imputation processes will be used 
to replace missing data. However, every effort will be made to minimize missing data. Because 
missing observations have the potential to alter the results of analyses, we will examine whether 
the pattern of missing data is different among the groups. We will also examine the distribution 
of baseline covariates between those with and without missing outcome data. If there are no 
systematic differences between those with and without missing data, the data will be considered 
to be missing at random.  If there are significant differences in dropout or missing data patterns 
between treatment arms, we will conduct sensitivity analyses to determine the impact of missing 
information on the treatment comparisons. 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The primary dependent variable will be response status at Week 8 for each participant.  A 
positive response is defined as a decrease from baseline of at least 8 points on the CAPS-5 
score and a reduction of at least 1 risk level of alcohol use, as defined by WHO, at Week 8. 
Response data will be analyzed using mixed logistic regression with treatment group, 
measurement visit as a categorical variable, gender, site, presence/absence of anti-
depressants, and other potential confounders as explanatory variables. A treatment group by 
measurement visit interaction will be included to account for the longitudinal nature of the data 
with the Week 8 effect being the primary outcome of interest. A two-sided p-value will be 
reported from the primary analysis for the all pairwise comparisons of SL-BUP/XR-NTX 
treatment and placebo groups. 
As a complement to the primary outcome, the AUD and PTSD components of the composite will 
be evaluated individually. Difference in heavy alcohol use at Week 8 (defined as >4 standard 
drinks/sessions for men and >3 standard drinks/sessions for women) will be analyzed using a 
generalized-linear mixed model with treatment group, gender, site, presence/absence of anti-
depressants, and other potential confounders as explanatory variables. Difference in reduction 
of PTSD symptoms at Week 8 (as measured by the CAPS-5) will be analyzed using a 
generalized-linear mixed model with treatment group, gender, site, presence/absence of anti-
depressants, and other potential confounders as explanatory variables. For both outcomes, a 
treatment group by visit interaction term will be included to account for the longitudinal nature of 
the data, with Week 8 effect being the primary outcome of interest. 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
SL-BUP/XR-NTX treatment will be compared with the PLACEBO (PLC) group for the following 
secondary outcomes: 
• 
Examine differences in baseline psychophysiological measures, severity of PTSD and 
AUD, and treatment outcomes.  
• 
Examine whether BUP/NTRX improve psychophysiology measures at 8 Weeks (primary 
endpoint).  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 54  
 
• 
Examine whether the degree of change from baseline to 2-week psychophysiological 
measures are associated with AUD and PTSD outcomes at Week 8. 
*Psychophysiologic assessments are optional to not be a barrier to enrollment or randomization. 
Continuous data will be analyzed using MMRM with treatment group, gender, site, 
presence/absence of concomitant antidepressants, and other potential confounders as 
between-participant factors and visit (categorical) as a within-participant repeated measure. The 
model will also include the two-way interaction between treatment group and visit. When 
appropriate, significant differences between treatment groups will be further analyzed with post-
hoc comparisons. Adjusted marginal means (also called LS means) will be used to report and 
test for differences in mean change at Week 8 for the placebo and SL-BUP/XR-NTX groups 
providing 95% confidence intervals and a p-value for the difference between them. 
10.4.4 SAFETY ANALYSES 
The safety analyses population includes all randomized participants. These analyses will 
include those participants who have reported an adverse event as well as those who do not 
report an adverse event. The incidence of treatment emergent adverse events, type of adverse 
events, and frequency of withdrawals due to an adverse event will be summarized by treatment 
group. Appropriate statistical comparisons will be made between treatment groups in terms of 1) 
rates of adverse events, 2) discontinuation due to adverse events, and 3) side effect scales. 
Rates will be compared using time to event hazard analysis. Frequencies will be analyzed using 
the chi square or Fisher Exact test. The scales will be examined using non-parametric analyses 
when appropriate. This study is not powered as an equivalence study so the non-significance of 
differences between groups does not truly imply equivalence. 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
To assess medication adherence, blood samples collected at study Week 8 and Week 12 will 
be tested for buprenorphine and its metabolite, norbuprenorphine, using quantitative 
assessments. We will also incorporate a self-report medication adherence CRF that will be 
completed at each study visit. Results of pill counts will be summarized over time by treatment 
group. 
10.4.6 BASELINE DESCRIPTIVE STATISTICS 
Prior to the formal analysis of outcomes, all data will be examined using summary statistics 
(e.g., mean, standard deviation, median, etc.) and statistical graphs. Demographic variables 
(e.g., age, gender, race/ethnicity, etc.) will be compared between treatment groups using t-tests 
for continuous data and chi-square tests for categorical data. If necessary, non-parametric tests 
will also be used to compare demographic variables between treatment groups. Significant 
demographic variables will be included in all subsequent models. 
10.4.7 PLANNED SAFETY AND INTERIM ANALYSES  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 55  
 
The study will be monitored by the DSMB as detailed in Section 8.6. Baseline; participant 
disposition; study drug exposure; and primary and secondary outcome data will be summarized 
for each study review with a focus on participant safety. While there are study halting rules that 
will trigger a study review by the DSMB, there are no formal study stopping rules based on the 
safety review that would trigger permanent study termination without the review and 
recommendation of the DSMB. 
No formal interim analyses for efficacy are planned for this study. 
10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
No specific sub-group analyses are planned for this study. Any additions of such analyses will 
be discussed in the statistical analysis plan. 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
No adjustments for multiple comparisons are planned for the primary efficacy or safety 
outcomes. For the secondary outcomes, we will group by outcome domain and apply Benjamini-
Hochberg (1995) false discovery rate correction to maintain the nominal alpha level of 0.05. 
10.4.10 TABULATION OF INDIVIDUAL RESPONSE DATA 
Study data will be tabulated and summarized as described in 10.4.1. Additional details will be 
discussed in the statistical analysis plan. 
10.4.11 EXPLORATORY ANALYSES 
Certain measures included in the study were added at the suggestion of the Government 
Steering Committee to harmonize with the Simpson-Saxon study (including the PCL-5). The 
study plans to analyze all AUD and PTSD measures collected throughout the study and most 
can be analyzed using similar mixed modeling techniques described above for the secondary 
outcomes. Additionally, study group comparisons for all AUD and PTSD outcomes will be made 
across time from baseline to Week 12. All exploratory analyses will be described in the 
statistical analysis plan. 
10.5 SAMPLE SIZE 
The sample size for a proof-of-concept study should be large enough to be able to detect a drug 
effect or surrogate signal, but at the same time expose a minimum number of participants to an 
experimental drug combination in a reasonable timeframe within a restricted budget. Sample 
size was determined based on sample sizes used in similar double-mask, placebo-controlled 
studies of AUD and PTSD, and based on the estimated recruitment rate over the allotted 
enrollment timeline.  
With these factors in mind, we plan to enroll approximately 180 participants to allow for screen 
failures/dropouts prior to randomization.  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 56  
 
With respect to sample size, the goal is to obtain at least 90 participants randomized to either of 
the two retained arms (XRNTX/2mg BUP arm and PLACEBO arm).  Recruitment will occur over 
a 24-month enrollment period. If this goal is met with time left in the enrollment period, sites will 
be allowed to randomize additional participants but will not exceed the original planned sample 
size of 135 randomized participants across all 3 originally planned study arms. 
To ensure balance within each treatment group we will use stratified randomization on site, 
presence/absence of concomitant antidepressants, and gender. We plan to use blocking within 
each stratum of the randomization scheme to balance treatment assignments. We estimate that 
attrition will be approximately 30%. However, all randomized participants will remain in analysis 
(intent-to-treat) regardless of how long they participate in the study.  
For the primary outcome, we assume 90 randomized participants (allowing for screen 
failures/dropouts) allotted equally among the two study arms and with the success rates shown 
in the below table. We calculated power for two by two contingency tables for comparisons with 
each treatment arm and the Placebo arm using a Fisher’s Exact test with the Walters 
approximation applying a nominal two-sided alpha level of 0.05.  
In examining our primary outcome, we provide a table of power calculations with a range of 
potential placebo and treatment responses for a sample size of 45 in each group. The value in 
orange (0.560) is from the original protocol where the assumption was for an 11% (5/45) 
positive response rate in the placebo arm and a 31% (14/45) positive response rate in the active 
treatment arm. All cells shaded in yellow have a value of 0.7 or greater and all cells shaded in 
green have a value of 0.8 or greater. A sample size of 45 in each group will be able to detect a 
clinically meaningful difference between groups.  For example, a treatment response of ≥38% 
(17/45) in the active treatment arm (consistent with ALKS-4561 for depression) and ≤11% (5/45) 
in placebo arm (conceivable in a dual-diagnosed PTSD-alcohol population) would have power 
of 0.8 or greater.  In addition, a situation with more positive responses in the active treatment 
arm or fewer positive responses in the placebo arm would increase apparent power. 
 
 
  
  
Treatment Positives 
 
  
24% 
27% 
29% 
31% 
33% 
36% 
38% 
40% 
42% 
44% 
Placebo 
Positives 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
2% 
1 
0.860 0.908 0.941 0.964 0.979 0.988 0.993 0.996 0.998 0.999 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 57  
 
4% 
2 
0.714 0.791 0.853 0.900 0.934 0.958 0.975 0.985 0.991 0.995 
7% 
3 
0.556 0.651 0.734 0.804 0.861 0.905 0.937 0.960 0.975 0.985 
9% 
4 
0.409 0.506 0.600 0.687 0.762 0.826 0.877 0.916 0.944 0.964 
11% 
5 
0.286 0.375 0.467 0.560 0.647 0.726 0.795 0.851 0.895 0.929 
13% 
6 
0.192 0.265 0.348 0.437 0.527 0.615 0.696 0.767 0.828 0.877 
16% 
7 
0.125 0.180 0.248 0.326 0.412 0.500 0.587 0.669 0.743 0.807 
18% 
8 
0.081 0.119 0.170 0.235 0.309 0.392 0.478 0.565 0.647 0.723 
20% 
9 
0.057 0.079 0.114 0.163 0.224 0.295 0.375 0.460 0.545 0.628 
 
For secondary hypotheses, we estimate that with equal numbers of participants randomized to 
each of two treatments groups we will have >80% power to detect a medium effect size 
(Cohen’s f=0.25, two-sided alpha level of 0.05) at Week 8. Under optimal conditions, where the 
correlation between consecutive observations on the same participant is high, and the variability 
observed between pairs of time points is fairly constant, fewer participants would be required 
(see table below).  Under a less than ideal, worst-case situation where correlation between 
measurements is low and the variability observed between pairs of time points changes, the 
proposed sample size is still large enough to detect a moderate effect size, even after 
accounting for screen failures and drop-outs. 
Estimated Sample Sizes per Group for Detecting a Moderate Effect Size at 80% Power 
Modeling Conditions 
AUD 
Outcome 
PTSD 
Outcome 
Higher of PTSD/AUD with 
Screen Failures and Drop-
outs (+15) 
High Correlation, Constant Variance 
42 
30 
57 
High Correlation, Non-constant 
Variance 
42 
63 
78 
Low Correlation, Constant Variance 
81 
57 
96 
Low-Correlation, Non-constant Variance 
81 
120 
135 
For the Psychophysiological and Fear Conditioning analyses, a total sample size of 90 (45 per 
group) will allow for a conservative dataset with over 80% power to detect significant differences 
between the treatment group and the placebo group at the α = 0.05 level. Estimates were based 
on means and standard deviations from previous study samples. 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 58  
 
10.6 MEASURES TO MINIMIZE BIAS 
 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
To minimize bias, a placebo drug is employed as the comparison group to active study drug and 
the study is conducted in a double-masked fashion in that both the participants and the 
Independent Assessors who are assessing study outcomes are masked to treatment 
assignment. The only individuals at the site with access to treatment assignment information are 
the research pharmacists. 
At baseline, participants who meet eligibility criteria are randomized to treatment A 
(buprenorphine 2mg SL with naltrexone 380mg IM) or treatment B (SL placebo and IM placebo) 
in a double-mask fashion for 8 weeks. The treatment allocation ratio for the treatment vs. 
placebo regimens is 1:1 and is stratified by site, presence of concomitant antidepressants, and 
gender using a random permuted block scheme with variable block size. The randomization 
schedule is created by the PASA statistician who coordinates with the local research 
pharmacies and develops the web-based randomization assignment system. At Week 8, the 
participants remain on the assigned treatment and dose from Week 8 to Week 12. 
10.6.2 EVALUATION OF SUCCESS OF MASKING  
Any unmasking of study participants or study staff is reported as a protocol deviation to the PI 
(Davis), LSI, and PASA Consortium Management. However, the site should not have to report 
which treatment that the participant is assigned unless such information is needed to ensure the 
safety of the participant.  At the end of the study, the participant is asked to complete a survey 
as to whether he/she could tell which treatment arm was assigned, and if so, which treatment 
and why.  
10.6.3 BREAKING THE STUDY MASK/PARTICIPANT CODE 
The local site pharmacy maintains the masking record, which can be broken only upon request 
by the treating provider in order to protect the participant from a life-threatening event.  In the 
event of an emergency, the research pharmacists may unmask without advance permission 
from PASA Consortium Management, but the site must report the unmasking within 24 hours by 
contacting the PASA Consortium Management. If the mask is ever broken on any individual 
participant, the pharmacist must record that fact in the pharmacy study records and report to PI, 
LSI, and PASA Consortium Management.  
In instances where the study mask needs to be broken, permission and approval to break the 
mask should be obtained in advance by a research pharmacist from appropriate PASA 
Consortium Management point of contact as defined in the pharmacy study medication 
accountability binder. PASA Consortium Management includes: 
• 
Tracy Nolen, Ph.D., PASA Consortium Leadership 
o Principal Scientist, RTI International 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 59  
 
