Developing and Evaluating a Positive Valence Treatment for Alcohol Use Disorder With Anxiety or Depression
Phase: NA
Conditions: Alcohol Use Disorder, Anxiety, Depression
Sponsor: Laureate Institute for Brain Research, Inc.

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Developing and Evaluating a Positive Valence 
Treatment for Alcohol Use Disorder with Anxiety or 
Depression. 
Protocol Number: 2022-003 
National Clinical Trial (NCT) Identified Number:  <Number, once assigned by 
CT.gov> 
Principal Investigator:  Robin Aupperle, PhD 
Sponsor: Laureate Institute for Brain Research 
“Sponsor” indicates an institution, foundation, or individual who takes responsibility for and initiates a 
clinical investigation; often times this is the university with which the Principal Investigator is affiliated.  
Grant Title: Developing and Evaluating a Positive Valence Treatment for Alcohol 
Use Disorder with Anxiety or Depression. 
Grant Number:  R34 AA030688 
Funded by: The William K. Warren Foundation 
Version Number:  v.2.0 
04 April 2023 

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CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by 
the recipient that no unpublished information contained herein will be published or disclosed without 
prior approval of the Principal Investigator or other participating study leadership.  
 

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
INVESTIGATOR’S SIGNATURE .............................................................................................................................. 2 
1 
PROTOCOL SUMMARY ............................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................................ 3 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities .......................................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale .................................................................................................................................... 8 
2.2 
Background........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................. 10 
2.3.1 
Known Potential Risks ................................................................................................... 10 
2.3.2 
Known Potential Benefits .............................................................................................. 16 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 16 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 16 
4 
STUDY DESIGN ........................................................................................................................................... 18 
4.1 
Overall Design .................................................................................................................................... 18 
4.2 
Scientific Rationale for Study Design.............................................................................................. 18 
4.3 
Justification for Intervention ............................................................................................................. 19 
4.4 
End-of-Study Definition ..................................................................................................................... 19 
5 
STUDY POPULATION ................................................................................................................................ 19 
5.1 
Inclusion Criteria ................................................................................................................................ 19 
5.2 
Exclusion Criteria ............................................................................................................................... 20 
5.3 
Lifestyle Considerations .................................................................................................................... 21 
5.4 
Screen Failures .................................................................................................................................. 21 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 21 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ............................................ 23 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ...................................... 23 
6.1.1 
Study Intervention or Experimental Manipulation Description ................................. 23 
6.1.2 
Administration and/or Dosing ....................................................................................... 23 
6.2 
Fidelity ................................................................................................................................................. 24 
6.2.1 
Interventionist Training and Tracking .......................................................................... 24 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 24 
6.4 
Study Intervention/Experimental Manipulation Adherence.......................................................... 24 
6.5 
Concomitant Therapy ........................................................................................................................ 25 
6.5.1 
Rescue Therapy ............................................................................................................. 25 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................................... 25 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ............................................. 25 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 26 
7.3 
Lost to Follow-Up ............................................................................................................................... 26 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 27 
8.1 
Endpoint and Other Non-Safety Assessments .............................................................................. 27 
8.2 
Safety Assessments .......................................................................................................................... 31 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 31 
8.3.1 
Definition of Adverse Events ........................................................................................ 31 

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8.3.2 
Definition of Serious Adverse Events .......................................................................... 31 
8.3.3 
Classification of an Adverse Event .............................................................................. 32 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 33 
8.3.5 
Adverse Event Reporting .............................................................................................. 33 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 34 
8.3.7 
Reporting Events to Participants ................................................................................. 34 
8.3.8 
Events of Special Interest ............................................................................................. 34 
8.3.9 
Reporting of Pregnancy ................................................................................................ 34 
8.4 
Unanticipated Problems .................................................................................................................... 34 
8.4.1 
Definition of Unanticipated Problems .......................................................................... 34 
8.4.2 
Unanticipated Problems Reporting .............................................................................. 35 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 35 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 35 
9.1 
Statistical Hypotheses ....................................................................................................................... 35 
9.2 
Sample Size Determination .............................................................................................................. 36 
9.3 
Populations for Analyses .................................................................................................................. 36 
9.4 
Statistical Analyses............................................................................................................................ 36 
9.4.1 
General Approach ................................................................................................ ……3636 
9.4.2 
Analysis of the Primary Endpoint(s) ........................................................................ 3636 
9.4.3 
Analysis of the Secondary Endpoint(s) ........................................................................... 
9.4.4 
Safety Analyses .............................................................................................................. 36 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 38 
9.4.6 
Planned Interim Analyses ............................................................................................. 38 
9.4.7 
Sub-Group Analyses ..................................................................................................... 38 
9.4.8 
Tabulation of Individual Participant Data .................................................................... 38 
9.4.9 
Exploratory Analyses ..................................................................................................... 38 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 39 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 39 
10.1.1 
Informed Consent Process ........................................................................................... 39 
10.1.2 
Study Discontinuation and Closure ............................................................................. 40 
10.1.3 
Confidentiality and Privacy ........................................................................................... 40 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 41 
10.1.5 
Key Roles and Study Governance .............................................................................. 41 
10.1.6 
Safety Oversight ............................................................................................................. 41 
10.1.7 
Clinical Monitoring .......................................................................................................... 42 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 42 
10.1.9 
Data Handling and Record Keeping ............................................................................ 42 
10.1.10 
Protocol Deviations ........................................................................................................ 43 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 43 
10.1.12 
Conflict of Interest Policy .............................................................................................. 43 
10.2 
Additional Considerations ................................................................................................................. 43 
10.3 
Abbreviations and Special Terms ................................................................................................... 43 
11 
REFERENCES ............................................................................................................................................. 46 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 
21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
 
Study investigators and staff who are responsible for the conduct, management, or oversight of this 
clinical trial have completed Human Subjects Protection and ICH GCP Training. 
 
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(s) 
must be obtained before any participant is consented. 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(s) will be IRB approved; a determination will be made regarding whether a new consent 
needs to be obtained from participants who provided consent, using a previously approved consent 
form. 
 
 

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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines. 
 
Principal Investigator: 
Signed: 
 
Date: 
 
 
Name:  Robin Aupperle, PhD 
 
Title: 
Principal Investigator, Laureate Institute for Brain Research (LIBR) 
 
Investigator Contact Information 
Affiliation: Laureate Institute for Brain Research (LIBR) 
Address: 6655 S. Yale Ave., Tulsa, OK 74136 
Telephone: 918-502-5744 
Email: raupperle@libr.net 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title:
Developing and Evaluating a Positive Valence Treatment for Alcohol Use 
Disorder with Anxiety or Depression  
Grant Number:
R34 AA030688 (NOA not yet received)
 
Study Description:
The proposed study consists of two phases. During Phase 1, we will 
recruit a small sample of participants to complete a psychosocial 
intervention termed Affective Modulation of Positivity (AMP) for 
individuals suffering from comorbid depression or anxiety disorders and 
alcohol use disorder (AMP-A). These participants will be asked to provide 
both qualitative and quantitative input about the AMP-A intervention. 
Based on their input and clinician input, the AMP-A manual will be 
modified for use in Phase 2. The goal is to recruit up to 20 participants in 
order to ensure we have at least 8 participants who complete all sessions 
of AMP-A. Phase 2 is a randomized clinical trial (RCT) protocol in which 
individuals suffering from comorbid depression or anxiety disorders and 
alcohol use disorder will be randomized to complete AMP-A or a more 
traditional cognitive-behavioral therapy (CBT) intervention. We will 
recruit up to 100 participants in order to reach a target of N=60. Assessed 
outcomes will include participant acceptability and completion rates, 
participant compliance with the intervention, positive and negative 
affect, substance use- and depression and anxiety-related symptom 
severity, functional disability, and neural reactivity to reward and alcohol 
cues during functional magnetic resonance imaging (fMRI).  
 
Objectives:
 
Primary Objective: For Phase 1, the primary objective is to assess 
participant and clinician feedback on acceptability and satisfaction of the 
AMP-A intervention. For Phase 2, the primary objective is to  assess for 
potential clinical utility of AMP-A utilizing an RCT comparison of AMP-A 
and CBT interventions. The primary outcome for the RCT will be positive 
affect at the post-treatment time point.  
 
Secondary Objectives: Secondary outcomes for the RCT include social 
connectedness and psychological well-at the post-treatment time point. 
 
Tertiary/Exploratory Objectives: Exploratory outcomes for the RCT phase 
include anticipation, responsiveness, and recall of positive (non-drug) 
experiences and positive reinforcement motives to use alcohol, level of 
alcohol use and anxiety and depression symptoms, as well as neural 
reactivity to reward and alcohol cues during fMRI.  
Endpoints:
Primary Endpoint: Post-treatment (i.e., within two weeks of completing 
the intervention). 
Secondary Endpoints: Three month follow-up (i.e., 12-15 weeks after 
completing the intervention) 

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Study Population:
For Phase 1, the goal is to recruit up to 20 participants in order to ensure 
we have at least 8 participants who complete all sessions of AMP-A.  
Participants will be adults, age 18-65, meeting diagnostic criteria for 
alcohol use disorder and elevated anxiety or depressive symptoms. All 
genders, races, and ethnicities will be included. Phase 2 will include up to 
100 participants to be enrolled and randomized to AMP-A versus CBT, 
using the same inclusion/exclusion criteria as Phase 1. Participants who 
meet additional safety criteria for being able to complete MRI will also be 
offered the opportunity to complete these aspects of the Phase 2 
protocol.  
Phase or Stage:
Phase I/II
Description of 
Sites/Facilities Enrolling 
Participants: 
Laureate Institute for Brain Research (Tulsa, OK) is the only site enrolling 
participants in this study. 
 
Description of Study 
Intervention/Experimental 
Manipulation: 
In Phase 1, the study intervention will consist of 12 sessions of AMP-A
conducted in individual sessions. Each session will last approximately 1 
hour in duration and sessions will be scheduled once or twice weekly. In 
Phase 2, the study interventions will consist of 12 sessions of either AMP-
A or CBT conducted in individual sessions lasting approximately 1 hour in 
duration and scheduled once or twice weekly. 
Study Duration:
24 months
Participant Duration:
18 – 24 weeks
1.2 
SCHEMA  
Phase 1 
 
Total N: 8 completers (up to 20 enrolled) 
Pre-screen potential participants by inclusion and exclusion criteria as part of the Screening 
protocol (WIRB # 20101611) and additional self-report/interview assessments

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Visit 1 
 
 
 
 
 
 
 
 
 
Visit 2-13 
 
  
 
Visit 14-15 
 
 
 
 
 
Visit 16 
 
All participants receive positive 
affect training  
Administer study intervention Sessions 1-12 and self-report questionnaires, alcohol 
breathalyzer 
Post-Intervention assessments 
Self-report and feedback questionnaires and interviews, urine drug test, alcohol breathalyzer (see 
Section 1.3, Schedule of Activities) 
3 month follow-Up assessment 
Self-report and feedback questionnaires and interviews, urine drug test, alcohol breathalyzer (see 
Section 1.3, Schedule of Activities) 
Conduct informed consent process and baseline assessments for current protocol:  
Self-report questionnaires and interviews, alcohol breathalyzer, urine drug test 
(see Section 1.3, Schedule of Activities)

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Phase 2 
 
 
 
  
 
 
Visit 1 
 
 
 
 
 
 
 
 
 
Visit 2-13 
 
  
 
Visit 14-15 
 
 
 
 
 
Visit 16 
 
 
 
 
 
 
Total N: 80 
Pre-screen potential participants by inclusion and exclusion criteria as part of the Screening 
protocol (WIRB # 20101611) and additional self-report/interview assessments
Participants randomized to receive positive affect 
training or CBT 
Administer study intervention Sessions 1-12 and self-report questionnaires 
Post-Intervention assessments 
Self-report questionnaires and interviews, urine drug test, alcohol breathalyzer, neuroimaging 
(see Section 1.3, Schedule of Activities) 
3 month follow-Up assessment 
Self-report questionnaires and interviews, urine drug test, alcohol breathalyzer (see Section 1.3, 
Schedule of Activities) 
Conduct informed consent process and baseline assessments for current protocol:  
Self-report questionnaires and interviews, alcohol breathalyzer, urine drug test 
(see Section 1.3, Schedule of Activities)

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1.3 
SCHEDULE OF ACTIVITIES  
Phase 1: 
 
Phase 2: 
 
Pre-screening 
(Pre-consent) 
 
Visit 1 
(pre-training) 
Visits 2-13 
(training) 
 
Visit  14-15  
(post-training) 
Visit 16  
(3 month 
follow-up) 
Review Eligibility from LIBR Screening Protocol (includes 
demographics, clinical history) 
X (as part of 
Screening 
protocol) 
 
 
MINI/PHQ/OASIS/PHEN-X 30 Day 
X 
X
 
 
Informed Consent 
 
X 
 
 
Outcome Evaluation 
 
 
 
 
PROMIS Alcohol Use,  Positive Affect, 
Depression, Anxiety, and Meaning and 
Purpose, NIH Toolbox Loneliness, Sheehan 
Disability Scale, Homework Rating Scales, 
Working Alliance Inventory, adherence and 
acceptability scale, Distress/Endorsement 
Validation Scale, Timeline Followback 
 
X 
X 
X 
X 
All other self-report measures
 
X 
 
X 
X 
Feedback Questionnaires 
 
X 
X 
X 
X
Qualitative feedback interviews
 
 
 
X 
Intervention – AMP-A
 
 
X 
 
 
Pre-screening 
(Pre-consent) 
 
Visit 1 
(pre-training) 
Visits 2-13 
(training) 
 
Visit  14  
(post-training) 
Visit 15  
(3 month 
follow-up) 
Review Eligibility from LIBR Screening Protocol (includes 
demographics, clinical history) 
X (as part of 
Screening 
protocol) 
 
 
MINI/PHQ/OASIS/PHEN-X 30 Day 
X 
X
 
 
Informed Consent 
 
X 
 
 
PRISM-5 to confirm AUD diagnosis 
 
X 
 
 
Columbia Suicide Severity Rating Scale 
 
X 
 
X 
Outcome Evaluation 
 
 
 
 
PROMIS Alcohol Use,  Positive Affect, 
Depression, Anxiety, Sheehan Disability Scale, 
Homework Rating Scales, Working Alliance 
Inventory, adherence and acceptability scale, 
Distress/Endorsement Validation Scale, 
Timeline Followback 
 
X 
X 
X 
X 
All other self-report measures
 
X 
 
X 
X 
Structural and functional neuroimaging
 
X 
 
X 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Substance use disorder is a problem that impacts 21.6 million people in the United States, with 
prevalence rates of the disorders and associated mental health outcomes (i.e., suicide) increasing 
significantly over the past decade1-6. The 12-month prevalence of alcohol use disorder specifically is 
approximately 9%7.  Substance use disorder, including alcohol use disorder, is characterized by 
enhanced neural responsivity to drug (alcohol) cues, but reduced neural responsivity to non-drug 
reward cues8-11. These effects may be exacerbated by comorbid major depressive disorder (MDD) or 
symptoms of anhedonia12, comorbidities which are particularly high amongst alcohol use disorder7. 
Response rates for current interventions with alcohol use disorder are rather poor, with only 58% 
experiencing benefits greater than control conditions13. There is a need to identify interventions that 
may target reward responsivity in a way that would promote recovery, reduce affective disturbance, and 
support better long-term functioning for individuals suffering from alcohol use disorder and comorbid 
depression and anxiety disorders. Positive affect interventions have recently been developed and tested 
in other populations (i.e., HIV, anxiety/depression) as a way of enhancing positive valence and reward 
processing14 15. These interventions have shown significant promise in these populations, but have yet to 
be examined in the context of alcohol use disorder. The current pilot study would test the feasibility and 
acceptability of an 12-session protocol of positive affect training with populations suffering from 
comorbid alcohol use disorder and depression or anxiety disorders, and explore the impact of the 
intervention on positive affect, negative affect, alcohol use and craving, and neural response patterns 
during reward and drug cue processing. The primary outcome for the current study is completion rate, 
with secondary outcomes including participant acceptability ratings. Exploratory outcomes include self-
reported positive affect symptoms, negative affect symptoms, anhedonia, Sheehan Disability Scale, 
alcohol breathalyzer use, time til first use, frequency of use, and striatal and OFC activation in response 
to alcohol cues and non-alcohol reward (monetary). Primary endpoint is the post-intervention time 
point (within 2 weeks of completing intervention), with secondary endpoint being the three month 
follow-up.  
 
2.2 
BACKGROUND  
 
 
Pre-screening 
(Pre-consent) 
 
Visit 1 
(pre-training) 
Visits 2-13 
(training) 
 
Visit  14  
(post-training) 
Visit 15  
(3 month 
follow-up) 
Intervention – AMP-A or CBT
 