• 
Nathan Vandergrift, Ph.D., PASA Consortium Leadership 
o Senior Research Statistician, RTI International  
• 
Thomas Kosten, MD, PASA Consortium Leadership 
o Medical Monitor, Professor of Psychiatry, Neuroscience, Pharmacology, 
Immunology & Pathology Baylor College of Medicine, Michael E DeBakey VAMC 
(Houston, TX) 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff maintain appropriate medical and research records for this study, in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of participants. All physical research data are stored in either locked files or 
secure computers, which are always kept in locked rooms at the local sites. All electronic 
research data are stored on the secure VA server behind the VA firewall. An Accounting of 
Disclosure (AOD) is maintained by the CRC that lists any disclosure of individually identifiable 
information outside the VA. The manual spreadsheet includes the date of the disclosure, nature 
or description of the individually identifiable information disclosed, purpose of each disclosure 
and the name and address of person or agency to which the disclosure was made. Besides the 
PI, the study staff, the IRB, and the PASA Consortium; people who ensure quality from the local 
site where the research is being done, federal and other regulatory agencies have access to all 
the research data.  
Source documentation includes any documents used to record all original data from participants 
that support and verify information recorded on the Case Report Forms, such as medical 
records, screening visits, telephone conversations, study procedures, self-report instruments, 
diagnostic and study-related data, and study visits.  
The study monitor, authorized representatives of the PASA Consortium, representatives of the 
IRB or research oversight administrators may inspect all documents and records required to be 
maintained by the investigator, including, but not limited to, research records and pharmacy 
records for the participants in this study.  The investigational site must provide direct access to 
all trial related sites, source data/documents, and reports for monitoring and auditing by the 
PASA Consortium, and inspection by local and regulatory authorities. 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
Quality Control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution. The QC 
monitors will verify that the clinical trial is conducted, and data are generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
13 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS  
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 60  
 
13.1 ETHICAL STANDARD  
The local site investigator is responsible for ensuring that this study is conducted in full 
conformity with Regulations for the Protection of Human Participants of Research codified 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 11, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312), and ICH E2, 
E3, E6, E8 and E9. 
13.2 INSTITUTIONAL REVIEW BOARD  
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
13.3 INFORMED CONSENT PROCESS  
Potential participants are given ample time to consider the informed consent, along with other 
options for treatment presented by the research assistant, investigators and/or treatment team.  
They may have as much time as needed (no time limit) to read and consider the risks and 
benefits of the study participation and they may involve family members, significant others, and 
primary treatment team in the decision on whether or not to participate in the study.  Participants 
are informed that refusal to participate in research projects will not change their eligibility for VA 
services, treatment, or disability payments.  No guarantees are made for symptom improvement 
during the research study.  Compensation is commensurate with time and inconvenience 
needed to complete the procedures.   
Prior to entering the study, a member of the study team provides the potential participant with 
detailed information regarding the study’s purpose, procedures, potential risks and benefits, 
alternative treatment, compensation and other required elements. This is done by a study team 
member in a private setting and documented on a signed and dated informed consent form. The 
investigators are responsible for answering questions pertaining to the study medication and 
their side effects. A participant’s willingness to take part in the study is subsequently 
documented in the medical records. If a participant agrees to participate, his/her consent is 
recorded on the Agreement to Participate in Research Form, VA Form 10-1086. Informed 
consent requires that the participant understand the details of the study, including its risks and 
benefits, and agrees without coercion to participation. The signed and dated consent form is 
distributed to: Participant’s study file (original) and participant (copy). A note is entered by the 
CRC into the participant’s medical record to document the process of informed consent. 
All participants must have the capacity to provide their own informed consent.  Surrogate 
consent is not allowed. Only those patients with capacity for informed consent are eligible.  
Persons who lack capacity to give independent informed consent (i.e., severe cognitive disorder 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 61  
 
such as dementia, severe traumatic brain injury, or other known cognitive or psychotic disorder 
that impairs decision making) are not eligible to be enrolled.  Persons with a terminal illness, 
minors, and prisoners cannot be recruited or enrolled in this study. 
Protection of participants from harm must be balanced against the potential for benefit to 
participants themselves, and to other persons with their disorders, that may arise from research 
participation. Since new treatments must eventually be tested in persons suffering from the 
condition, a policy totally excluding vulnerable participants from research would preclude the 
development of improved treatment for persons with AUD or PTSD. This study specifically recruits 
veterans and service members, as well as non-veterans, with AUD or PTSD, which may be 
considered as a vulnerable patient population. Vulnerable populations, i.e., prisoners, individuals 
with mental retardation, minors, persons with dementia or severe cognitive disorders, and persons 
deemed legally incompetent are not eligible for this study. The decision-making capacity of 
individuals with AUD or PTSD at this stage of recovery is typically intact, however, veterans are 
accustomed to taking and following direct orders, which requires a greater need for researcher to 
prevent coercion, either directly or indirectly. Potential participants are given ample time to read 
and consider the informed consent with other treatment options explained in the consent form. 
Family members, significant others, and primary treatment teams may also be involved in the 
decision-making process if the potential participant wishes. For veterans and service members, 
they are also informed that declining participation in a study does not change their eligibility to VA 
services, treatment, disability or other VA benefits. Those individuals who are economically or 
educationally disadvantaged may be considered vulnerable. The VA population includes 
individuals in this category; however, the study keeps payments to participants at a minimum to 
avoid coercion based on economic hardship. In addition, the informed consent is written at a 
grade school level of education to minimize vulnerability to the educationally disadvantaged. 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY  
Among Veterans and service members, concerns about confidentiality, stigma associated with 
receiving any form of mental-health care and concerns related to present military policies 
underlie low rates of treatment 
Participants’ confidentiality is strictly held in trust by the participating investigators, their staff, 
and the PASA Consortium and their agents. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated are held 
in strict confidence. No information concerning the study, or the data is released to any 
unauthorized third party without prior written approval of the PASA Consortium. 
The study participant’s contact information is securely stored at each clinical site for internal 
use during the study. At the end of the study, all records are kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations.  
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, are transmitted to and stored at the PASA Consortium Data Coordinating Center 
(DCC). This does not include the participant’s contact or direct identifying information. Rather, 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 62  
 
individual participants and their research data are identified by a unique study identification 
number. The study database will contain dates: date of study entry, dates of assessments, 
dates of adverse events, date of death (if applicable and unlikely). The study data entry and 
study management systems used by the clinical site and by the PASA Consortium DCC 
research staff are secured, and password protected. At the end of the study, all study 
databases are de-identified and archived at the PASA Consortium DCC. In addition, 
information about SAEs and any pregnancy will go to Alkermes (providing the study drug 
naltrexone and its injectable placebo kits).   
As part of QA processes a data use agreement is in place between VA and Dr. Weathers who 
will be reviewing recorded CAPS interviews for both training and maintaining assessor quality.  
To address concerns about confidentiality, we will obtain a Certificate of Confidentially (CoC). 
CoCs allow researchers to refuse to disclose names or other identifying characteristics of 
research participants in response to legal demands. Certificates are to researchers to help 
protect the privacy of human participants enrolled in sensitive, health-related research. This 
certificate protects identifiable research information from forced disclosure. It allows the 
investigator and others who have access to research records to refuse to disclose identifying 
information on research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research 
participants, Certificates of Confidentiality help achieve the research objectives and promote 
participation in studies by helping assure confidentiality and privacy to participants. 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
Samples collected under this protocol are not stored and are analyzed immediately for 
participant health safety purposes and toxicology screens. Samples are destroyed after 
analysis.  
Data stored for the study at the PASA Consortium DCC will be used for future analyses as well 
as potential regulatory submission. 
13.5 FUTURE USE OF STORED SPECIMENS  
Per Section 13.4.1, samples collected under this protocol will not be stored for future use of any 
kind. 
14 
DATA HANDLING AND RECORD KEEPING  
 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported.  


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 63  
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When making 
changes or corrections, cross out the original entry with a single line, and initial and date the 
change. DO NOT erase, overwrite, or use correction fluid or tape on the original.   
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) 
and clinical laboratory data will be entered into Medidata Rave, a 21 CFR Part 11-compliant 
data capture system provided by the PASA Consortium DCC. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify 
data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the source documents. 
14.2 STUDY RECORDS RETENTION  
All VA research records in accordance with the new Veteran Health Administration’s  Records 
Control Schedule 10-1 (RCS) policies for the Office of Research and Development which states 
that the LSI may destroy research records 6 years after the end of the fiscal year in which the 
IRB and R&D has been closed; however, before any destruction the LSI will need to obtain 
PASA Consortium approval.  Electronic data will be deleted from the VA secure network and 
hardcopy data will be destroyed according to the approved VA Records Management policies 
and secure practices. 
Only data collected as part of the study for analysis, study reporting and/or safety monitoring 
(e.g., SAE reports) will be transferred to the central DCC of the PASA Consortium.  The 
individual investigators at each site will get a final copy of the data collected at their site at the 
end of the study. None of these data will have direct identifiers, and the data will be retained 
centrally with no plans for destruction.  In the event of Consortium close-out, any data archived 
at the Consortium would be transferred to DOD CDMRP as the primary funder of the project. 
14.3 PROTOCOL DEVIATIONS  
Compliance with the protocol will be monitored throughout the study. Any deviations noted 
during conduct of the study are to be reported by the LSI, or their designee, to the IRB and 
PASA Consortium Management. A protocol deviation is any noncompliance with the clinical trial 
protocol, GCP, or Manual of Procedures (MOP) requirements. The noncompliance may be 
either on the part of the participant, the investigator, or the study site staff. The MOP details the 
process for reporting protocol deviations. 
14.4 PUBLICATION AND DATA SHARING POLICY 
The PASA Consortium will ensure results of the study are published and shared.  As such, this 
study will: 
• 
Following the Final Rule for Clinical Trials Registration and Results Information 
Submission (42 CFR Part 11), register with ClinicalTrials.gov and submit results. Primary 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 64  
 
outcome results from this trial will be submitted to ClinicalTrials.gov within 1 year of 
completion.  
• 
Publish results. Every attempt will be made to publish results in peer-reviewed journals. 
All final peer-reviewed journal manuscripts from this study will be submitted to the digital 
archive PubMed Central upon acceptance for publication. 
• 
Deposit data for data sharing with other researchers. Within the bounds of relevant IRB 
approvals and guidelines for protection of personally identifiable data, de-identified data 
from this study will be deposited in an appropriate, publicly available data repository.   
15 
AMENDMENTS 
 
As the study is being conducted, the PI will promptly inform the PASA Consortium of any 
changes in recruitment or in the protocol that are relevant to safety, as well as any actions taken 
by the IRB because of its continuing review of the study. In the event of any major changes in 
the status of an ongoing protocol, the Principal Investigator will inform the PASA Consortium’s 
program officer immediately. Such changes would include:  
• 
Amendments to the protocol 
• 
Temporary suspension of participant accrual, or of the protocol 
• 
Any change in informed consent or IRB approval status 
• 
Termination of participant accrual, or of the protocol 
• 
Other problems or issues that could affect the human participants in the study 
 
16 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the trial. The 
study leadership in conjunction with the GSC has established policies and procedures for all 
study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 65  
 
 
17 
LITERATURE REFERENCES  
 
 
 
1 Mokdad, A. H., Marks J. S., Stroup D. F. and Gerberding J. L. (2004). Actual causes of death in the United States, 
2000. JAMA 291(10): 1238-1245. 
2 Harwood, H. (2000). Updating Estimates of the Economic Costs of Alcohol Abuse in the United States: Estimates 
Update Methods, and Data. Rockville, Maryland, The Lewin Group for the National Institute on Alcohol Abuse and 
Alcoholism. 
3 Goldstein, R. B., Smith S. M., Chou S. P., Saha T. D., Jung J., Zhang H., Pickering R. P., Ruan W. J., Huang B. and 
Grant B. F. (2016). The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the 
National Epidemiologic Survey on Alcohol and Related Conditions-III" Soc Psychiatry Psychiatr Epidemiol 51(8): 
1137-1148. 
4 Grant, B. F., Goldstein R. B., Saha T. D., Chou S. P., Jung J., Zhang H., Pickering R. P., Ruan W. J., Smith S. M., 
Huang B. and Hasin D. S. (2015). Epidemiology of DSM-5 alcohol use disorder: results from the National 
Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry 72(8): 757-766. 
5 Blanco, C., Xu, Y., Brady, K., Perez-Fuentes, G., Okuda, M., and Wang, S. (2013). Comorbidity of posttraumatic 
stress disorder with alcohol dependence among US adults: results from National Epidemiological Survey on Alcohol 
and Related Conditions. Drug Alcohol Depend 132(3): 630-638. 
6 Tanielian, T. and Jaycox, L.H. eds., Invisible Wounds of War: Psychological and Cognitive Injuries, Their 
Consequences, and Services to Assist Recovery. Santa Monica, CA: RAND Corporation, 2008. 
https://www.rand.org/pubs/monographs/MG720.html.  
7 Petrakis, I. and Simpson, T. (2017). Posttraumatic stress disorder and alcohol use disorder: a critical review of 
pharmacologic treatments. Alcoholism: Clinical and Experimental Research 41(2): 226-237. PMID: 28102573. 
PMCID: PMC5375032 DOI: 10.1111/acer.13297. 
8 Zhou, Y., Crowlet, R.S., Ben, K., Prisinzano, T.E., Kreek, M.J. (2017).  Synergistic blockade of alcohol escalation 
drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone. Brain 
Res. 1662:75-86.  
9 Wee, S., Leandro, F., Vendruscolo, F., Misra, K.K., Schlosburg, J.E., Koob, G.F. (2012). A combination of 
buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence.  Science 
Translational Medicine 4(146):146.   
10 Rorick-Kehn, L. M., Witkin J. M., Statnick M. A., Eberle E. L., McKinzie J. H., Kahl S. D., Forster B. M., …..  
McKinzie D. L. (2014). LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist 
with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology 77: 131-
144. 
11 Fava, M., Memisoglu A., Thase M. E., Bodkin J. A., Trivedi M. H., de Somer M., Du Y., Leigh-Pemberton R., 
DiPetrillo L., Silverman B. and Ehrich E. (2016). Opioid modulation with buprenorphine/samidorphan as adjunctive 
treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J 
Psychiatry 173(5): 499-508. 
12 Li, W., Sun, H., Chen, H., Yang, X., Xiao, L., Liu, R., … Qiu, Z. (2016). Major depressive disorder and kappa opioid 
receptor antagonists. Translational Perioperative and Pain Medicine, 1(2), 4–16.  
13 Ling, W., Hillhouse, M. P., Saxon, A. J., Mooney, L. J., Thomas, C. M., Ang, A., … Rotrosen, J. (2016). 
Buprenorphine+naloxone plus naltrexone for the treatment of cocaine dependence: The Cocaine Use Reduction with 
Buprenorphine (CURB) Study. Addiction (Abingdon, England) 111(8), 1416–1427.  
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 66  
 
 
 
14 Stanciu, C.N., Glass, O.M., Penders, T.M. (2017). Use of Buprenorphine in treatment of refractory depression-A 
review of current literature. Asian J Psychiatr. 26:94-98. doi: 10.1016/j.ajp.2017.01.015. Epub 2017 Jan 27. 
15 Seal, K.H., Maguen, S., Bertenthal, D., Batki, S.L., Striebel, J., Stein, M.B., Madden, E., Neylan, T.C. (2016). 
Observational evidence for buprenorphine's impact on posttraumatic stress symptoms in veterans with chronic pain 
and opioid use disorder. J Clin Psychiatry 77(9):1182-1188. 
16 Ling, W., Hillhouse, M. P., Saxon, A. J., Mooney, L. J., Thomas, C. M., Ang, A., … Rotrosen, J. (2016). 
Buprenorphine+Naloxone plus Naltrexone for the Treatment of Cocaine Dependence: The Cocaine Use Reduction 
with Buprenorphine (CURB) Study. Addiction (Abingdon, England), 111(8), 1416–1427.  
17 Saxon AJ, Akerman SC, Liu CC, Sullivan MA, Silverman BL, Vocci FJ. (2018) Addiction. Extended-release 
naltrexone (XR-NTX) for opioid use disorder in clinical practice: Vivitrol's Cost and Treatment Outcomes Registry. 
Aug;113(8):1477-1487. doi: 10.1111/add.14199. Epub 2018 Apr 1. 
18 Witkiewitz, K., Hallgren, K. A., Kranzler, H. R., Mann, K. F., Hasin, D. S., Falk, D. E., … Anton, R. F. (2017). 
Clinical Validation of Reduced Alcohol Consumption After Treatment for Alcohol Dependence Using the World Health 
Organization Risk Drinking Levels. Alcoholism, Clinical and Experimental Research 41(1), 179–186.  
19 Rothbaum, B. O., Price, M., Jovanovic, T., Norrholm, S. D., Gerardi, M., Dunlop, B., … Ressler, K. J. (2014). A 
randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for 
posttraumatic stress disorder in Iraq and Afghanistan War veterans. Am J Psychiatry 171(6):640-8. doi: 
10.1176/appi.ajp.2014.13121625. 
20 Norrholm, S. D., Jovanovic, T., Gerardi, M., Breazeale, K. G., Price, M., Davis, M., … Rothbaum, B. O. (2016). 
Baseline psychophysiological and cortisol reactivity as a predictor of PTSD treatment outcome in virtual reality 
exposure therapy. Behav Res Ther 82:28-37. doi: 10.1016/j.brat.2016.05.002. Epub 2016 May 7. 
21 Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, 
G.C. (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a 
structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59(20):22-33. 
22 Sullivan, J.T., Sykora, K.; Schneiderman, J.; Naranjo, C.A.; and Sellers, E.M. Assessment of alcohol withdrawal: 
The revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar). British J of Addiction 84:1353-
1357, 1989. 
23 Doyle, S. R., & Donovan, D. M. (2009). A validation study of the alcohol dependence scale. J Studies on Alcohol 
and Drugs, 70(5), 689–699. 
24 Wesson, D. R., & Ling, W. (2003). The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs, 35(2), 
253–9. 
25 Corrigan, J.D., Bogner, J. (2007). Initial reliability and validity of the Ohio State University TBI Identification Method. 
J Head Trauma Rehabil 22(6):318–329. 
26 Bogner, J., Corrigan, J.D. (2009). Reliability and predictive validity of the Ohio State University TBI Identification 
Method with prisoners. J Head Trauma Rehabil 24(4):279–291. 
27 Patton, J.H., Stanford, M.S., Barratt, E.S. (1995) Factor structure of the Barratt impulsiveness scale. Journal of 
Clinical Psychology 51:768-774. 
28 Weathers, F.W., Blake, D.D., Schnurr, P.P., Kaloupek, D.G., Marx, B.P., & Keane, T.M. (2013). The Life Events 
Checklist for DSM-5 (LEC-5). Instrument available from the National Center for PTSD 
29 Gray, M., Litz, B., Hsu, J., & Lombardo, T. (2004). Psychometric properties of the Life Events Checklist. 
ASSESSMENT 11:330-341.  
 


Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid PTSD 
AS1400265-A5
 
 
Page | 67  
 
 
 
30 Sobell, L.C. & Sobell, M.B. (2000). Alcohol Timeline Followback (TFLB). In American Psychiatric Association (Ed.), 
Handbook of Psychiatric Measures (pp. 477-479). Washington, DC: American Psychiatric Association. 
31 Weathers, F.W., Blake, D.D., Schnurr, P.P., Kaloupek, D.G., Marx, B.P., & Keane, T.M. (2013). The Clinician-
Administered PTSD Scale for DSM-5 (CAPS-5). National Center for PTSD. 
32 Weathers, F. W., Bovin, M. J., Lee, D. J., Sloan, D. M., Schnurr, P. P., Kaloupek, D. G., Keane, T. M., & Marx, B. 
P. (2017). The Clinician-Administered PTSD Scale for DSM–5 (CAPS-5): 
Development and Initial Psychometric Evaluation in Military Veterans. Psychological Assessment. May 11. doi: 
10.1037/pas0000486. [Epub ahead of print] 
33 Posner, K., Brown, G.K., Stanley, B., Brent, D.A., Yershova, K.V., Oquendo, M.A., Currier, G.W., Melvin, G.A., 
Greenhill, L., Shen, S., Mann, J.J. (2011). The Columbia-Suicide Severity Rating Scale: Initial validity and internal 
consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 168(12): 1266-77.  
34 Weathers, F.W., Litz, B.T., Keane, T.M., Palmieri, P.A., Marx, B.P., & Schnurr, P.P. (2013). The PTSD Checklist for 
DSM-5 (PCL-5). Scale available from the National Center for PTSD. 
35 Blevins, C. A., Weathers, F. W., Davis, M. T., Witte, T. K., & Domino, J. L. (2015). The Posttraumatic Stress 
Disorder Checklist for DSM-5 (PCL-5): Development and initial psychometric evaluation. J Traumatic Stress 
28:489–498.  
36 Kiluk, B. D., Dreifuss, J. A., Weiss, R. D., Morgenstern, J., & Carroll, K. M. (2013). The Short Inventory of Problems 
– Revised (SIP-R): Psychometric properties within a large, diverse sample of substance use disorder treatment 
seekers. Psychology of Addictive Behaviors: Journal of the Society of Psychologists in Addictive Behaviors 27(1), 
307–314. 
37 Anton, R.F., Moak, D.H., Latham, P.K. (1996).  The obsessive-compulsive drinking scale: A new method of 
assessing outcome in alcoholism treatment studies. Arch Gen Psychiatry 53(3):225-31. 
38 Courtney, K. E., Ashenhurst, J., Bacio, G., Moallem, N., Bujarski, S., Hartwell, E., & Ray, L. A. (2013). Craving and 
subjective responses to alcohol administration: validation of the Desires for Alcohol Questionnaire in the human 
laboratory. Journal of Studies on Alcohol and Drugs 74(5), 797–802. 
39 Guy W. (1976). ECDEU Assessment Manual for Psychopharmacology, Revised Edition. Washington, DC, US 
Department on Health, Education and Welfare. 
40 Kroenke, K., Spitzer, R.L., Williams, J.B. (2001), The PHQ-9: validity of a brief depression severity measure. J Gen 
Intern Med 16(9):606-13. 
41 Ware, J., Kosinski, M., Keller, S. A. (1996) 12-Item Short-Form Health Survey: construction of scales and 
preliminary tests of reliability and validity. Medical Care 34(3):220-233. 
42 Anton, R.F., O'Malley, S.S., Ciraulo, D.A., Cisler, R.A., Couper, D., Donovan, D.M., ….. Zweben A (2006). 
COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol 
dependence: the COMBINE study: a randomized controlled trial. JAMA 295(17):2003-17. 
43 Roberts, N.P., Roberts, P.A., Jones, N., Bisson, J.I. (2016). Psychological therapies for post-traumatic stress 
disorder and comorbid substance use disorder. Cochrane Database Syst Rev. 4;4:CD010204. doi: 
0.1002/14651858.CD010204.pub2. 

SAP_001.pdf: 
Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page i   
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number:  AS140026-A5 
Kappa Opioid Receptor Antagonism for the Treatment of Alcohol Use Disorder and Comorbid 
PTSD 
 
SAP VERSION: 
V4.0 
 
SAP DATE: 
August 2019 
 
PI/SPONSOR: 
Lori Davis, MD 
 
 
Ismene Petrakis, MD 
 
PREPARED BY: 
RTI International. 
 
 
3040 Cornwallis Rd 
 
 
Research Triangle Park, NC 27709-2104 
 
AUTHOR (S): 
Nathan Vandergrift, PhD 
 
 
Shawn Hirsch, MPH 
 
 
 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page ii   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 
# 
Implemented 
By 
Revision 
Date 
Approval 
Date 
Reason 
1.0 
Shawn Hirsch 
N/A 
N/A 
First version in Draft 
Protocol Amendment Version 7 is pending 
approval 
2.0 
Shawn Hirsch 
02/23/2022 
N/A 
1. Changed the Fear Potentiated Startle 
(FPS) outcome data from secondary to 
exploratory outcome 
2. Added further clarification for the TLFB 
derived outcome measures 
3.0 
Shawn Hirsch 
03/29/2022 
N/A 
Removed evaluation of the FPS assessment 
from this primary SAP; those analyses will 
be detailed in a secondary supplemental 
SAP, as needed 
4.0 
Lori Davis and 
Shawn Hirsch 
04/19/2022 
N/A 
1. For the primary outcome definition, 
changed a positive response for PTSD 
from a ≥ 8 point CAPS-5 decrease from 
baseline to ≥ 10 point decrease from 
baseline;  
2. Clarified that the AUD outcome 
measure is the average number of 
drinks consumed over a 28 consecutive 
day look-back period (and not based on 
drinking days) 
3. Added change in PeTH value from 
baseline to Weeks 8 and 12  to 
exploratory outcomes 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page iii   
 
 
 
 
The undersigned acknowledge they have reviewed the Statistical Analysis Plan and agree 
with the approach it presents. Changes to this Statistical Analysis Plan will be coordinated 
with and approved by the undersigned or their designated representatives. 
 