 
X 
 

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Often considered to be the foundation of drug and alcohol treatment, psychosocial treatments can 
serve as stand-alone treatment or used in combination with pharmacological intervention while being 
implemented individually or within groups16 17.  A strong evidence base exists for several psychosocial 
treatments or interventions including cognitive-behavioral therapy (CBT), contingency management 
(CM), and motivational enhancement/motivational interviewing (MI)16 17.  A recent meta-analysis 
demonstrated that nearly 2.5 times as many substance- or alcohol-users achieved post-treatment 
and/or clinically significant abstinence when an intervention program included an evidence-based 
psychological treatment17. However, response rates for substance and alcohol use treatment are usually 
only small to moderate in effect and produce improvement over control conditions in only about 58% of 
cases13. Given this and the increased rates of substance and alcohol use, and the detrimental and 
catastrophic mental health outcomes (i.e., suicide), it is clear that novel treatments are needed that may 
target specific neural and behavioral deficits and that may improve rates of treatment response in both 
substance use and mental health domains.  
One of the hallmark characteristics of substance and alcohol use disorders involve increased desire for 
the drug, with the drug being excessively salient at the expense of other, more natural, reinforcers or 
rewards (i.e., social relationships, goal attainment, etc.9-11. Addiction across various substances is 
accompanied by alterations in blood flow and activity within reward processing regions (i.e., dopamine-
dependent sites), such as the striatum, amygdala, orbitofrontal cortex (OFC), and other prefrontal sites 
(i.e., anterior cingulate cortex [ACC], dorsolateral prefrontal cortex [dlPFC])18. However, substance and 
alcohol use disorder has also been found to relate to decreased neural sensitivity (i.e., within striatum, 
OFC, and amygdala) to non-drug reward, such as monetary reward or verbal feedback19-24. Appropriate 
valuation of natural reinforcers is known to be important for goal selection and action, and likely for 
motivating choices that are supportive of an individual’s future well-being…and thus important for 
recovery from addiction25. Indeed, there has been some indication that reward-related behavioral 
responses or brain activation/metabolites may be predictive of treatment outcome for substance use 
disorder, including alcohol use disorder specifically26-30. In addition, individuals with alcohol use 
disorders are at least 2 – 3.5 times more likely to be diagnosed with mood or anxiety disorders; with up 
to about 40% of patients meeting criteria for MDD or an anxiety disorder7 31. Mood and anxiety 
disorders, and the hallmark symptom of anhedonia, are also associated with reduced responsivity within 
reward circuitry, including striatum, OFC, and ACC regions32-34. Thus, enhancement of non-drug reward 
responsivity could be beneficial not only for addiction but also for comorbid symptoms of anxiety and 
depression.  
The positive affect system is thought to guide people toward situations with reward potential, and is 
characterized by positive emotions (e.g., joy, excitement, happiness), cognitions (e.g., attentional bias 
for reward-relevant stimuli), and approach behaviors (e.g., curiosity, social initiation) that together 
facilitate the acquisition of psychosocial resources that promote overall health and well-being15. 
Manualized positive affect interventions used in other populations are often conducted using either 5- 
or 10-session protocols that focus on enhance positive affect in several ways, including amplifying 
response to positive events, gratitude expression, acts of kindness, affirming values, engaging in 
meaningful activities, optimism, etc.  There is mounting evidence that it is possible to enhance positive 

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affect across a variety of populations, including normative populations35, depression36, anxiety15, and 
chronic health conditions (e.g., heart disease, HIV14 37. There is also initial evidence that interventions 
targeting aspects of positive affect (i.e., compassion training) may alter activity in reward circuitry, 
including the OFC and striatum38. While there has been a few studies using very specific interventions 
(e.g., gratitude exercises39) or more traditional cognitive-behavioral interventions that may enhance 
approach motivations (e.g., behavioral activation40), there have been no studies utilizing comprehensive, 
manualized interventions for enhancing multiple facets of positive affect with substance or alcohol use 
disorders. The current study would examine (1) the feasibility, acceptability, and potential utility of 
conducting an 12-session positive affect intervention (AMP-A) nwith populations experiencing comorbid 
alcohol use disorder and depressive or anxiety disorders and (2) the feasibility of a randomized clinical 
trial (RCT) protocol comparing a 12-session positive affect intervention (modified based on Phase 1) to a 
more traditional cognitive-behavioral therapy (CBT) intervention. 
We have conducted a prior study with AMP-A (LIBR Protocol # 2019-010-02), which was instrumental in 
helping us develop and refine the treatment manual, and provide rationale for application for grant 
funding. Thus, the current proposed, 2-phase study will further this work, developing the AMP-A 
intervention based on further piloting and examining initial clinical utility through an RCT.    
 
2.3 
RISK/BENEFIT ASSESSMENT  
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Potential Risks 
Risks associated with MRI (Phase 2 only): MRI scanning uses powerful magnetic fields and weak radio 
frequency pulses (electromagnetic radiation), neither of which has been associated with adverse 
effects in patients or laboratory animals when studied under clinical imaging protocols. However, as 
in the clinical setting, subjects must be free of any external or implanted ferrous material. People are 
at risk for injury from the MRI magnet if they have pacemakers or other implanted electrical devices, 
brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a large 
artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), 
permanent eyeliner, implanted delivery pump, or shrapnel fragments. Additionally, fast switching of 
the magnetic field gradients in some MRI pulse sequences may occasionally cause peripheral nerve 
stimulation that in some subjects produces muscle twitching or paresthesias, especially in the torso. 
Because MRI is performed in confined quarters, the feeling of being isolated or confined may cause 
physical discomfort, anxiety, or claustrophobia. It is expected that a very low percentage of subjects 
will be unable or unwilling to complete participation. The noise from the scanner is loud enough to 
damage hearing to the unprotected ear.  

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Risks associated with treatment: It is possible that participants may experience adverse effects to 
treatment in the form of worsening mental health or substance use symptoms or behaviors. 
Risks associated with screening, interviewing, and assessments: The risks of the screening evaluation 
and assessments are minimal and most likely risks include fatigue and discomfort or irritability with 
the nature of questions and/or testing procedures. Some of the questions in the interviews may be 
distressing or uncomfortable to answer and the most likely risk is psychological distress. 
 
Risks associated with Alcohol Cue Exposure: 
Risk: Alcohol cue exposure is a conventional method in experimental addiction studies. Functional 
neuroimaging with MRI (fMRI) with alcohol cue exposure tasks is a routine method to activate and 
depict neurocircuits involved in alcohol craving. There are over 300 published studies indexed at the 
National Library of Medicine’s website (www.pubmed.com) with alcohol cue exposure fMRI among 
alcohol users. The only risk that is associated with these paradigms other than minimal risks 
associated with fMRI in general is the increased level of alcohol craving among participants. 
 
Strategies for protecting against or minimizing all potential risks identified: 
Risks associate with MRI (phase2  only): A safety-screening questionnaire will be completed by each 
subject prior to entering the MR environment. The safety pre-screening questionnaire probes for 
subjects for possible occupational exposure to metal slivers or shavings remnants of which may 
remain lodged in the subjects head or neck. Subjects with surgical clips or shrapnel, cochlear 
implants, or any other form of ferrous metal body implanted in or on their body will be excluded. All 
subjects with any form of implant wires or electronic device implants will be excluded. All persons 
involved in this protocol will receive MR safety training conducted at LIBR by the Institute’s MR safety 
officer. 
 
To minimize the effects of peripheral nerve stimulation, we will employ MRI sequences that have 
been used at LIBR in thousands of scans with only a few reports of mild peripheral nerve stimulation. 
Additionally, subjects will be provided a squeeze ball by which they can notify the research team that 
the scan should be stopped should they experience muscle twitching. 
 
Pregnancy testing with immediate results will ensure that no pregnant participant receives an MRI. 
Any positive pregnancy test results would be discussed with the participant, and counseling will be 
provided should the participant indicate distress concerning the result. 
 
We intend to minimize claustrophobic problems using a series of procedures: 1) by giving a detailed 
explanation of the environment prior to scanning, 2) allowing subjects the opportunity to habituate 
to the scanner environment by resting in LIBR’s mock scanner prior to their real scan, 3) maintaining 
voice contact with the subjects at all times, 4) maintaining visual contact of the patient in the scanner 
using observational cameras placed inside the scanner room, and 5) providing subject an emergency 
squeeze ball to signal the MRI technician to stop. 

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To minimize the risk of hearing damage, all participants will be fitted with hearing protection and be 
required to wear the hearing protection for the duration of the MRI scanning. 
Plans for handling incidental findings: 
Incidental scan findings: In addition to standard T1-weighted MP-RAGE and functional fMRI EPI 
sequences used for the research component of the study, we will also obtain T2-weighted FLAIR 
images which are sensitive to CNS and white matter abnormalities. For each subject, a set of T1- and 
T2-weighted images will be sent via PACS and evaluated by a neuroradiologist (Integris Radiology 
Group, Oklahoma City, OK) for the presence of unanticipated abnormalities (e.g., tumors). The 
neuroradiologist will recommend referral to a physician if incidental findings are discovered which 
warrant follow-up evaluation. Upon detection of such incidental findings during MRI scanning, a 
physician researcher from LIBR will verbally communicate the discovery to the subject. The physician 
researcher will also provide written communication of the incidental finding to the subject. The 
written communication will guide the participant to make the discovery known to their primary-care 
physician. In addition, once the participant provides written consent authorizing the release of 
his/her medical records and MR images, LIBR will provide a digital copy of the MRI scans to the 
primary-care physician. Additionally, detection and disclosure of incidental findings will be 
documented in a database contained on LIBR's computer cluster. 
Strategies to manage and protect the privacy of participants and confidentiality of research data: 
We have instituted the following measures to protect the privacy of participants and confidentiality 
of research data: 
 Data will be collected by LIBR staff who completed training in human subjects’ research, HIPAA, 
and research integrity, on research data management, confidentiality and mandatory reporting, 
and project specific training on the protocol.   
 To protect confidentiality, no personally identifying information will be coded on questionnaires, 
interviews, brain imaging data, or other study records. Further, subjects will not be identified in 
any reports or publications. All de-identified hard-copy data will be stored in locked file cabinets 
in a locked office. A unique subject identification number is assigned to each participant, and 
linked to the study participant name in an electronic file managed in accordance with ISO 27000 
standards as specified below with access limited the PI, Study Psychiatrist or Physician, and 
designated Study Coordinator.   
 The original signed consents, screening form, locator form with contact information, the 
Research Privacy Form, and any other forms or papers containing personally identifiable 
information (PII) will be stored in a secured medical records room with access granted only to 
authorized study personnel. 
 Electronic data will be stored securely on servers and databases accessible only to study 
personnel. 
 