 
Signature: 
 
Date: 
 
Print Name: 
Lori Davis 
 
 
Title: 
Study Clinical Lead 
 
 
Role: 
Principal Investigator 
 
 
 
Signature: 
 
Date: 
 
Print Name: 
Nathan Vandergrift 
 
 
Title: 
Senior Statistician 
 
 
Role: 
Senior Statistician/Alternate-PI 
 
 
 
 
Signature: 
 
Date: 
 
Print Name: 
Shawn Hirsch 
 
 
Title: 
Statistician   
 
 
Role: 
Lead Statistician  
 
 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 1   
 
Contents 
1 BACKGROUND AND PROTOCOL HISTORY 
4 
2 PURPOSE OF THE ANALYSES 
6 
3 STUDY OBJECTIVES AND OUTCOMES 
7 
3.1 STUDY OBJECTIVES 
7 
3.1.1 PRIMARY SAFETY OBJECTIVES 
7 
3.1.2 PRIMARY EFFICACY OBJECTIVES 
7 
3.1.3 EXPLORATORY EFFICACY OBJECTIVES 
7 
3.2 OUTCOMES 
7 
3.2.1 PRIMARY EFFICACY OUTCOMES 
8 
3.2.2 EXPLORATORY EFFICACY OUTCOMES 
8 
3.2.3 SAFETY OUTCOMES 
8 
4 STUDY METHODS 
8 
4.1 OVERALL STUDY DESIGN AND PLAN 
8 
4.2 STUDY POPULATION 
9 
4.2.1 SUBJECT CHARACTERISTICS 
9 
4.3 STUDY ARM ASSIGNMENT AND RANDOMIZATION 
11 
4.4 MASKING AND DATA LOCK 
11 
4.4.1 GENERAL MASKING PROCEDURES 
11 
4.4.2 DATABASE LOCK 
11 
4.5 STUDY FLOW CHART OF ASSESSMENTS AND EVALUATIONS 
12 
5 ANALYSIS POPULATIONS 
13 
5.1 INTENTION-TO-TREAT 
13 
5.2 PER-PROTOCOL 
13 
6 SAMPLE SIZE DETERMINATION 
13 
7 STATISTICAL / ANALYTICAL ISSUES 
14 
7.1 GENERAL RULES 
14 
7.2 ADJUSTMENTS FOR COVARIATES 
14 
7.3 HANDLING OF DROPOUTS AND MISSING DATA 
15 
7.4 INTERIM ANALYSES AND DATA MONITORING 
15 
7.5 MASKED DATA REVIEW 
16 
7.6 MULTICENTER STUDIES 
16 
7.7 MULTIPLE COMPARISONS AND MULTIPLICITY 
16 
7.8 EXAMINATION OF SUBGROUPS 
16 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 2   
 
7.9 ASSESSMENT WINDOWS 
16 
8 STUDY SUBJECT CHARACTERIZATION 
17 
8.1 SUBJECT DISPOSITION 
17 
8.2 PROTOCOL DEVIATIONS 
17 
8.3 STUDY DRUG EXPOSURE AND ADHERENCE 
17 
8.4 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
17 
9 EFFICACY AND SAFETY ANALYSES 
17 
9.1 OVERVIEW OF ANALYSIS METHODS 
17 
9.2 EFFICACY AND SAFETY OUTCOME VARIABLES 
18 
9.3 PRIMARY EFFICACY ANALYSIS METHODS 
24 
9.4 EXPLORATORY EFFICACY ANALYSIS METHODS 
25 
9.5 SAFETY ANALYSIS METHODS 
26 
9.6 ADHERENCE AND RETENTION ANALYSIS METHODS 
27 
10 REFERENCES 
28 
 
 
 
 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 3   
 
LIST OF ABBREVIATIONS  
Abbreviation: Deciphered: 
ADS 
Alcohol Dependence Scale 
AE 
Adverse event 
AUD 
Alcohol Use Disorder 
BrAC 
Breathalyzed alcohol concentration 
BIS 
Barratt Impulsivity Scale 
BUP 
Buprenorphine 
CAPS-5 
Clinician Administered PTSD Scale for DSM-5 
CGI-S/CGI-I 
Clinical Global Impression-Severity & Clinical Global Impression-Improvement 
CIWA-Ar 
Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised 
COWS 
Clinical Opiate Withdrawal Scale 
CREEF 
Connecticut Research & Education Foundation  
CRC 
Clinical Research Coordinator  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DAQ 
Desire of Alcohol Questionnaire 
DoD 
Department of Defense 
DSM-5 
Diagnostic and Statistical Manual-5th Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FPS 
Fear-Potentiated Startle 
GSC 
Government Steering Committee 
H&P 
History and Physical  
HR 
Heart rate 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
KOR 
Kappa opioid receptor 
LEC-5 
Life Events Checklist for DSM-5 
MINI-5 
Mini-International Neuropsychiatric Interview for DSM-5 
MMRM 
Mixed-Effect Model of Repeated Measure 
msec 
Millisecond 
N/A 
Not Applicable 
NTX 
Naltrexone 
OCDS 
Obsessive Compulsive Drinking Scale 
OSU-TBI 
Ohio State University Traumatic Brain Injury Identification Method (Short Form) 
PASA 
Pharmacotherapies for Alcohol and Substance Abuse Consortium 
PCL-5 
PTSD Checklist for DSM-5 
PEth 
Phosphatidyl ethanol 
PHQ-9 
Patient Health Questionnaire 
PI 
Principal Investigator 
PLC 
Placebo 
PTSD 
Post-Traumatic Stress Disorder 
RCT 
Randomized Controlled Trial  
SAE 
Serious adverse event 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 4   
 
SIP 
Short Inventory of Problems 
SL  
Sublingual 
SNRI 
Serotonin and norepinephrine reuptake inhibitors 
SSRI 
Selective serotonin reuptake inhibitors 
T 
Telephone visit 
TLFB 
Timeline Follow Back 
TRD 
Treatment Resistant Depression 
TREAC 
Tuscaloosa Research & Education Advancement Corporation 
TSH 
Thyroid Stimulating Hormone 
TVAMC 
Tuscaloosa VA Medical Center 
VA 
Veteran’s Administration 
VACT 
VA Connecticut Healthcare System 
VR-12 
Veterans RAND 12-item Health Survey 
WHO 
World Health Organization 
XR 
Extended release 
XR-NTX 
Extended-release injectable naltrexone 
1 BACKGROUND AND PROTOCOL HISTORY 
Alcohol use disorder (AUD) is highly prevalent in U.S. service members and among military 
Veterans and has a large detrimental impact on society.  AUD affects 18 million Americans.  One 
important comorbid condition for individuals with AUD is PTSD. PTSD has a past year and lifetime 
prevalence of 4.7% and 6.1%, respectively.  The odds of having PTSD are 30% greater for those with 
a lifetime AUD than those with no lifetime AUD.  Taken from the other direction, those with lifetime 
PTSD are at greater risk of having an AUD (20% increased risk) compared to those without PTSD. 
Comorbidity is associated with many detrimental outcomes including significant social instability, 
disability, and more severe symptoms, higher rates of relapse, suicidal behaviors, and medical 
complications. ,   Currently, there are only four FDA–approved medications (disulfiram, oral and 
long-acting injectable naltrexone, and acamprosate) to treat AUD and two (sertraline and paroxetine) 
to treat PTSD. Despite a growing body of research in this area, there is no medication with clear 
evidence of efficacy in AUD-PTSD comorbidity and there are no FDA-approved medications to treat 
these disorders when they co-occur. New treatment strategies are urgently needed. This study 
addresses the substantial deficit in pharmacologic treatments for comorbid PTSD and AUD.  
 
The use of a medications that result in KOR antagonist effects represents a novel potential treatment 
for Veterans and Service Members with comorbid AUD and PTSD. Endogenous opioid systems in 
the brain are involved in regulation of mood, stress modulation, and cravings. Kappa opioid receptors 
(KOR) are densely localized in limbic and cortical areas comprising the brain reward system, which 
play a role in modulating stress and in promoting addictive behaviors. Endogenous dynorphins, called 
k-selective opioid peptides, are released during the stress response and contribute to the anxiogenic 
and dysphoric responses to the stressful experience. Further, the KOR dynorphin system impacts 
stress-induced drug and alcohol seeking behavior.  In animal models of alcohol dependence, KORs 
are implicated in the excessive alcohol consumption, particularly during withdrawal. KOR 
antagonists block the actions of endogenous dynorphins and block the stress-induced reinstatement of 
extinguished cocaine- and ethanol-seeking behaviors in animals. Studies for animal models of cocaine 
dependence have shown promise for using a combination of buprenorphine and naltrexone, without 
producing opioid dependence. 
 
KOR antagonists may be beneficial in the treatment of addictions, PTSD, and major depressive 
disorder. An example includes a short-acting potent KOR antagonist with selectivity over other 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 5   
 
opioid receptors (CERC-501) which has demonstrated antidepressant-like effects in animal models of 
depression and been shown to reduce ethanol self-administration in alcohol-preferring rats.  CERC-
501 is currently unavailable for additional studies due to its being purchased by another 
pharmaceutical company that is pursuing its use in major depression as the first approved indication. 
 
Another medication that acts as a net KOR antagonist is ALKS-5461, which is a combination drug 
formulation of buprenorphine and samidorphan.  Buprenorphine acts as an antagonist at kappa and 
partial agonist of the mu receptors and samidorphan is a mu opioid receptor antagonist, resulting in a 
pharmacologically net effect of kappa-opioid receptor antagonism (i.e. the same mechanism of action 
as the combination approach proposed in this application). The combination drug binds with high 
affinity to opioid receptors with low net intrinsic signaling activity.  ALKS-5461 is intended to 
support opioid tone in the brain regions with impaired endogenous activity and dampen opioid tone in 
upregulated regions. In a recent study, adjunctive ALKS-5461 significantly reduced depression scores 
compared to placebo in patients with treatment resistant depression.   Following a positive phase II 
trial, ALKS-5461 was granted Fast Track Designation by the FDA for treatment resistant depression 
(TRD) in October 2013.  In 2014, two of three core phase II trials showed that ALKS-5461 at daily 
doses of 0.5mg/0.5mg and 2mg/2mg were safe and well-tolerated but, disappointingly, the trials 
failed to meet their primary efficacy endpoints, due in part to an unusually strong placebo effect. 
However, some endpoints trended towards efficacy for 2mg/2mg/d and a statistically significant 
signal on the depression endpoint. In a sequential parallel comparison design study (stage 1 double-
blind placebo-controlled parallel comparison with higher proportion of patients randomized to 
placebo than to active drug and those patients who meet placebo nonresponse are re-randomized in 
stage 2 to drug or placebo), the 2mg/2mg and 8mg/8mg doses of ALKS 5461 were tested in patients 
with TRD.20 The 2/2 dose was significantly better that placebo across the three depression outcomes.  
Although there was significant improvement in the 8mg/8mg dosage, it did not achieve statistical 
significance. The medication was well tolerated and there was no evidence of opioid withdrawal on 
treatment discontinuation. Three additional Phase 3 studies showed efficacy ALKS-5461 2mg/2mg in 
subjects with TRD maintained on their SSRI, SNRI or bupropion. 
 
Protocol History: 
• 
V(2): 
o Eliminated references to ‘sponsor’ since this is not an IND study 
o Added inclusion criteria: Must have a CIWA-Ar score of < 8 prior to randomization. 
o Defined that: ‘Current diagnosis of moderate or severe non-alcohol substance use 
disorder (except for caffeine and nicotine) during the preceding 1 month’, would be 
determined per PI discretion, based on participant screening interview. 
o Removed FIBSER assessment.  
o Updated eligibility and medication b/on decisions re: allowable concomitant 
medications.   
o Updated inclusion and exclusion wording 
o Updated based on Alkermes SAE reporting requirements 
• 
V(3): 
o Updated exclusion criteria #2 and #4 
o Revised incentive payment wording 
o Clarified that research pharmacist will dispense buprenorphine 
o Revised which MINI modules are required for completion 
o Added military sexual trauma software to FPS  
o Clarified SAE reporting items; AE definition; and added study halting rules 
• 
V(4):  


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 6   
 
o Updated site information from Atlanta (AREEF) to Detroit (Wayne State University) 
o Added Birmingham VA as a satellite site for the Tuscaloosa VA 
o Simplified exclusion criteria to remove redundant wording about SUD 
o Clarified a visit will be cancelled if urine drug screen is positive for opiates or 
breathalyzer > 0.02 at any visit 
o Clarified C-SSRS can be done at screening or baseline 
o Removed CG-I and CG-S assessments at Weeks 1, 2, 6, and 10 
o Removed gabapentin (Neurontin), Abilify (aripiprazole), melatonin, and beta-
blockers from ‘unallowable’ medication list 
• 
V(5):  
o Removed the high dose treatment arm (8 mg of SL-Buprenorphine) 
o Allow non-Veterans to be enrolled. 
o Changed exclusion criteria to QTcF >500 msec on ECG 
• 
V(6):  
o Revisions to address safety precautions to re-open study enrollment: 
▪ 
Added section 7.3.7 (COVID-19 Safety Procedures) 
▪ 
Psychophysiology assessment put on-hold 
▪ 
In-person visits required at screening/baseline, Week 4, Week 8, and Week 
12 (due to required labs or med injections) 
▪ 
Telehealth visits allowed at Week 1, Week 2, Week 6, Week 10, and Week 
14 
• 
Specific assessments not conducted over telehealth visits include 
vitals, BrAC, and CIWA and COWS (specific questions) 
• 
V(7):  
o Expand recruitment area for Tuscaloosa to include Central Alabama VA Healthcare 
System (CAVAHS) 
o Updated to 37-month study period that includes 32-month enrollment period 
o Restarted the psychophysiological assessment, but is optional (were on-hold due to 
COVID) 
o Closed enrollment at the Wayne State/Detroit site 
o Updated prohibited medication list to exclude Lamotrigine, Quetiapine, and 
Atomoxetine 
o Revised I/E criteria (ALT and AST now allowed to be >5 ULN) 
2 PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) contains detailed information about statistical analysis to be 
performed to test the therapeutic actions of kappa-opioid receptor antagonism. We propose a proof-
of-concept study to evaluate the effects of sublingual buprenorphine (BUP; Subutex) combined with 
extended-release injectable naltrexone (NTRX; Vivitrol) in the treatment of comorbid PTSD and 
AUD. No formal interim analyses will be conducted.  As such, all analyses described will be 
performed at the end of the study excluding any efficacy and/or safety summaries provided for the 
DSMB, which are described in Section 7.4. 
 
The deliverable will be data that advances the understanding of KOR antagonistic pharmacology in 
the treatment of comorbid AUD and PTSD with the aim to inform a decision about proceeding with 
full development of soon-to-be marketed KOR antagonists for the treatment of comorbid AUD and 
PTSD. Finding a novel pharmacologic treatment approach to improve the clinical outcomes for 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 7   
 
Veterans and military Service-Members with comorbid PTSD and AUD is the focus of this project, 
which aligns exceptionally well with the goals of the PASA Consortium. 
3 STUDY OBJECTIVES AND OUTCOMES 
3.1 Study Objectives 
The specific aim of this study is to evaluate the effects of sublingual buprenorphine (BUP; 
Subutex) combined with extended-release injectable naltrexone (NTRX; Vivitrol) in the treatment 
of comorbid PTSD and AUD. 
 
The objectives of this aim are to compare safety and efficacy endpoints in the treatment group 
versus placebo after 8 weeks (with an additional follow up period extending to 12 weeks).  
 
The study team hypothesizes that the efficacy of BUP/NTRX in the treatment of comorbid PTSD 
and moderate-to-severe AUD will be greatest in the treatment group followed by a very minimal 
effect for the placebo group.  
 
SAP version 3.0 was updated to remove the evaluation of the Fear Potentiated Startle (FPS) 
assessment from this primary SAP. The FPS was changed from a secondary objective to an 
exploratory objective in SAP version 2.0 due to the pause in the FPS assessment as a result of the 
COVID pandemic. Exploratory analyses of the FPS assessment will be included and described in 
a secondary supplemental SAP, as needed.  
 
3.1.1 Primary Safety Objectives 
1. Determine if adverse event rates, severity, and relatedness differ between the 
BUP/NLTRX group compared to the placebo group over the 8-week study 
period. 
3.1.2 Primary Efficacy Objectives 
1. To evaluate the efficacy of BUP/NTRX in the treatment of comorbid PTSD and 
moderate-to-severe AUD based on a matrix outcome of response in terms of both 
PTSD and AUD outcomes over the 8-week study period.  
2. Determine if percent of heavy drinking days (defined as >4 standard 
drinks/sessions for men and >3 standard drinks/sessions for women) as assessed 
by the Timeline Follow-Back (TLFB) are reduced for BUP/NTRX treatment over 
the 8-week study period. 
3. Determine if PTSD symptoms, as measured by the change in the Clinician 
Administered PTSD Scale for DSM-5 (CAPS-5), are reduced for BUP/NTRX 
treatment over the 8-week study period. 
3.1.3 Exploratory Efficacy Objectives 
1. Examine if longer treatment is needed to show efficacy in the primary 
outcome measure between treatment groups at week 12.  
3.2 Outcomes 
A brief description of the safety and efficacy outcomes are described below. Additional detail 
regarding the definition of each of these outcomes is located in Section 9.2. 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 8   
 
3.2.1 Primary Efficacy Outcomes 
As mentioned above, the primary outcome is a matrix outcome of response in terms of 
both PTSD and AUD outcomes. The derivation of this measure will be a binary “yes/no” 
outcome. The PTSD outcome will be assessed using the CAPS-5 and be defined as “yes” if 
there is a decrease ≥ 10 points from baseline to week 8. The AUD outcome will be assessed 
using the TLFB and %HDD. The AUD outcome will be defined as “yes” if there is a 
reduction >1-shift in World Health Organization (WHO) risk levels of alcohol use from 
baseline to week 8 (note: the look-back period will consist of 28 consecutive days).  
As a complement to the primary outcome, we will also examine each of the components 
individually (CAPS-5 Total Symptom Severity Score and %HDD) 
3.2.2 Exploratory Efficacy Outcomes 
3.2.2.1 PTSD score as measured by the PTSD Checklist for DSM-5 (PCL-5) 
3.2.2.2 Depression score as measured by the Patient Health Questionnaire (PHQ-9) 
3.2.2.3 Physical and Mental Health Summary scores as measured by the Veterans 
Rand 12-Item Health Survey (VR-12) 
3.2.2.4 Change in phosphatidyl ethanol (Peth) from baseline to weeks 8 and 12 
3.2.3 Safety Outcomes 
Rates, severity and relatedness of adverse events including serious adverse events, study 
drug-related adverse events, and deaths will be evaluated. See section 8 of the protocol for 
specific details on safety parameters (i.e. definitions of AEs) and classifications (i.e. 
severity, relationship, and expectedness definitions). 
4 STUDY METHODS 
4.1 Overall Study Design and Plan 
This randomized, double-blind, placebo-controlled, multi-site study evaluates the efficacy of SL-
BUP combined with XR-NTX in the treatment of comorbid AUD and PTSD. Recruitment is 
based on convenience sampling of treatment-seeking veterans and active duty service members. 
Following screening and baseline visits, eligible patients are randomization to receive one of two 
treatments in a double-blind fashion for 12 weeks: 
• 
Treatment A (SL-BUP 2mg and XR-NTX 380mg) or  
• 
Treatment B (SL-PLC and XR-PLC).  
The treatment allocation ratio for the treatment vs. placebo (PLC) regimens is 1:1 and is stratified 
by site, presence of concomitant antidepressants, and gender using a random permuted block 
scheme with variable block size (see below Figure). The study population will consist of ~90 
Veterans with combat-related PTSD and co-morbid AUD. Detailed eligibility criteria for 
participant inclusion in this study are included in Section 4.2, below.  


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 9   
 
 
4.2 Study Population 
4.2.1 Subject Characteristics 
 
The study population is defined by the following eligibility criteria: 
 
Inclusion Criteria 
To be enrolled in this study, participants must meet the following criteria. 
1. Male or female, 18 to 65 years of age, capable of reading and understanding English, and 
able to provide written informed consent (i.e. no surrogate). 
2. Current moderate to severe AUD as determined by MINI International Neuropsychiatric 
Interview for DSM-5 (MINI-5). 
3. At least two recent episodes of heavy drinking (>5 standard drinks/sessions for men and 
>4 standard drinks/sessions for women) over the past 30 days, and heavy drinking pattern 
defined as 14 drinks per week for women and 21 drinks per week for men for at least 2 of 
a 4-week interval within the 90 days prior to baseline; i.e. at least Moderate Risk level on 
WHO category. 
4. PTSD diagnosis defined by MINI-5 at screening; symptoms must be present according to 
the DSM-5 criteria, i.e. minimum number in each cluster: at least 1 B symptom, 1 C 
symptoms, 2 D symptoms and 2 E symptoms. 
5. Clinician Administered PTSD Scale for DSM-5 (CAPS-5) total score ≥26 for the past one 
week at baseline. 
6. Females of child-bearing potential must be using medically acceptable birth control (e.g. 
oral, implantable, injectable, or transdermal contraceptives; intrauterine device; double-
barrier method) AND not be pregnant OR have plans for pregnancy or breastfeeding during 
the study.  
N= 180  
N= ~90 Randomized  
SL-buprenorphine 2mg 
and 
XR-naltrexone 380mg  
n= 45 
Baseline      1 
    2         4         
6 
8 
10     
12  
14 (week) 
SL-placebo and XR-
placebo  
n= 45 
Screened 
Study Design: RCT of KOR Antagonist in the treatment of Comorbid AUD and PTSD 
Baseline (2-day) 
Psychophysiology  
Week 2 (1-day) 
Psychophysiology  
Week 8 (2-day) 
Psychophysiology  
Week 12 
Med D/C   
Week 14 
COWS 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 10   
 
7. Must have a CIWA-Ar score of < 8 prior to randomization. 
8. Willing and able to refrain from medications thought to influence alcohol consumption 
(other formulations of naltrexone, disulfiram, acamprosate, topiramate, ondansatron, 
baclofen, and gabapentin).  
9. Willing and able to refrain from psychotropic medications: stimulants/ADHD treatment, 
Alzheimer’s medications, antipsychotics, benzodiazepines, antianxiety medications, 
mood stabilizers, and other sedatives.  
 
 
Exclusion Criteria: 
 
To be enrolled in this study, participants must not meet the following criteria. 
1. 
Current diagnosis of DSM-5 bipolar I, schizophrenia, schizoaffective, and/or major 
depressive disorder with psychotic features (defined by MINI-5 at screening). 
2. 
Increased risk of suicide that necessitates inpatient treatment or warrants therapy 
excluded by the protocol, and/or current suicidal plan, per investigator clinical 
judgement, based on interview and defined on the Columbia Suicidality Severity 
Rating Scale (C-SSRS). 
3. 
Treatment with trauma-focused therapy for PTSD (e.g. Cognitive Processing 
Therapy, Prolonged Exposure, or EMDR) within two weeks of baseline study visit.  
Note: Supportive psychotherapy in process for PTSD at time of Screening may be 
continued. 
4. 
Current diagnosis of moderate or severe non-alcohol substance use disorder (except 
for caffeine and nicotine) during the preceding 1 month, based on participant 
screening interview. Participants must agree to abstain from illicit drugs during the 
study. Patients who utilize cannabis but do not meet substance use disorder criteria 
are permitted. 
5. 
Use of opioids within 2 weeks of baseline or opioid use disorder in the previous 90 
days. 
6. 
History of severe traumatic brain injury (TBI) per Ohio State University TBI 
Identification Method. Note: history of mild or moderate TBI is allowed. 
7. 
Any clinically significant, uncontrolled, or medical/surgical condition that would 
contraindicate use of SL-BUP + XR-NTX, or limit ability to complete study 
assessments, including seizures (other than childhood febrile seizures), severe renal 
insufficiency, significant arrhythmia or heart block, heart failure, or myocardial 
infarction within the past 2 years, severe thrombocytopenia or hemophilia, severe 
hepatic failure, complete hearing loss, and/or need for surgery that might interfere 
with ability to participate.  
8. 
Clinically significant laboratory abnormalities, including a thyroid stimulating 
hormone (TSH) >1.5 times upper limit of normal, hyperthyroidism, and aspartate 
aminotransferase and/or alanine aminotransferase > 3 times upper limit of normal; 
cardiovascular findings QTcF >500 msec on electrocardiogram (ECG) or blood 
pressure >190/110.  
9. 
History of allergic reaction, bronchospasm or hypersensitivity to a naltrexone or 
buprenorphine. 
10. 
Unable or unwilling to refrain from medications thought to influence alcohol 
consumption (see inclusion criteria above.)  
11. 
Unable or unwilling to refrain from psychotropic medications (see inclusion criteria 
above); with the exception of stable doses of antidepressants, prazosin, and non-


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 11   
 
benzodiazepine hypnotics and non-benzodiazepine anxiolytics to treat PTSD or 
insomnia.   
12. 
Persons who are imprisoned, of minor age, diagnosed with dementia, diagnosed with 
a terminal illness, or otherwise require a surrogate to provide informed consent.  
4.3 Study Arm Assignment and Randomization 
At baseline, participants who meet eligibility criteria are randomized to treatment A 
(buprenorphine 2mg SL with naltrexone 380mg IM) or treatment B (SL placebo and IM placebo). 
The treatment allocation ratio for the treatment vs. placebo regimens is 1:1 and is stratified by 
site, presence of concomitant antidepressants, and gender using a random permuted block scheme 
with variable block size. The randomization schedule is created by the PASA statistician who 
coordinates with the local research pharmacies and develops the web-based randomization 
assignment system. At week 8, the participants will remain on the assigned treatment and dose 
from week 8 to 12.  
4.4 Masking and Data Lock 
4.4.1 General Masking Procedures 
This is a double-blind study so participants and study staff are masked to treatment 
assignment.  Any unmasking will be reported as a protocol deviation.  In the event of an 
emergency, study investigators may unmask without advance permissions but must promptly 
report the unmasking within 24 hours by contacting PASA leadership. 
4.4.2 Database Lock 
The database will be locked after the completion of all study follow-up visits for all 
participants. Once all participants have completed all follow-up visits, a final query report 
will be generated and the study coordinators will address data queries within Medidata Rave. 
The database will be locked after all final queries have been resolved (estimated ~2 weeks 
after all follow-up visits completed).  Randomization assignment will not be unmasked 
beyond the details of Section 4.4.1 until after database lock is finalized. 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 12   
 