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Plans for ensuring necessary medical or professional intervention in the event of psychological 
distress, or worsening of mental health or substance use symptoms/behaviors: 
The researchers are trained to frequently inquire the subjects about their willingness and ability to 
continue with testing. If the subjects express concerns about continuing with testing, the research 
assistants will stop testing, offer a break, or, in case the subject is not willing to continue, terminate 
the testing session. If subjects report psychological distress, suicidal ideation, or intent to harm self or 
others, Dr. Aupperle, Dr. Paulus, or their licensed designee, will be contacted immediately to ensure 
appropriate care and compliance with mandated reporting to authorities. Subjects may be referred 
for professional intervention, as deemed appropriate, including calling emergency personnel (911) if 
needed. A current list of local mental health treatment programs will be provided to all subjects at 
screening. Information reported will be kept in confidence with the exception that disclosure of 
suicidality, homicidality, or child or elder abuse warrant reporting to appropriate authorities. 
Risks associated with Alcohol Cue Exposure: 
We will assess the level of craving after the cue exposure sessions inside or outside MR scanner to 
ensure that subjects will not leave the center with a significant level of craving. Different craving 
reduction methods, such as relaxation, distraction or reappraisal will be instructed to the study staff to 
help participants to reduce any potential craving. 
Risks Associated with Intervention:  
All subjects will be informed of the procedures/strategies involved in the intervention protocol during 
the informed consent process. Anxiety and depressive symptoms (including suicidal ideation) and 
substance use behavior will be monitored weekly throughout the intervention by using validated 
symptom questionnaires. This will allow for detection of any worsening of symptoms during 
completion of the study. This will be supplemented by observation by the clinician working with each 
participant. If symptoms worsen during the course of the study, the subject will be assessed 
individually by Dr. Aupperle, Dr. Paulus, or their licensed designee as needed. If symptoms worsen 
significantly such that additional evaluation, emergency services, or other clinical treatments is 
needed, appropriate referrals will be made (as described in the contingency plan for suicidality, 
below). If a subject has a clinical issue in between treatment sessions that does not reflect a 
psychiatric emergency, they will be able to reach a LIBR clinician during official hours (weekdays 
between 0800 and 1700). On weekends and off-hours (evenings and nights) they will be able to call a 
24-hour per day on call service for LIBR, which is provided through the Call Center of Laureate 
Psychiatric Clinic and Hospital.  In case of clinical emergency between sessions, subjects will be 
instructed to contact 911 or Tulsa Community Outreach Psychiatric Emergency Services (COPES – 918 
744 4800). 
Contingency plans for monitoring suicidality, worsening clinical symptoms, or other mental health 
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All volunteers who are deemed a serious suicide risk will be excluded from the study. All research 
volunteers will undergo routine, state-of-the-art screening and diagnostic assessments at LIBR. 
The screening will be conducted by a clinician interviewer (who holds either a nursing or MD 
degree, or a MA or PhD degree in clinical or counseling psychology, and has received extensive 
training and experience in the evaluation and management of patients with major psychiatric 
disorders). In the evaluation of suicidal risk, we specifically will exclude from participation any 
volunteer who endorses having developed a plan to attempt suicide and has intent to attempt 
suicide in the near future (i.e., in the next month). Any volunteer who is excluded from 
participation for these reasons will be referred for emergency care according to written LIBR 
policies for managing potentially suicidal patients, as described below. 
While the participants are in this study they will be monitored for the development of suicide risk 
or for worsening in their clinical illness by a clinician. This will be conducted using the weekly self-
report assessments and clinical observation, as described above. If concerns arise when the 
participant is physically present at the Laureate Institute for Brain Research, psychologist Robin 
Aupperle, PhD is available on site to address any concerns that arise. If Dr. Aupperle is unavailable 
or further evaluation is deemed necessary, psychiatrists Dr. Martin Paulus, and Sahib Khalsa will 
be available.  
For patients who are at the LIBR facility and are deemed to constitute a serious risk for suicide, the 
LIBR policy requires that they be escorted by two clinicians to the onsite, 24-hour emergency 
facility at Laureate Psychiatric Clinic and Hospital (which is located about 100 yards from the LIBR 
facility). If participants refuse to be escorted to this facility and leave the LIBR premises, the study 
clinician will contact the Community Outreach Psychiatric Emergency Services (COPES – 918 744 
4800), which is available 24 hours per day to send a mobile unit to the person’s home. 
For participants who develop serious suicidal ideation while not on the LIBR premises, these 
participants will be instructed to call 911 or to go to the nearest emergency room if they feel they 
are a threat to themselves or others. They will also be given the contact details of the Tulsa 
Community Outreach Psychiatric Emergency Services (COPES – 918 744 4800). If they report 
serious suicidal ideation while in another treatment center (e.g., 12&12 or WIR), they will be 
connected with emergency support staff at those treatment centers as well. 
For participants who have clinical issues that do not reflect a psychiatric emergency, they will be 
given a telephone number where they can reach a LIBR clinician during those hours when LIBR is 
officially staffed by clinicians (weekdays between 0800 and 1700) and encouraged to call their 
treatment providers external to the study (e.g., treatment providers at 12&12 or WIR). For 
weekends and off-hours (evenings and nights) they are provided a second telephone number 
where they can reach the 24-hour per day on call service for LIBR, which is provided through the 
Call Center of Laureate Psychiatric Clinic and Hospital. 
Upon study completion, patients who are currently under treatment by an external provider will 
be referred to their own clinician. Subjects who are dropped from study participation, or patients 
who complete the study and are not under the care of a clinician, will be provided a referral to a 

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psychiatrist or other mental health professional at one of the following clinics (regardless of the 
reported level of post-treatment symptoms): 
 
Outpatient (insured) 
Laureate Psychiatric Clinic and Hospital 
6655 South Yale Ave 
Tulsa OK, 74136 
(918) 481-4000 
 
Department of Psychiatry (sliding scale) 
University of Oklahoma College of Medicine 
Tulsa OK, 74136 
(918) 619 4400  
 
Outpatient (uninsured) 
Tulsa Center for Behavioral Health (sliding scale) 
2323 South Harvard Ave 
Tulsa, OK, 74114 
(918) 239 2100 
 
Counseling and Recovery Services (sliding scale) 
7010 South Yale Ave, Suite 215 
Tulsa OK, 74136 
(918) 492 2554 
 
Family & Children's Services 
650 S Peoria Ave  
Tulsa, OK 74120 
918-587-9471 
 
CREOKS 
4103 S Yale Ave Ste. B  
Tulsa, OK 74135 
918-382-7300 
 
Inpatient 
Laureate Psychiatric Clinic and Hospital 
6655 South Yale Ave 
Tulsa OK, 74136 
 
(918) 481 4000 
 

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Individually tailored referrals will be made for participants who reside outside of the Tulsa region, 
so that they will be referred to psychiatric or substance use services that are located near their 
home or workplace.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
The interventions being utilized in the study (Positive Affect training; CBT) have been shown by previous 
research to enhance positive affect and/or to decrease negative affect for some people and we 
hypothesize that it may also be helpful for individuals suffering from substance use. All participants in 
this study will be assigned to receive an active intervention. Therefore, there is a possibility that 
participants will benefit from participation in this study. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The risk in this study is low, given that the assessment procedures are non-invasive and have minimal 
risks, all participants will receive the active intervention. The study will be the first to examining the 
feasibility and potential utility of targeting positive affect for individuals suffering from substance use 
and the intervention may benefit participants in the study. Thus, the minimal risks involved in the study 
are outweighed by the potential benefits.  
 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
Primary
Phase 1: Examine the 
feasibility and acceptability 
of conducting AMP-A with 
individuals suffering from 
substance use disorder. 
Primary outcomes will 
include treatment 
completion rate and 
participant and clinician 
feedback on acceptability 
and feasibility and input from 
qualitative interviews with 
participants and clinicians. 
 
 
Primary endpoint: 
post-intervention 
(within 
approximately 2 
weeks after 
completing 
training). 
Secondary 
endpoint is 
approximately 3 
months after 
completing the 
intervention.  
 
 
Outcome to assess feasibility 
and acceptability.  
N/A
For Phase 2, primary 
objective is to assess the 
impact of AMP-A versus CBT 
Primary endpoint: 
post-intervention 
(within 
Outcomes to assess potential 
clinical benefit of positive 
affect training.   

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS 
PUTATIVE 
MECHANISMS OF 
ACTION 
on positive affect.
approximately 2 
weeks after 
completing 
training). 
Secondary 
endpoint is 
approximately 3 
months after 
completing the 
intervention.  
 
 
Secondary
The secondary objective(s) if 
Phase 2 is to explore the 
potential impact of AMP-A 
versus CBT on psychological 
well-beng and social 
connectedness.  
Primary endpoint: 
post-intervention 
(within 
approximately 2 
weeks after 
completing 
training). 
Secondary 
endpoint is 
approximately 3 
months after 
completing the 
intervention.  
 