4.5 Study Flow Chart of Assessments and Evaluations 
 
Assessments  
Schedule of Assessments: Screening, Baseline, Week (#) or Telephone (T) Visit 
Screen 
Baseline 
Baseline 
(Day 2) 
Week 1 
Week 2 
T 
Week 4 
T 
Week 6 
T 
Week 8 
Week  8 
(Day 2) 
T 
Week 10 
T 
Week 12 
T 
Week 14 
PAYMENTS 
25 
 
75 
30 
60 
 
30 
 
30 
 
 
80 
 
30 
 
40 
 
20 
Assessments to Qualify for Study and Characterize Population 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking Status 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H&P 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VS, BMI, BrAC 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Labs/ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pregnancy 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
CIWA-Ar 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
COWS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
ADS  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OSU-TBI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychophysiology Study 
Fear Conditioning 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Psychophysiological 
Stress Reactivity  
 
X  
 
X 
 
X  
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
Alcohol Related Outcomes  
TLFB 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
OCDS 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
Peth 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Serum BUP 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
SIP 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
DAQ  
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
PTSD Related Outcomes 
LEC-5 Checklist 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCL-5 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
CAPS-5 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Psychological Symptoms and Quality of Life 
C-SSRS 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
PHQ-9 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
VR-12 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
CGI-S 
 
X 
 
X 
X 
 
X 
 
X 
 
X  
 
 
X 
 
X 
 
 
CGI-I 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
Adverse Events and Concomitant Medications 
Con-Meds 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Adverse Events 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug*** 
Dispense Drug 
 
 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
Pill Counts 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
Study Drug Knowledge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 13   
 
5 ANALYSIS POPULATIONS 
5.1 Intention-to-Treat 
The primary and exploratory analyses will be based on the intention-to-treat (ITT) principle, with 
data from all participants analyzed according to the arm to which they were randomized 
irrespective of the amount intervention received. This includes participants initially randomized 
to the high-dose treatment arm (SL-BUP 8mg and XR-NTX 380mg) that was removed from the 
protocol (Version 5). Participants who receive intervention but do not complete the study will be 
used in all analyses for which data are available. This approach ignores noncompliance, protocol 
deviations, withdrawal and lost-to-follow-ups. Analysis of the ITT population avoids 
overoptimistic estimates of the efficacy of an intervention resulting from the removal of non-
compliers, accepting that protocol deviations occur in actual clinical practice (Heritier, Gebski, & 
Keech, 2003).   
 
5.2 Per-Protocol 
As in most clinical trials, some participants may not adhere to the intervention they were 
randomized to receive, reducing fidelity to the intervention as designed and potentially changing 
the effectiveness of the intervention. The most likely form of noncompliance will be lack of 
adherence to the randomized medication. The potential impact of this noncompliance is 
underestimating the magnitude of the true treatment effect. To assess this, in addition to the ITT 
analyses, we will also conduct all analyses at the primary time point (8-weeks) using a per 
protocol population; defined as completion of the NTX/Placebo injections at baseline and week 4, 
as well as completion of 80% of Buprenorphine pills dispensed from baseline through week 8. 
The per-protocol analysis provides an estimate of the true efficacy of an intervention (i.e., among 
those who completed the treatment as planned) (Ranganathan, Pramesh, & Aggarwal, 2016). No 
other analysis populations are defined for this protocol.   
6 SAMPLE SIZE DETERMINATION 
The sample size for a proof-of-concept study should be large enough to be able to detect a drug effect 
or surrogate signal, but at the same time expose a minimum number of subjects to an experimental 
drug combination in a reasonable timeframe within a restricted budget. Sample size was determined 
based on sample sizes used in similar double-blind, placebo-controlled studies of PTSD and AUD, 
and based on the estimated recruitment rate over the allotted enrollment timeline. With these factors 
in mind, we plan to enroll approximately 180 participants to allow screen failures/drop-out prior to 
randomization of approximately 90 participants across three sites (45 in each treatment arm) within a 
24-month enrollment period. We estimate that attrition will be approximately 30%. However, all 
randomized participants will remain in analysis (intent-to-treat) regardless of how long they 
participate in the study. 
For the primary outcome, we assumed the following success rates based on a similar previous study: 
Placebo arm 5/45 (11%) or less and 2mg BUP/NLTRX arm 17/45 (38%) or greater. We calculated 
power for two by two contingency tables for comparison of the treatment and Placebo arm using a 
Fisher’s Exact test with the Walters approximation applying a nominal two-sided alpha level of 0.05. 
We observe power of 80% or greater for the above assumptions. In addition, a situation with more 
positive responses in the active treatment arm or fewer positive responses in the placebo arm would 
increase apparent power.  


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 14   
 
For secondary outcomes, we estimate that we will have >80% power to detect a medium effect size 
(Cohen’s f=0.25, two-sided alpha level of 0.05) at 8 weeks. Under optimal conditions, where the 
correlation between consecutive observations on the same participant is high, and the variability 
observed between pairs of time points is fairly constant, fewer participants would be required (see 
table below).  Under a less than ideal, worst-case situation where correlation between measurements 
is low and the variability observed between pairs of time points changes, the proposed sample size is 
still large enough to detect a moderate effect size, even after accounting for screen failures and drop-
outs. 
For the Psychophysiological and Fear Conditioning analyses, a total sample size of 90 (45 per group) 
will allow for a conservative dataset with over 80% power to detect significant differences between 
the treatment group against the placebo group at the α = 0.05 level. Estimates were based on means 
and standard deviations from previous study samples. 
 
Estimated Sample Sizes per Group for Detecting a Moderate Effect Size at 80% Power 
Modeling Conditions 
AUD Outcome 
PTSD Outcome 
Higher of PTSD/AUD with Screen 
Failures and Drop-outs (+15) 
High Correlation, Constant Variance 
42 
30 
57 
High Correlation, Non-constant Variance 
42 
63 
78 
Low Correlation, Constant Variance 
81 
57 
96 
Low-Correlation, Non-constant Variance 
81 
120 
135 
7 STATISTICAL / ANALYTICAL ISSUES 
7.1 General Rules 
All statistical computations will be performed and data summaries will be created using SAS 9.4 
or higher. If additional statistical packages are required, these will be discussed in the study 
report. For summaries of study data, categorical measures will be summarized in tables listing the 
frequency and the percentage of participants; continuous data will be summarized by presenting 
mean, standard deviation, median and range; and ordinal data will be summarized by only 
presenting median and range. Model-based analyses described in Section 9 will be used to obtain 
point estimates and associated confidence intervals for various measures as well as p-values for 
comparisons of data between treatment groups. Note: initial models will include the high dose 
treatment arm; however, if the model cannot converge due to the small number of participants 
randomized to this arm prior to removal from the study, then the model will only compare 
outcomes between the low dose and placebo treatments.  P-values presented will be based on 
two-sided tests unless otherwise specified and generally only adjusted for randomization factors 
(study site, gender, and presence of concomitant antidepressants). Note: in the event a model 
cannot converge due to small sample sizes for a specific randomization factor, it will be removed 
from the model. For continuous outcomes, checks of normality will be performed and if required, 
transformations or non-parametric tests will be employed.  
7.2 Adjustments for Covariates  
Since this is a randomized, double-blind, placebo-controlled study with equal balance in the 
treatment arms, no adjustment for demographic or baseline characteristics is planned. However, 
any assessment of the impact of covariates or adjustments for them will be done in an exploratory 
manner only and described in the study report. 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 15   
 
7.3 Handling of Dropouts and Missing Data 
Analysis of the primary and exploratory outcomes will be based on a mixed-effect model of 
repeated measures (MMRM) using data from all time points to account for missing data and 
thereby maximize information used for the analyses. These models treat missing data as ignorable 
missing, assuming any missing data are missing at random. No imputation processes will be used 
to replace missing data. However, every effort will be made to minimize missing data.  
Additionally, because missing observations have the potential to alter the results of analyses, we 
will examine whether the pattern of missing data is different among the groups. If there are no 
systematic differences between those with and without missing data, the data will be considered 
to be missing at random. If there are significant differences in dropout or missing data patterns 
between treatment arms, we will conduct sensitivity analyses to determine the impact of missing 
information on the treatment comparisons. 
 
7.4 Interim Analyses and Data Monitoring 
The PASA Consortium Leadership has established a Data Safety Monitoring Board (DSMB) to 
oversee this study. Members of the DSMB are independent of the study investigators and include 
representatives with substance abuse, pharmacology and psychology/psychiatry expertise, a 
biostatistician and an ethicist. None will have financial, scientific, or conflicts of interest which 
might interfere with their unbiased assessment of the progress of the trial. The DSMB will meet 
at least once every four months as specified in the DSMB charter to review the study, although 
may be convened between planned meetings to discuss study issues related to adverse 
events/safety. This protocol will be approved by the DSMB prior to initiation of recruitment. 
While there are study halting rules that will trigger a study review by the DSMB (details found in 
the protocol), there are no formal study stopping rules based on the safety review that would 
trigger permanent study termination without the review and recommendation of the DSMB. 
 
This study may be suspended or prematurely terminated if there is reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to the investigator, DoD Grants Officer Representative (GOR) 
for further distribution to the Programmatic Panel, PASA Consortium PI (or designee), DSMB, 
and regulatory authorities. If the study is prematurely terminated or suspended, the PI will 
promptly inform the IRB and will provide the reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
A pattern of AEs indicating that SL-BUP + XR-NTX is inappropriate or unsafe 
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
New information emerges that suggests the risks are increased beyond an acceptable limit 
and outweigh benefits 
• 
Significant and recurring protocol violations that threaten the integrity of the study data 
• 
Data that are not sufficiently complete and/or evaluable  
• 
Continuing and ongoing serious noncompliance with human research protections and 
regulations that warrants study closure 
• 
Determination of futility. While there are no formal assessments of futility for efficacy, 
the study may be terminated if operationally futile, e.g. there is an inability to enroll or 
retain study participants. The study may resume once concerns about safety, protocol 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 16   
 
compliance, data quality is addressed and satisfy the PASA Consortium, IRB and/or other 
regulatory agencies.   
• 
Generally, any study suspension that could occur will be based upon review of the study 
and recommendations made by the DSMB. Details of safety oversight and associated 
study halting rules are provided in Sections 8.6 and 8.5, respectively. 
• 
A local site that is not performing for one of the reasons above, may be selectively 
terminated and replaced with a new site. 
 
A description of the report to be provided to the DSMB is listed in Appendix A. 
7.5 Masked Data Review 
A masked data review of outcome data for this study is not planned. 
7.6 Multicenter Studies 
This is a 3-center study including Tuscaloosa Research & Education Advancement Corporation 
(TREAC)/Tuscaloosa VA Medical Center (TVAMC), Connecticut Research & Education 
Foundation (CREEF)/VA Connecticut Healthcare System (VACT), and Wayne State University.  
Although we initially expected the total number of enrolled participants to be roughly equal 
across the three study sites, only one participant from the Wayne State site enrolled and 
completed the study. Since randomization was stratified based on study site, site will be included 
as a term in all model-based analyses. Since only one participant was enrolled at Wayne State, 
this participant will be removed during sensitivity analyses so comparisons can be made between 
study site. 
7.7 Multiple Comparisons and Multiplicity 
One single primary formal hypothesis test is planned for this study at the 0.05 level of 
significance, which is the comparison of the SL-BUP + XR-NTX treatment group vs. placebo for 
the primary outcome at the primary timepoint (Week 8). Additionally, regardless of significance 
of the primary outcome, statistical significance of the secondary outcomes will be assessed, with 
adjustment for multiple comparisons using the Benjamini-Hochberg false discovery rate 
correction to maintain the nominal alpha level of 0.05 (Benjamini & Hochberg, 1995)  Primary 
and secondary hypothesis tests resulting in nonsignificant p-values will be interpreted as 
inconclusive. All other treatment group comparisons will be considered descriptive in nature with 
no adjustment for multiple comparisons, and all confidence intervals will be generated using 95% 
bounds. 
7.8 Examination of Subgroups 
No subgroup analyses are planned at this time. 
7.9 Assessment Windows 
All screening assessments will be performed prior to Day 0 (study baseline/admission). Screening 
will take place over 1 to 14 days and include the study instruments listed in the table above 
(section 4.5). Most screening assessments are repeated at Day 0 if occurring more than one-month 
post screening. The most recent data collected during the screening/baseline period will be used 
for summarizing and analyzing baseline data.  
 