 
Outcomes to assess potential 
clinical benefit of positive 
affect training.   
Neural and 
behavioral 
responsivity to 
reward and 
positive affect 
processing (as 
assessed in the 
tertiary 
objectives) 
Tertiary/Exploratory 
A tertiary objective is to 
explore the potential impact 
ofAMP-A versus CBT on self-
reported anticipation, 
responsiveness, and recall of 
positive (non-drug) 
experiences and positive 
reinforcement motives to use 
alcohol, levels of alcohol use 
and anxiety and depressive 
symptoms, and neural 
responses during processing 
of positively valenced or 
alcohol-related cues. 
 
Primary endpoint: 
post-intervention 
(within 
approximately 2 
weeks after 
completing 
training).  
 
 
Outcomes to further assess 
the clinical potential of AMP-
A and the potential neural 
and behavioral mechanisms 
of clinical effects.  
N/A
 

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4 
STUDY DESIGN 
 
4.1 
OVERALL DESIGN 
 
Phase 1 of this study is a non-randomized, single-arm, single-site Phase I/II clinical trial conducted at 
Laureate Institute for Brain Research (LIBR) in Tulsa, OK. The primary objective for this study is to 
examine the feasibility and acceptability of conducting positive affect training with individuals suffering 
from substance use disorder. Primary outcome will include treatment completion rate; secondary 
outcome will include the score on a participant feedback questionnaire. We hypothesize that the 
majority of participants (>60%) will complete all 12 sessions of the intervention and that participant 
feedback concerning the intervention will be at least moderately favorable on average. Secondary 
outcomes will include qualitative input from participants and clinicians concerning the AMP-A protocol, 
which will be used for informing modifications to the intervention protocol. The exploratory objectiv is 
to explore the potential impact of training on positive and negative affect, symptom severity, and 
functional disability. We hypothesize that positive affect will significantly increase from baseline to post-
intervention, while negative affect, alcohol-related craving, and functional disability will significantly 
decrease. 
 
Phase 2 of this study is a randomized, two-arm, single-site Phase I/II clinical trial conducted at Laureate 
Institute for Brain Research (LIBR) in Tulsa, OK. The primary objective for this study is to examine the 
feasibility of conducting an RCT comparing positive affect training (AMP-A) to cognitive-behavioral 
therapy (CBT) with individuals suffering from co-occuring alcohol use disorder and depression or anxiety 
symptos. Primary outcome will include positive affect; secondary outcomes will include psychological 
well-being and social connectedness. Exploratory outcomes include self-reported anticipation, 
responsiveness, and recall of positive (non-drug) experiences and positive reinforcement motives to use 
alcohol, levels of alcohol use and anxiety and depressive symptoms, and neural responses during 
processing of positively valenced or alcohol-related cues. We hypothesize that activation with striatal 
and orbitofrontal cortex (OFC) regions to alcohol-UNrelated reward cues will increase from baseline to 
post-intervention, while striatal and OFC response to alcohol-related cues will decrease from baseline to 
post-intervention. Primary endpoint is post-treatment, secondary endpoint is 3 months post-treatment 
for self-report measures (neuroimaging will only be completed at pre- and post-treatment). 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The current study is focused on further developing the AMP-A manual through piloting and clinician and 
therapist feedback, assessing the feasibility and acceptability of AMP-A, and examining the potential 
clinical utility of AMP-A through an RCT design with CBT as the comparator intervention. We 
hypothesize that AMP-A could have clinical utility for co-occuring alcohol use disorder and 
anxiety/depression symptom due to its direct targeting of reward and positive valence processing, 
which has often been identified as dysfunctional for individuals with substance use and mood and 
anxiety disorders. Given our primary objective of assessing feasibility and acceptability of the 
intervention in the Phase 1, we are not including a control group and all participants will receive AMP-A. 
In Phase 2, we will assess clinical utility of AMP-A through an initial RCT comparing AMP-A to CBT. The 

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results will  be used to inform larger RCTs comparing the efficacy of AMP-A and CBT for comorbid AUD 
and depression/anxiety.  
 
4.3 
JUSTIFICATION FOR INTERVENTION 
 
The positive affect intervention protocol employed in Phase 1 is based on previous work showing that a 
12-session AMP-A training is sufficient for exerting clinical benefit in various populations, including HIV 
and anxiety populations (as well as a recent pilot we conducted with individuals experiencing co-
occuring alcohol use disorder and depression/anxiety symptoms).  The protocol is based specifically on 
the protocol used in these previous studies. Clinicians in the study will be trained by investigators (Dr. 
Charles Taylor) who have implemented this protocol in previous studies. 
  
The 12-session AMP-A intervention to be employed in Phase 2 will be a slightly modified version of that 
used in Phase 1, as it will be modified based on quantitative and qualitative feedback from participants 
and clinicians. CBT interventions for comorbid AUD and anxiety or depression have been found to have 
small but significant beneficial affects compared to treatment as usual 41. The CBT intervention used as a 
comparison is a modified version of a protocol being used for comorbid substance use and anxiety by 
collaborator, Dr. Wolitzky-Taylor at UCLA (R34-AA025364). 
 
4.4 
END-OF-STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed the baseline 
assessment, at least 7 intervention sessions, and the 3-month follow-up assessment.  
 
The end of the study is defined as completion of the 3-month follow-up assessment shown in the 
Schedule of Activities (SoA), Section 1.3.] 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria (for 
both Phases 1 and 2): 
(1) Age between 18 and 65 years old. 
(2) Meeting diagnostic criteria for alcohol use disorder 42 according to the DSM-5. 
(3) Significant depression or anxiety symptoms as indexed by scoring Patient Health 
Questionnaire (PHQ-9) ≥ 10 and/or Overall Anxiety Severity and Impairment Scale 
(OASIS) ≥ 8. 
(4) Below normative levels of positive affect as indexed by PROMIS Positive Affect <50. 
(5) Able to provide written informed consent. 
(6) Have sufficient proficiency in the English language to understand and 
complete interviews, questionnaires, and all other study procedures. 

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5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
(1) Unwillingness or inability to complete any of the major aspects of the study protocol, including 
self-report or behavioral assessment. However, failing to complete some individual aspects of 
these assessment sessions will be acceptable (i.e., being unwilling to answer individual items 
on some questionnaires or being unwilling to complete a behavioral task). In addition, the 
neuroimaging portion of the protocol will be optional. 
(2) Non-correctable vision or hearing problems. 
(3) No telephone or easy access to telephone. 
(4) Diagnosis of Schizophrenia spectrum, other psychotic disorders, or bipolar I disorder. 
(5) Active suicidal ideation with plan and intent to attempt suicide within the next month. 
(6) Has a history of unstable liver or renal insufficiency; glaucoma; significant and unstable 
cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, 
rheumatologic, or metabolic disturbance; or any other condition that, in the opinion of the 
investigator, would make participation not be in the best interest (e.g., compromise the well-
being) of the subject or that could prevent, limit, or confound the protocol-specified 
assessments. 
(7) A positive test for drugs of abuse, including alcohol (breath test), cocaine, marijuana, opiates, 
amphetamines, methamphetamines, phencyclidine, benzodiazepines, barbiturates, 
methadone, and oxycodone at the time of baseline assessments. Participants will be asked to 
refrain from using alcohol within 24 hours prior to assessment sessions and to refrain from 
using marijuana within 48 hours of assessment sessions. 
(8) Current use of a medication or change in the dose or prescription of a medication within the 6 
weeks prior to enrolling in the study that could potentially affect brain functioning (e.g., 
stimulants, anxiolytics, antipsychotics, mood stabilizers, anti-hypertensives). The current use 
of antidepressants (i.e., SSRIs) will not be excluded as long as the dose has remained 
consistent for 6 weeks prior to baseline assessment sessions. While individuals reporting use 
of benzodiazepines will be excluded; individuals with sporadic use (i.e., less than once per 
week) may be included, but will be asked to refrain from using within 72 hours prior to 
assessment sessions. Inclusion of individuals reporting other types of medications or 
supplements not listed or considered this far will be at the discretion of the PI according to 
evidence in the literature of it affecting brain function or brain blood flow.  
(9) Taking drugs that affect the fMRI hemodynamic response (e.g., methylphenidate, 
acetazolamide, and excessive caffeine intake > 1000 mg/day) – Phase 2 only 
(10) Concurrent engagement in psychosocial treatments that specifically target alcohol use 
disorder or mood/anxiety symptoms and began within 12 weeks of baseline assessments. 
Individuals concurrently receiving psychosocial treatments for other symptoms, or that are 
not specifically targeting symptoms (e.g., ongoing support groups) will not be excluded as 
long as the dose of treatment (i.e., frequency of sessions) has not changed significantly within 
6 weeks prior to enrolling in the study. 
(11) MRI contraindications (for those in Phase 2 opting into this portion) including: cardiac 
pacemaker, metal fragments in eyes/skin/body (shrapnel), aortic/aneurysm clips, prosthesis, 
by-pass surgery/coronary artery clips, hearing aid, heart valve replacement, shunt (ventricular 
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persons who have ever been a professional metal worker/welder, history of eye surgery/eyes 
washed out because of metal, vision problems uncorrectable with lenses, inability to lie still on 
one’s back for 60-120 minutes; prior neurosurgery; tattoos or cosmetic makeup with metal 
dyes, unwillingness to remove body piercings, and pregnancy – Phase 2 only 
(12) Moderate to severe traumatic brain injury (>30 min. loss of consciousness or >24 hours 
posttraumatic amnesia) or other neurocognitive disorder with evidence of neurological 
deficits, neurological disorders, or severe or unstable medical conditions that might be 
compromised by participation in the study (to be determined by primary care provider). 
(13) Severity of alcohol use disorder requiring more intensive treatment (i.e., intensive outpatient 
or residential), as determined by baseline assessments conducted by licensed clinicians. 
(14) Given the current study involves development of the positive affect intervention, we will not 
enroll any special vulnerable populations (pregnant women, fetuses, neonates, prisoners, 
children).  
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Other than the target of increasing positive affect related activities and decreasing use of alcohol, no 
additional changes in health lifestyle (i.e., diet) are implemented with patients as part of this protocol. 
Participants will not be asked to discontinue any current/ongoing medical care. 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently entered in the study. Individuals who do not meet the criteria for participation in this trial 
(screen failure) because of meeting one or more exclusion criteria that are likely to change over time 
may be rescreened. Examples include the successful treatment of a comorbid mental health disorder 
being excluded, or a change in treatment status. Rescreened participants will be assigned the same 
participant number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruitment of study participants: Study participants will be recruited through other protocols ongoing 
at LIBR (Screening protocol (WIRB # 20101611; schedule Visits for NeuroCAPS protocol (WIRB 
#20183208), which recruit through community advertisements and referral from mental health and 
substance use clinics. Additionally, they will be recruited through study-specific radio and Facebook 
advertisements. The recruitment materials are provided with this protocol. We anticipate screening 
approximately 150 individuals to obtain the targeted 90 (20 in phase 1; 100 in Phase 2) participants that 
meet criteria for the study. Potential participants will be screened by phone or in-person using the WIRB 
screening protocol 20101611 to determine initial eligibility and baseline symptom severity. Patients will 
accordingly complete a diagnostic interview with study personnel using an abbreviated version of the 
Mini International Neuropsychiatric Interview (MINI V7.0)43 and the computer-assisted Psychiatric 
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sections on Panic Disorder (PD), Social Anxiety Disorder (SAD), Posttraumatic Stress Disorder (PTSD), 
Generalized Anxiety Disorder (GAD), Obsessive-Compulsive Disorder (OCD) and Major Depressive 
Disorder (MDD) and several modules to provide further clinical information (Suicidality, 
Manic/Hypomanic Episode, Eating Disorders, and Psychotic Disorders). The PRISM-5 will be conducted to 
confirm in more detail the diagnosis of alcohol and other substance use disorders. In addition, the 
Overall Anxiety Severity and Impairment Scale (OASIS45), Patient Health Questionnaire (PHQ-946) are 
conducted as part of the LIBR screening protocol to be used in identifying individuals meeting criteria for 
the current study. These questionnaires may be repeated in the current protocol to confirm that 
participants still meet criteria for the study. They additionally will complete screening to determine that 
sensory processing (i.e., vision, hearing) are sufficient to complete the study protocol. All participants 
(whether or not they meet eligibility criteria following the baseline session) will be provided with 
community mental health referrals as needed.  
Provisions for recruiting non-English speaking participants: Non-English speaking subjects will not be 
recruited. 
Gender/Minority/Pediatric Inclusion for Research: Women and minorities will be included in the study 
without prejudice according to their representation in the study population. All efforts will be made to 
ensure that our subject population closely resembles the gender, ethnic and racial composition of the 
Tulsa region and the programs we are recruitingfrom (i.e., Women in Recovery and 12&12 programs.) 
Children are not included in this protocol due to its focus on identifying the feasibility of this 
intervention for adults with SUDs. 
 
Measures to increase retention: 
• At the baseline visit, we will collect detailed contact information for each enrolled subject, 
including email, home/work/cell phone, and permanent address. In addition, for each subject 
we will collect contact information for 1-2 relatives, partner, and/or friends. 
• Transportation (e.g., cab fare) will be provided to/from sessions for those who indicate this is 
an obstacle to participation.  
• Subjects will be offered their brain pictures printed on a keepsake item (e.g., mousepad, t-shirt, 
mug) at study completion. 
• All follow-up time points will be preferably completed in person. However, if absolutely 
necessary, subjects will be offered the opportunity of completing them over the phone rather 
than having them withdraw from the study. 
 Participant will be asked during baseline assessment the likelihood of being able to complete all 
study sessions. The assessor will then discuss ay obstacles identified that may prevent 
completion and troubleshoot solutions. All participants will be provided text or voicemail 
reminders about each study session. 
 
Payment for Participation. For baseline, post-training, and followup procedures, study compensation 
will involve $25 per hour for completion of self-report and behavioral assessment and $50 per hour 
for completion of neuroimaging procedures. For neuroimaging procedures in Phase 2, participants will 
be provided an additional $0-$55 per session based on MRI task performance. Participants will be 
compensated $30 for completion of each follow-up assessment session. Compensation will be 
prorated per half hour for those who do not complete all aspects of the protocol. Participants will not 
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Payments will be provided to subjects via the ClinCard System, a global electronic payment technology 
(similar to a debit card). After each visit, subjects will have their account credited with the amount 
paid for their participation in the study.  
 
For compensation of assessments and feedback questionnaires completed at the intervention 
sessions, participant will be provided $5/session. This will be provided regardless of whether the 
participant attends a session (as surveys may be sent via a link to be completed online). No 
compensation will be provided for procedures associated with the intervention itself. 
 
For completion of focus groups, therapy participants will be provided $50 and be provided snacks 
during the focus groups.  
 
Clinicians will be recruited from external clinics to review the manual and provide input during 
continuing education seminars we provide. Food and beverages will be provided but no payment will 
be provided to clinicians.  
 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
Following completion of baseline assessments, participants in Phase 1 will be asked to complete 12 
sessions of the positive affect intervention (AMP-A), conducted once or twice weekly and with each 
session lasting 1 - 1.5 hours. If the content of sessions is too much to cover for any one client, the 
intervention may be extended to 14 sessions as needed. Participants in Phase 2 will be randomized to 
complete either (1) a slightly modified 12 session AMP-A intervention or (2) a 12-session CBT 
intervention, each conducted once or twice weekly and with each session lasting 1 - 1.5 hours. 
In both phases, participants will be expected to complete all intervention sessions within 16 weeks of 
starting the first session. Each session will be completed as individual therapy sessions (i.e., one-on-one 
with a therapist). Therapy sessions may be delivered via videoconferencing (e.g., using Zoom, GoTo, or 
similar technologies). Participants will be informed that confidentiality of information shared during 
videoconferencing cannot be guaranteed. Participants will be allowed to participate via audio only 
connections as requested. 
AMP-A will involving positive emotion enhancement exercises established in prior studies, including 
noticing and amplifying positive emotions, practicing gratitude, engaging in acts of kindness, and 
pleasurable or meaningful activities, identifying strengths and values, being optimistic, engaging in 
activities meant to make others happy, and living life to its fullest15. We will use the protocol developed 
by Taylor et al.15 with modifications to specifically address alcohol use, based on previous work47, and 
further modified based on our prior pilot study. The general structure of each session will follow 
standard cognitive behavioral treatment regimens as follows: (1) meet with clinician to review 
completion of the prior week's exercises, including self-monitoring forms of emotions and exercise 
completion; (2) identify and troubleshoot any issues that arose during exercise completion; (3) 

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introduce material about a new positive emotion enhancement activity; (4) identify concrete exercises 
to implement for the upcoming week. The manual to be used in this study is included with the 
protocol. The intervention manual is provided with this submission.  
The CBT intervention to be implemented in Phase 2 will consist of 12 sessions that include motivational 
interviewing and cognitive-behavioral strategies established in prior studies41, including evaluating the 
consequences of alcohol use, discussing high-risk situations and triggers, conduct self-monitoring of 
the relationship between thoughts, emotions and alcohol use, identification and building of useful 
lifestyle changes, problem solving strategies, communication skills, and social support. 
 
6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
 
The interventions will be delivered by a licensed doctoral or master’s level clinician or a therapist in 
training (i.e., clinical psychology post-doctoral fellows or graduate students). Each therapist will 
complete in-person or video-recorded workshops in each intervention (conducted by Charles Taylor, 
PhD for AMP-A; by Kate Wolitzky-Tayzlor, PhD for CBT), read articles and manuals related to the 
treatment, and watch videos of previous therapy sessions conducted as part of the study as they are 
available. Each therapy session is video and audio recorded and at least 20% of sessions will be 
randomly selected for fidelity ratings by Drs. Taylor, Wolitzky-Taylor or their trainees. Skill acquisition 
and fidelity will be assessed by a fidelity form created by Drs. Wolitzky and Taylor specific to the 
intervention being delivered. Each therapist will attend weekly consultation and supervision with the PI 
and/or consultants, Drs. Taylor and Wolitzky-Taylor. Therapists will also be asked to complete surveys 
concerning therapist allegiance and expectancies. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
For Phase 1, all participants will receive the active intervention protocol focused on the positive valence 
system. Thus, there is no blinding or randomization.  
 