Participants will visit their respective site to complete study procedures at weeks 1, 2, 4, 6, 8, 10, 
and 12. The visit windows for these in-person visits is +/- 7-days.  It is important to confirm 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 17   
 
appointment with subjects at each visit, so that if adjustments need to be made so that the subject 
does not run out of medication between the scheduled in-person visits. The CRC will make a 
telephone contact with the participant between face-to-face visits to remind the participant of the 
next office visit and to check on adherence to the study medication and if there have been any 
adverse events. While every attempt is made to retain the participant in the study on medication 
for the full 12 weeks, the participant may discontinue medication at any point and remain in the 
study for assessments through week 12. Out-of-window visits or assessments must be reported as 
protocol deviations.  If any exclusions are made for these reasons, these exclusions will be 
described in the study report.   
8 STUDY SUBJECT CHARACTERIZATION 
8.1 Subject Disposition 
Participant eligibility status will be summarized and overall disposition of study participants will 
be described using a standard CONSORT diagram.  The number of participants randomized and 
those completing or discontinuing from study therapy will be summarized. 
8.2 Protocol Deviations 
Protocol deviations will be listed with information such as type of deviation, time of occurrence, 
and reason.  Incidence of protocol deviations will also be summarized overall and for each 
protocol deviation category.  Incidence rate of protocol deviations will be calculated as the 
number of deviations divided by number of participant days. 
8.3 Study Drug Exposure and Adherence 
A dosing/pill count log will record the doses given each week (or since the last in-person visits) 
and whether the doses were distributed and taken per protocol. A descriptive table of overall 
dosing will be provided along with a listing of missed doses and reasons for the missed doses. To 
assess medication adherence, blood samples collected at study weeks 8 and 12 will be tested for 
buprenorphine and its metabolite, norbuprenorphine, using quantitative assessments. Results will 
be summarized graphically (box-plots) over time for the active treatment study group.  
8.4 Demographic and Baseline Characteristics 
All data collected at baseline will be summarized descriptively for the entire efficacy (intent-to-
treat) population. Demographic variables of interest include, but are not limited to, age (years), 
gender, race and ethnicity, veteran status, service-connected disability, and education level. 
Baseline efficacy variables include, but are not limited to CAPS-5, PCL-5, %HDD, PHQ-9, and 
VR-12. 
9 EFFICACY AND SAFETY ANALYSES 
9.1 Overview of Analysis Methods 
The statistical goal for the study is to evaluate the effects of sublingual buprenorphine (BUP; 
Subutex) combined with extended-release injectable naltrexone (NTRX; Vivitrol) in the treatment 
of comorbid PTSD and AUD. Although the analyses will use data collected from baseline 
through week 12, the primary hypothesis that the primary outcome differs between the treatment 
arm vs. placebo will be tested at Week 8. The analysis also will formally test treatment 
differences for the PTSD and AUD outcomes, independently. Primary and exploratory analyses 
will use model-based approaches that take advantage of the longitudinal structure of the outcome 
data to address missing data caused by patient loss to follow-up or nonresponse and take into 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 18   
 
consideration correlated data collected across time. Additional analytic details are in the sections 
below. 
9.2 Efficacy and Safety Outcome Variables  
 
 
 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
 
   
Draft 4.0 2023-04-19; Page 19   
 
 
 
Variable 
Type 
Definition 
Primary Outcomes  
Composite AUD + PTSD 
outcome 
Binary (Yes/No) 
A positive response is defined as a decrease from baseline of at least 10 points on 
the CAPS-5 score (Schnurr et al., 2022) and a reduction of at least 1 risk level of 
alcohol use, as defined by WHO, at week 8. AUD data is collected on the TLFB, 
a semi-structured interview that uses a calendar prompt and other memory aids to 
facilitate accurate recall of the numbers of drinks consumed each day during a 
given target period (Sobell et al., 1996). The definition of WHO risk drinking 
levels are defined by Knox et al. (2018), and displayed in the below table  
 
 
 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
 
   
Draft 4.0 2023-04-19; Page 20   
 
Variable 
Type 
Definition 
The TLFB assessment is given at screening, baseline, and weeks 1, 2, 4, 6, 8, 10, 
and 12. The screening measurement uses a 90-day recall period whereas the 
subsequent (post treatment follow up) measurements use a recall period of “since 
the last measurement.” The baseline WHO risk level will be derived from TLFB 
data collected at both the screening and baseline visit. The look-back period to 
define the WHO risk level will be conducted over 28 consecutive days and based 
on the average number of reported standard drinks during those 28 consecutive 
days. Each derived outcome measure for a specific timepoint will be based on the 
baseline visit date. In the event 28 consecutive days are not captured for the full 
look-back period, participant data will be excluded from analyses in the event the 
number of total days included in look-back period is less than one standard 
deviation of the entire population. 
Percent Heavy Drinking 
Days (%HDD) 
Continuous (range 
between 0 and 100) 
Percent Heavy Drinking Days (%HDD) is measured via the Timeline Follow 
Back instrument (Sobell et al., 1996). The screening (baseline) measurement uses 
a 90-day recall period whereas the subsequent (post treatment follow up) 
measurements use a recall period of “since the last measurement.” Baseline 
%HDD will be derived from TLFB data collected at both the screening and 
baseline visit. The look-back period to define %HDD will be conducted over 28 
consecutive days and based on the number of heavy drinking days reported 
during this time period. Each derived outcome measure for a specific timepoint 
will be based on the baseline visit date. In the event 28 consecutive days are not 
captured for the full look-back period, participant data will be excluded from 
analyses in the event the number of total days included in look-back period is less 
than one standard deviation of the entire population. 
A heavy drinking day is defined as follows: 
>4 standard drinks/sessions for men and >3 standard drinks/sessions for women 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
 
   
Draft 4.0 2023-04-19; Page 21   
 
Variable 
Type 
Definition 
CAPS-5 Total Symptom 
Severity Score 
Continuous (range 
between 0 and 80) 
CAPS-5 total symptom severity score is measured via the Clinician-Administered 
PTSD Scale For DSM-5 (CAPS-5).  The score is calculated by summing severity 
scores for the 20 DSM-5 PTSD symptoms (Weathers et al., 2013), with a higher 
score indicating worse PTSD symptoms.  
Exploratory Outcomes 
PCL-5 Score 
Continuous (range 
between 0 and 80) 
The PCL-5 is a 20-item self-report measure that assesses the 20 DSM-5 
symptoms of PTSD. Its purposes include screening for PTSD and/or provisional 
diagnosis, and monitoring symptom change before, during, and after treatment. A 
total symptom severity score ranging from 0 to 80 is possible (Weathers et al., 
2013).  The score is calculated by summing each of the 20 DSM-5 PTSD 
questions, with a higher score indicating worse PTSD symptoms. 
PHQ-9 Score 
Continuous (range 
between 0 and 27) 
Depression symptoms will be assessed using the validated PHQ-9 (Kroenke, 
Spitzer, & Williams, 2001) in support of exploratory analyses. The PHQ-9 was 
developed as a short form of the full Patient Health Questionnaire (which was a 
self-administered version of the PRIME-MD instrument). Severity scores range 
from 0 to 27, with a score of 5 to 9 representing mild depression, a score of 10 to 
14 representing moderate depression, and a score of 15 or greater representing a 
severe level of depression (Kroenke et al., 2001).  
VR-12 Scores (physical 
and mental health 
summaries) 
Continuous (T-
score with a mean 
of 50 and standard 
deviation of 10) 
The VR-12© was developed from the Veterans RAND 36 Item Health Survey 
(VR-36©; formerly called the Veterans SF-36), which was adapted from the 
RAND 36-Item Health Survey (RAND 36 version 1.0) at the RAND Corporation 
and the Medical Outcomes Study. The twelve items provide an estimate for eight 
domains of functional health and well-being: physical functioning, role-physical, 
bodily pain, general health, vitality, social functioning, role-emotional, and 
mental health. Together, the first four domains constitute a Physical Health 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
 
   
Draft 4.0 2023-04-19; Page 22   
 
Variable 
Type 
Definition 
summary (PCS) measure, and the second 4 constitute a Mental Health summary 
(MCS) measure (Ware, Kosinski, & Keller, 1996). PCS and MCS scores are 
derived using an algorithm that is referenced to a metric centered at 50.0 using the 
2000–2002 US Medical Expenditure Panel Survey population. 
Phosphatidyl ethanol 
(PEth) 
Continuous (range 
between 0 and >210 
ng/mL) 
Phosphatidyl ethanols (PEth) are a series of abnormal phospholipids located in 
the cell membrane and formed in the presence of ethanol and phospholipase D. 
PEth serves as a biomarker of alcohol ingestion in the past 2-3 weeks using liquid 
chromatography tandem mass spectrometric assessment of human blood (whole 
or dried spots). PEth in blood if often used as a marker of chronic alcohol use and 
was collected at baseline and weeks 8 and 12. 
At the present time, the international scientific community has not yet established 
a cut-off value for PEth concentration in blood to be used for differentiating an 
acceptable social ethanol intake (<40 g for males and <20 g for females, 
according to the WHO parameters), from an at-risk-alcohol-use (40–60 g/die) and 
chronic excessive drinking behavior (>60 g/die). However, per LabCorp, PEth 
levels in excess of 20 ng/mL are considered evidence of moderate to heavy 
ethanol consumption. 
Safety Outcomes  
Adverse Events  
Counts and 
proportions 
Total number and proportion of treatment emergent adverse events. Comparison 
of AE rates by treatment group will also be stratified by type and severity. 
Withdrawals due to 
Adverse Events  
Proportion 
Proportions of individuals by treatment group who withdrew from the study due 
to adverse events 
 
Adherence and Retention Outcomes 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
 
   
Draft 4.0 2023-04-19; Page 23   
 
Variable 
Type 
Definition 
Serum Buprenorphine and 
Norbuprenorphine 
Continuous 
Buprenorphine and its metabolite norbuprenorphine are assayed using liquid 
chromatography tandem mass spectrometry by a commercial laboratory. Sample 
results are available via the commercial laboratory portal using a study specific 
username/password combination and the unique participant code/requisition 
number.  
 
To assess medication adherence, blood samples collected at study weeks 8 and 12 
will be tested for buprenorphine and its metabolite, norbuprenorphine, using 
quantitative assessments. 
Pill Count 
Count and 
proportion 
A dosing log case report form (CRF) is completed weekly (or since the last in-
person visit) for each participant. The number of completed NTX injections 
received (at baseline, week 4, and week 8) is recorded, as well as the number of 
missed SL-BUP pills per week. For each medication (NTX and SL-BUP), the 
proportion of subjects who missed any treatment will be derived, as well as the 
total number of missed injections or pills, per participant. 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 24   
 
9.3 Primary Efficacy Analysis Methods 
The primary outcome for this study is a binary measure assessed at weeks 4, 8, and 12. A positive 
response is defined as a decrease from baseline of at least 10 points on the CAPS-5 score 
(Schnurr et al., 2022) and a reduction of at least 1 risk level of alcohol use, as defined by WHO 
(Knox et al. 2018). The treatment effect on comorbid PTSD + AUD over time will be assessed 
using a mixed logistic regression model. The model will be used to generate point and interval 
estimates of the risk differences and to test differences in proportions of PTSD+AUD resolution 
between treatment groups at the 8-week visit (primary timepoint), as well as at weeks 4 and 12 
(secondary timepoints). The model will include fixed effects for the treatment group, visit (as a 
categorical variable), gender, site, presence/absence of anti-depressants, treatment-by-visit 
interaction, and random effects for participant (see model statement below). This approach will 
provide consistent estimates and valid inferences under missing at random (MAR) data 
assumptions while accounting for correlation among multiple measures on the same participant. 
This mixed model will improve the power of the study and the precision of all estimates by 
allowing all available measures for an individual to be incorporated in the analysis, even if other 
timepoints are missing. Sensitivity analysis maybe considered by excluding participants that have 
a low or moderate WHO risk level at baseline. This model is further described below: 
g(E(Yij)) = β0 + β1Visitij + β2Siteij + β3Treatmentij + β4Genderij + β5Anti-depressantij + 
β6(Treatment*Visit)i + si + εij 
Where g(E(.)) indicates the identity link function on the expected value of Y, Yij is the jth 
measure of PTSD+AUD measurement in subject i, β0 is the intercept, β1 through β6 are 
coefficients, si is a random subject effect and εij is the residual error term.  
Statistical analysis modeling will be carried out utilizing SAS/STAT PROC GLIMMIX (SAS 
Institute Inc. 2017) with the general structure of the SAS code for this model is listed below. 
Generalized linear mixed models (GLMMs) are a flexible generalization of the linear mixed 
effect model that allows response outcomes to have an error distribution other than the normal 
distribution (McCullagh, & Nelder, 1989). The GLMM will employ random intercepts for the 
between participants’ part of the covariance model, and the within participants’ part of the 
covariance model will be initially assumed as autoregressive. The study’s primary hypothesis will 
be tested and associated odds ratio obtained using the ‘oddsratio’ statement which estimates the 
risk difference in PSTD+AUD resolution between the treatment arms.  
 
proc glimmix data=anlydata; 
   class patient treat gender visit site antidepress; 
   model primoutcome = treat gender visit site antidepress  
   treat*visit/ solution link=logit dist=binary oddsratio; 
   random int / type=ar(1) subject=patient; 
   ods select parameterestimates Oddsratios; 
run; 
 
9.3.1 CAPS 
As mentioned above, the CAPS-5 is a continuous measure that is assessed at baseline and 
weeks 4, 8, and 12. The CAPS-5 Total Symptom Severity Score ranges from 0 to 80, with 
higher scores indicating greater PTSD symptoms (Weathers et al., 2018). The treatment 
effect on the clinical criteria of PTSD as measured by the CAPS-5 over time will be 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 25   
 
assessed using a generalized-linear mixed model to account for temporal correlation 
between measurements and the clustering of the data. This model will include fixed effects 
for treatment group, visit (as a categorical variable), gender, site, presence/absence of anti-
depressants, and a treatment-by-visit interaction term, and a random effect for participant 
(see model statement below).  
 
Yij = β0 + β1Visitij + β2Siteij + β3Treatmentij + β4Genderij + β5Anti-depressantij + 
β6(Treatment*Visit)i + si + εij 
Where Yij is the jth measure of CAPS-5 in subject i, β0 is the intercept, β1 through β6 are 
coefficients, si is a random subject effect and εij is the residual error term.  
 
Statistical analysis modeling will be carried out utilizing SAS/STAT PROC MIXED 
(Littell, Milliken, Stroup, Wolfinger, & Schabenberger, 2006) with the general structure of 
the SAS code for this model shown below. Adjusted marginal means (also called LS means) 
will be used to report and test for differences in mean change in CAPS-5 score at 8 weeks 
for the placebo and BUP/NTRX groups, providing 95% confidence intervals and a p-value 
for the difference between them.  
 
proc mixed data = anlydata; 
 
class patient treat gender visit site antidepress; 
  
model CAPS5_Score = treat gender visit site antidepress  
    treat*visit /s; 
 
random int / subject= patient; 
 
repeated visit / type=cs subject= patient;  
 
lsmeans treat*visit;  
run; 
 
9.3.2 %HDD 
As mentioned above, %HDD is assessed by the TLFB and is collected at baseline and 
weeks 2, 4, 6, 8, 10, and 12. The treatment effect on the clinical criteria of AUD as 
measured by %HDD over time will be assessed using a generalized-linear mixed model to 
account for temporal correlation between measurements and the clustering of the data. A 
similar model to that listed in Section 9.3.1 will be run to produce adjusted marginal means 
to report and test for differences in mean %HDD for the placebo and BUP/NTRX groups, 
providing 95% confidence intervals and a p-value for the difference between them. NOTE: 
the lookback period to derive %HDD will be performed at 28-days, each derived measure at 
a specific timepoint based on the baseline visit date. Sensitivity analysis maybe also 
performed using a 14-day look-back period. 
 
9.4 Exploratory Efficacy Analysis Methods 
 
9.4.1 PCL-5 
While the CAPS-5 is considered the gold standard for diagnosing PTSD, the PCL-5 is often 
used to screen for PTSD and monitor symptom changes before, during, and after treatment. 
A total symptom severity score ranges from 0 to 80 (Weathers et al., 2013).  The PCL-5 is 
collected at baseline and weeks 1, 2, 4, 6, 8, 10, and 12. The treatment effect on PTSD as 
measured by the PCL-5 over time will be assessed using a generalized-linear mixed model 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 26   
 
to account for temporal correlation between measurements and the clustering of the data. A 
similar model to that listed in Section 9.3.1 will be run to produce adjusted marginal means 
to report and test for differences in mean PCL-5 for the placebo and BUP/NTRX group, 
providing 95% confidence intervals and a p-value for the difference between them.  
 
9.4.2 PHQ-9 
The PHQ-9 is the major depressive disorder (MDD) module of the full PHQ. This 
instrument is used to provisionally screen, diagnose, and monitor depression and grade 
severity of symptoms in general medical and mental health settings (Kroenke K., Spitzer R., 
Williams, J., 2001). A total symptom severity score ranges from 0 to 27. The PHQ-9 is 
collected at baseline and weeks 4, 8, and 12. The treatment effect on depression as 
measured by the PHQ-9 over time will be assessed using a generalized-linear mixed model 
to account for temporal correlation between measurements and the clustering of the data. A 
similar model to that listed in Section 9.3.1 will be run to produce adjusted marginal means 
to report and test for differences in mean PHQ-9 for the placebo and BUP/NTRX group, 
providing 95% confidence intervals and a p-value for the difference between them. 
 
9.4.3 VR-12 
The VR-12 is a patient-reported global health measure that is used to assess a patient’s 
overall perspective of their health (Jones, Kazis, Lee, et al., 2001). Answers on the 12-item 
questionnaire are summarized into two scores, a physical component score (PCS) and a 
mental component score (MCS). The PCS and MCS scores are derived using an algorithm 
that is referenced to a metric centered at 50.0 (with a standard deviation of 10) using the 
2000–2002 US Medical Expenditure Panel Survey population. The VR-12 is collected at 
baseline and weeks 8 and 12. The treatment effect on these global health measures over 
time will be assessed using a generalized-linear mixed model to account for temporal 
correlation between measurements and the clustering of the data. A similar model to that 
listed in Section 9.3.1 will be run to produce adjusted marginal means to report and test for 
differences in mean PCS and MCS for the placebo and BUP/NTRX group, providing 95% 
confidence intervals and a p-value for the difference between them. 
 
9.4.4 Phosphatidyl Ethanol (PEth) 
Testing for phosphatidyl ethanol (PEth) is a relatively new tool for detecting and grossly 
quantifying a person's chronic alcohol consumption. PEth values were collected at baseline 
and weeks 8 and 12. At each collection timepoint, results were reported as either “positive” 
or “negative”, and if “positive”, the PEth value in the blood was reported in ng/mL. For 
analysis purposes, “negative” results will have a PEth value inputted as 5 ng/mL, the 
midpoint of the ‘not detectable range’ (which is reported as less than 10 ng/mL). The 
treatment effect on PEth measurement over time will be assessed using a generalized-linear 
mixed model to account for temporal correlation between measurements and the clustering 
of the data. A similar model to that listed in Section 9.3.1 will be run to produce adjusted 
marginal means to report and test for differences in mean PEth for the placebo and 
BUP/NTRX group, providing 95% confidence intervals and a p-value for the difference 
between them. 
 
9.5 Safety Analysis Methods 
9.5.1 Adverse Events 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 27   
 
Any AEs will be listed and summarized by system organ class and preferred event term.  
Summaries will include the number of individuals experiencing events over the duration of 
the study. These summaries will be created for all AEs and AEs by severity (mild or 
moderate vs. severe or greater). Summaries will be provided by treatment group. If models 
can be run, point and confidence interval estimates of the risk difference will be obtained by 
modeling the probability of experiencing at least one adverse event. The model is specified 
with the equation: 
 
g(E(Yij)) = β0 + β1Treatmentij + si + εij 
Where g(E(.)) indicates the identity link function on the expected value of Y, Yij is the 
occurrence of an AE outcome (any AE, any SAE, and any related AE) in subject i, β0 is the 
intercept, β1 is the treatment group coefficients, si is a random subject effect, and εij is the 
residual error term.  
Point and confidence intervals for the difference in experienced AE proportion between 
treatment groups will be estimated with a generalized linear mixed model (GLMM), 
assuming a binomial distribution and identity link. GLMMs are a flexible generalization of 
the linear mixed effect model that allows response outcomes to have an error distribution 
other than the normal distribution (McCullagh, & Nelder, 1989). Statistical analysis 
modeling will be carried out utilizing SAS/STAT PROC GLIMMIX (SAS Institute Inc. 
2017) with the general structure of the SAS code for this model is listed below: 
proc glimmix data=anlyaedata; 
   class patient treatment; 
   model any_ae = treatment / link=identity dist=binomial; 
   random int / subject=patient; 
run; 
 
A similar model will be run for the difference in proportion of withdrawn subjects due to 
adverse events between treatment groups. If the above specified models cannot be fit due to 
limitations of the study data, frequencies will be analyzed using chi-square test. 
9.6 Adherence and Retention Analysis Methods 
9.6.1 Buprenorphine and Norbuprenorphine Assays 
Buprenorphine and its metabolite norbuprenorphine are assayed using liquid 
chromatography tandem mass spectrometry by a commercial laboratory at weeks 8 and 12. 
Processed blood samples to quantify and compare the amount of buprenorphine and 
norbuprenorphine at weeks 8 and 12 by treatment group will be evaluated using an 
independent group T-test. 
 
9.6.2 Pill Count and Received Injections 
A self-report medication adherence case report form (CRF) is administered at each visit to 
document the completion of NTX injection and the number of missed and taken SL-BUP 
pills. For each medication (NTX and SL-BUP), the proportion of subjects who missed any 
treatment will be derived, as well as the total number of missed injections or pills per visit 
by treatment group. Differences in self-reported medication adherence by treatment group 
will be presented in the form of line bars (numbers of missed SL-BUP pills) or bar charts 
(proportion of missed NTX injections). 


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 28   
 
10 REFERENCES 
Benjamini, Y. and Hochberg, Y. (1995) Controlling the False Discovery Rate: A Practical and 
Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society, Series B, 57, 
289-300. 
Jones D., Kazis L., Lee A., Rogers W., Skinner K., Cassar L., Wilson N., Hendricks A. Health status 
assessments using the Veterans SF-36 and SF-12. Methods for evaluating outcomes in the 
Veterans Health Administration. Journal of Ambulatory Care Management 2001; 24(3):1-19. 
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J 
Gen Intern Med. 2001;16(9):606–613. doi:10.1046/j.1525-1497.2001.016009606.x 
Knox J, Wall M, Witkiewitz K, Kranzler HR, Falk D, Litten R, Mann K, O'Malley SS, Scodes J, 
Anton R, Hasin DS; Alcohol Clinical Trials (ACTIVE) Workgroup. Reduction in Nonabstinent 
WHO Drinking Risk Levels and Change in Risk for Liver Disease and Positive AUDIT-C Scores: 
Prospective 3-Year Follow-Up Results in the U.S. General Population. Alcohol Clin Exp Res. 
2018 Nov;42(11):2256-2265. doi: 10.1111/acer.13884. Epub 2018 Oct 3. PMID: 30204248; 
PMCID: PMC6263142.Littell, R. C., Milliken, G. A., Stroup, W. W., Wolfinger, R. D., and 
Schabenberger, O. (2006). SAS® for Mixed Models, Second Edition, Cary, NC: SAS Institute Inc. 
McCullagh, P, & Nelder, J. A. (1989). Generalized Linear Models, 2nd ed. Chapman & Hall/CRC 
Press. 
SAS Institute Inc. 2017. SAS/STAT® 14.3 User’s Guide. Cary, NC: SAS Institute Inc. 
Sobell LC, Sobell MB, Buchan G, Cleland PA, Fedoroff I, Leo GI (1996). The reliability of the 
Timeline Followback method applied to drug, cigarette, and cannabis use. Paper presented at the 
30th Annual Meeting of the Association for Advancement of Behavior Therapy, New York, NY, 
November 1996. 
Schnurr PP, Chard KM, Ruzek JI, et al. Comparison of Prolonged Exposure vs Cognitive Processing 
 
Therapy for Treatment of Posttraumatic Stress Disorder Among US Veterans: A Randomized 
 
Clinical Trial. JAMA Netw Open. 2022;5(1):e2136921. Published 2022 Jan 4. 
 
doi:10.1001/jamanetworkopen.2021.36921 
Ware, J., Kosinski, M., Keller, SD. (1996). A 12-Item Short-Form Health Survey: construction of 
scales and preliminary tests of reliability and validity. Med Care, 34, 220-33. 
Doi:10.1097/00005650-199603000-00003. 
Weathers F., Litz B., Keane T., Palmieri T., Marx B., Schnurr P. (2013). The PTSD Checklist for 
DSM-5 (PCL-5). Scales available from the National Center for PTSD at www.ptsd.va.gov 
Weathers, F. W., Bovin, M. J., Lee, D. J., Sloan, D. M., Schnurr, P. P., Kaloupek, D. G., & Marx, B. 
P. (2018). The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): Development and 
initial psychometric evaluation in military Veterans. Psychological Assessment, 30, 383-395. 
doi:10.1037/pas0000486. 
Appendix A DSMB Report 
 
The following will be included in a report provided for periodic review of the study by the DSMB 
committee: 
 
a) A summary table of demographic information on all participants including age, sex, race, 
ethnicity, and whether the participant has served in the US military.  


Network 
AS140026-A5 Statistical Analysis Plan 
 
 
 
   
Draft 4.0 2023-04-19; Page 29   
 
b) A summary table of disposition. Specifically: # of individuals consented, randomized, 
admitted, and completing each study visit, as well as final disposition based on final study 
status. 
c) A summary table of overall study therapy receipt and completion.  Specifically: Proportion of 
BUP doses taken and missed and NTX injections received. 
d) A listing of all adverse events (including SAEs) and summary of proportion of subjects by 
day with at least one AE. 
e) A listing of all protocol deviations and summary of proportion of subjects with at least one 
deviation. 
f) Tabulation of primary and exploratory endpoints by study site. 
 
Appendix B List of Potential Tables and Figures 
Tables 
a) Demographics and Baseline Characteristics by Treatment Group 
b) Comparison of Primary Composite Outcome Measure by Treatment Group 
c) Comparison of Change in %HDD by Treatment Group 
d) Comparison of Change in CAPS-5 by Treatment Group 
e) Comparison of Change in PCL-5 by Treatment Group 
f) Comparison of Change in PHQ-9 by Treatment Group 
g) Comparison of Change in VR-12 Measures by Treatment Group 
h) Comparison of AEs by Treatment Group 
Figures 
a) Study CONSORT 
b) Line plots with error bars for mean change from baseline by treatment group for the 
following outcome measures: CAPS-5, %HDD, PCL-5, PHQ-9, and VR-12 
c) Box and whisker plots for vital measures 
d) Bar charts for missed SL-BUP and NTX injections by treatment group