For Phase 2, participants will be randomized to receive the positive affect intervention or CBT. 
Randomization will be stratified by sex (male/female). Assessors and participants will remain blind to 
intervention until after all baseline assessments have been completed.  
 
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
The participants will be asked to complete the Homework rating scale (HRS) at each intervention visit. In 
addition, copies of any homework sheets will be copied and kept with their research records to allow for 
evaluation of how well individuals complied with homework instructions. The therapists will also be 
asked to rate compliance to and engagement in the intervention after each session.  
 

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6.5 
CONCOMITANT THERAPY 
 
All participants will be permitted to continue their ongoing pharmacologic or therapy treatments. 
However, participants for whom changes in medication or therapy “dosage” are planned for the one 
week duration of the study will be excluded. 
 
6.5.1 RESCUE THERAPY 
Include content in this section if applicable, otherwise note as “N/A.” 
 
List all medications, treatments, and/or procedures that may be provided during the study for “rescue 
therapy” and relevant instructions about administration of rescue medications.  
 
Example text provided as a guide, customize as needed: 
 
The study site will not supply rescue therapy. In the case that participants experience significant 
worsening of symptoms over the course of the proposed intervention, their participation may be 
terminated and the participant would be referred to their current clinicians external to the study and/or 
be provided additional referrals to supplement the current treatments they are receiving external to the 
study.  
 
 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
Participants will be informed that participation is completely voluntary and they are allowed to 
withdraw from the study at any time. If a participant indicates they are unwilling to do the primary 
aspects of the study (e.g., neuroimaging or neurofeedback sessions), they will be excluded from 
participation. However if a subject discontinues from the neuroimaging session (after having begun the 
scanning session) but does not withdraw from the study – for example, due to experiencing 
psychological distress during scanning – they will be allowed to complete the remaining study as 
indicated by the study protocol. 
 
Over the course of the study (each intervention session), suicide risk will be assessed using the QIDS48 or 
BDI suicide ideation item, substance use severity will be monitored using PROMIS Substance Use49, and 
anxiety and depressive symptoms will be monitored using the PROMIS Anxiety and Depression scales. If 
a participant reports any increase in suicidal ideation, use of substances of abuse, or significant 
worsening of mental health symptoms (i.e., increase of >5 on the PROMIS total T scores), referrals will 
be provided as needed and further assessment will be conducted to determine whether it is in the 
participant’s best interest to withdraw from the study.  
 

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At the time of study intervention discontinuation or study withdrawal, the reason(s) for discontinuing 
the participant from the intervention, and methods for determining the need to discontinue will be 
documented. If a participant withdraws, they will be asked to complete the Withdrawn Questionnaire to 
indicate reasoning for withdrawing.  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
Significant study intervention non-compliance (attends less than 7 of the therapy sessions; is 
unable to attend a therapy session for more than 2 weeks consecutively)  
 
Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
 
Any event or medical condition or situation occurs such that continued collection of follow-up 
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study (see previous section for 
description of assessments to monitor for potential increase in suicide risk and worsening 
clinical symptoms). 
 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
The reason for participant discontinuation or withdrawal from the study will be recorded. Subjects who 
sign the informed consent form and are randomized but do not receive the study intervention may be 
replaced. Subjects who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are discontinued from the study, will not be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for a scheduled follow-up 
visit and study staff are unable to contact the participant after at least 3 attempts.  
 
The following actions must be taken if a participant fails to return for a follow-up assessment session: 
 
The site will attempt to contact the participant, ascertain if the participant wishes to and/or 
should continue in the study, and as needed, reschedule the missed visit (within one week of 
the originally scheduled date). 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls, 3 text messages, 
and, if necessary, an email or certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts will be documented in the participant’s 
medical record or study file. 
 
If there is any concern about the safety of a participant lost to follow-up (e.g., due to previously 
recorded suicidal ideation) and study staff are unable to reach the individual, then 
confidentiality may be broken and the COPES hotline (918-744-4800) may be called to help 
ensure safety of the participant. 
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
Self-report and Interviewer Measures: 
Participants will be asked to complete interview and pencil-and-paper questionnaires related to clinical 
symptoms, traits and personality characteristics, daily life function, and medical and mental health 
history. These questionnaires are listed below. The time points in which all measures are administered is 
provided in Section 1.3, Schedule of Activities. Pre-intervention self-report and interviewer-based 
assessments are estimated to take approximately 3-4 hours to complete in total. Post-intervention self-
report assessment is estimated to take approximately 2-3 hours total, as will th 3-month time point. 
Weekly assessment measures are estimated to take 15-20 minutes to complete. If there are participants 
who are only able to complete part of the intervention (i.e., only able to attend a few of the sessions) 
either due to their own wish to terminate or due to exclusion criteria or clinical concerns (described 
above), they will only be asked to complete survey sessions for weeks that they attend. In addition to 
the measures listed in Table 1, participants in Phase 2 of the study will be asked to complete the therapy 
preferences questionnaire (submitted with protocol) to ascertain which therapy they would have 
preferred to receive (AMP-A or CBT). Participants will also be asked to completed the Withdrawn 
Questionnaire and Cultural Acceptability of Treatments Survey (CATS) and the Withdrawn Questionnaire 
after they complete or withdraw from treatment. If treatment is conducted via zoom, participants will 
also be asked to complete the TeleHealth Feedback Form. 
For Phase 1, focused on furtherdeveloping and refining the AMP-A protocol, we will also will include 
open-ended questions for focus groups conducted with participants who completed the preliminary 
version of AMP-A in our prior feasibility study (LIBR Protocol #2019-010-02), participants who complete 
AMP-A as part of Phase 1 of the current study, and substance use clinicians (N=5-10 that have 
implemented AMP-A; N=5-10 who are current clinicians in outpatient substance use disorder clinics and 
have been familiarized with AMP-A). The focus groups will use open-ended questions to obtain 
information concerning what was most/least helpful and what could be modified to optimize clarity and 
relevance for AUD+ANX/DEP (including content, materials, and sequencing). Focus group questions are 
included with this IRB application. The “End of Session” questionnaire50 will also be completed by all 
participants in the proposed Phase 1, after each therapy session, which will ask them to rate what was 
most/least helpful during that session, whether the session content was clear, and how the session 
content could be made more helpful. 
For phase 2, participants will also have the option of completing pre- and post-neuroimaging sessions, 
each of which is estimated to take approximately 3 hours total (1.5 hours of scanning, with ~.5 hours 
before and after for preparation and instructions and post-task ratings). 
 

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Table 1. Self-Report measures for each time point (Phase 1 and 2) 
Domain
Measure
Screening
Pre 
Therapy 
During 
Treatment 
Post 
Treatment 
Follow-Up 
Time Point 
(3 mo) 
Demographic
Demographics Form - Update
X
X
Update
Medical History Update
X
X
 
Tulsa Life Chart – web-based application
 
X
 
X
 
 
Patient Health Questionnaire (PHQ-951)
x 
X 
 
 
 
 
Overall Anxiety Severity and Impairment Scale 
(OASIS 51 
X 
x 
 
 
 
 
Psychiatric Research Interview for Substance and 
Mental Disorders (PRISM-5)44 
 
x 
 
 
 
 
Mini-International Neuropsychiatric Interview 
(MINI)43 
X
 
 
 
 
 
Columbia Suicide Severity Rating Scale (CSSR)52
 
x 
As needed 
x 
 
 
 
 
 
 
 
Substance Use
Customary Drinking and Drug Use Record (CDDR)53
Michigan Nicotine Reinforcement Questionnaire 
(MNRQ54; adapted for alcohol) 
X
X
Alcohol Craving Questionnaire Short Form (ACQ-
SF)55 
X
Each Week
X
X
Timeline Follow-Back56
X
Each week: 
# of drinks/ 
day 
X
X
PROMIS Alcohol Use49
X
Each Week
X
X
PROMIS Alcohol Use – Negative Consequences49
X
X
X
PROMIS Alcohol Use – Positive Consequences49
X
X
X
PROMIS Alcohol Use – Negative Expectancies49
X
X
X
PROMIS Alcohol Use – Positive Expectancies49
X
X
X
PROMIS Nicotine Dependence49
X
X
X
PROMIS Substance Use Severity49
X
X
X
Alcohol Breathalyzer
X
Each Week
X
X
 
Urine drug test
X 
 
X 
X 
 
PhenX Alcohol 30 Day Quantity and Frequency57
X
 
Mental Health, 
Positive and 
Negative 
Valence 
 
 
NIH PROMIS Scales for Positive Affect, Meaning and 
Purpose, Depression, Anxiety scales49 
X
Each Week
X
X
Quick Inventory of Depressive Symptomatology 
(QIDS)QIDS-SR48 
X
X
X
Mood and Anxiety Symptom Questionnaire-Short 
     form (MASQ)58 
X
X
X
Traumatic Events Questionnaire (TEQ)—update59
X
X
PTSD Checklist (PCL)60
X
PROMIS Anger, Perceived Stress, Self-Efficacy, and 
General Life Satisfaction scales49 
X
X
X
Sheehan Disability Scale (SDS)61
X
Each Week
X
X
UPPS Impulsive Behavior Scale62
X
X
X
Columbia Suicide Severity Scale52
X
X
Positive and Negative Affective Schedule (PANAS-
X)63 
X
X
X
Approach Avoidance Temperament Questionnaire64
X
X
X
NIH toolbox Friendship and Loneliness49
X
Every 2-3 
sessions 
X
X
Snaith—Hamilton Pleasure Scale (SHAPS)65
X
X
X
Sensitivity to Punishment and Sensitivity to Reward 
     Questionnaire (SPSRQ)66 
X
X
X
Temporal Experiences of Pleasure Scale (TEPS67
X
X
X
Social Connectedness Scale – Revised (SCS-R)68
X
X
X
Patient Health Questionnaire (PHQ)46
X
Overall Anxiety Severity And Impairment Scale 
(OASIS)45 
X
Savoring Beliefs Inventory (SBI)69
X
X
X
Responses to Positive Affect Scale (RPA)70
X
X
X
Emotion Values71
X
X
X
MINI Checklist72
X

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Health-related 
questionnaires 
Pittsburgh Sleep Quality Index73
X
X
International Physical Activity Questionnaire 
(IPAQ)74
X
X
Intervention
Session Attendance
Each Week
X
Credibility/Expectancy Questionnaire75
X
Session 2
Homework Rating Scales – Patient76
Each Week
Homework Compliance Rating – Therapist76
Each Week
Working Alliance Inventory77 (therapist and client)
Every 3-4 
sessions 
Withdrawn Questionnaire (included)
if 
withdraws  
Adherence and Acceptability Scale (AAS)78
X
Every 3-4 
sessions 
X
Distress/Endorsement Validation Scale (DEVS)79
X
Every 3-4 
sessions 
X
Therapy Improvement Scale (included)
X
Treatment Follow-up Form (included)
X
Feedback 
Surveys 
Telehealth Usability Questionnaire 80
X
End of Session Questionnaire – Participant 
Each week
 
Study Feedback Survey 
X
X 
Minority stress 
and 
discrimination 
Racism and Life Experiences Scales – Daily Life 
Experiences (RaLES-DLE) 81
X
 
Multigroup Ethnic Identity Measure – Revised 
(MEIM-R) 82
X 
 
Cultural Acceptability of Treatment Surveys 
(CATS)83 84 - modified
 
X 
 
Heterosexist Harassment, Rejection, and 
Discrimination Scale (HHRDS) 85
X 
 
Neuroimaging Session 
Scanning procedures will be conducted at two time points (pre- and post-intervention) for the current 
study. Prior to scanning, each subject will complete (1) self-report assessment of sleepiness (Karolinska 
Sleepiness Scale86) and state affect (Positive and Negative Affect Schedule [PANAS]63), (2) review of fMRI 
procedures and MRI safety screen and assessment of handedness (Edinburgh Handedness Inventory87), 
(3) the participant last use summary (PLUS; provided with this submission). In addition, all participants 
will complete urine drug tests and breathalyzer tests to confirm they are not under the influence of 
alcohol or recreational drugs at the time of assessment and all females of child-bearing age will 
complete a urine pregnancy test. Participants will be scanned in a GE Discovery MR750 3.0 Tesla scanner 
(GE Medical Systems) at the Laureate Institute for Brain Research. The scanner is equipped with system-
standard 8- and 32-channel brain coils. The multi-element brain arrays are highly sensitive MRI signal 
detectors offering vastly improved sensitivity for the detection of functional activation induced signal 
changes at high spatial and temporal resolutions, as well as anatomical MRI at very high spatial 
resolutions. The receivers allow for shorter readout times and reduced signal distortions and 
ventromedial signal dropout.  
MRI preparation: MRI eligibility will be confirmed prior to entry into the scanner. The subject 
will be asked to remove all ferromagnetic items. The subject will be trained on all fMRI tasks and given 
time to practice. If the subject requires vision correction, he or she will be fitted with plastic glasses 
closely matching his optic prescription. A urine sample will be collected for a pregnancy test (for female 
participants). Earplugs will be inserted prior to entering the scanner. The audio system will be explained 
so the participant will know how to communicate with the scanner operator and headphones will be 
placed over the ears. The subject will be reminded of the importance of staying still in the scanner. To 

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minimize motion, the participant’s head will be stabilized with a specially designed pillow under the 
neck and wedge-shaped cushions between the sides of the head and head-holder. Padding will be 
arranged to maximize comfort and a pillow will be placed under the knees to provide lower back relief. 
The MRI operator will put the head coil in position over the participant’s head, localize the head position 
on the scanner, and ensure that the subject can fully view the display screen at the end of the scanner 
gurney, where task images will be displayed, by looking in the mirror directly above their eyes. The 
response box will be positioned in the subject’s dominant hand and the subject will test the buttons. In 
the subjects’ non-dominant hand, the pulse oximeter is placed on one finger and the subject is provided 
the emergency squeeze ball. Once the subject is comfortable, the gurney will move into the magnet. The 
MRI technician will secure the scan room door, dim the scan room lights, and communicate with the 
participant through the console. In addition to the functional scans listed below, there will be localizer, 
anatomical, and diffusion tensor imaging scans to obtain data concerning white/gray matter structure 
and volume, as well as white matter integrity. In addition, there will be one “resting state” scan in which 
participants are asked to look at a fixation cross on the screen and to not think about anything in 
particular. At the completion of the MRI session, subjects will complete the Karolinska Sleepiness Scale 
(KSS)86 and Positive and Negative Affect Schedule – short form (PANAS)63. 
Physiological measures: 
Physiological noise estimation and correction will be acquired through physiological monitoring 
of pulse rate using a finger-tip pulse oximeter throughout the MRI session. An elevated pulse rate will 
generate a query from the scanner operator. Pulse rates above 90 beats per minute will prompt the 
scanner operator to ask participant if they are okay. The pulse oximeter sensors are connected to an In 
Vivo physiological monitoring system. Collection of physiological data during the scan will be linked to 
the behavioral tasks by a pulse marker generated by the magnet console and recorded on the 
physiological tracings. The concurrent information on pulse rate will be used to remove physiological 
fluctuations from the fMRI data. 
Tasks to be conducted during fMRI: 
 Reward Processing Task: To measure behavioral and neural responses to rewards and losses, 
participants will complete the monetary incentive delay task (MID), a well-established measure of 
reward processing88 89. This task dissociates anticipatory and consummatory phases of reward 
processing and has been shown to reliably activate brain regions implicated in regulating approach-
related response tendencies and reward sensitivity (e.g., ventral striatum). On each trial, participants are 
given a cue indicating potential reward (circle), loss (square), or no reward/loss (circle or square). In 
order to receive a specified reward or avoid a loss, participants are required to press a button within a 
certain duration of time (adapted for individual participant reaction times) following presentation of a 
white square (target cue). Task difficulty, based on reaction times collected during a practice session, is 
set such that each participant should succeed on ~66% of trials. The degree of potential reward or loss is 
varied on three levels indicated by the number of horizontal lines in a cue, i.e., one line indicates the 
lowest reward value (no reward), two lines an intermediate reward, and three lines the highest reward. 
For the MID task, participants can gain or lose points and earn an average of $30 (up to $55). The 

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primary outcomes of interest will be: (1) anticipation of reward vs. no-reward, (2) receipt of reward 
outcomes vs. no-reward outcomes, (3) anticipation of loss vs. no-loss, and (4) receipt of loss outcomes 
vs. no-loss outcomes. The Monetary Incentive Delay Task will take about 18 minutes to complete.  
Alcohol Cue Reactivity Task: In the Alcohol Cue Reactivity (DCR) paradigm, participants are presented 
with blocks of cues that are either alcohol-related (beer, wine, and/or liquor) or neutral. Images are 
taken from the previously validated databases90, International Affective Picture System (IAPS91), or 
stimuli used in previous fMRI studies related to alcohol cue processing92. Each image will be presented 
for approximately 5 seconds, with fixation cross presented on the screen in between. After each block of 
pictures (i.e., 20-30 seconds of pictures, or 4-6 pictures), participants are asked to rate their craving for 
alcohol  on a one to four scale, with one being “No Urge” and four being “Strong Urge” to use. Total scan 
time for this task is approximately 10 minutes. At the beginning and end of the imaging sessions, 
subjects will complete a Karolinska Sleepiness Scale (KSS)86. 
 
8.2 
SAFETY ASSESSMENTS 
Safety and tolerability of the intervention will be assessed using the participant feedback and 
acceptability questionnaires mentioned above (DEVS79, AAS78), and the clinical symptom measures and 
interviews discussed in previous sections. Any spontaneously reported events will also be recorded by 
study staff. 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
 
This protocol uses the definition of adverse event from 21 CFR 312.32 (a): any untoward medical 
occurrence associated with the use of an intervention in humans, whether or not considered 
intervention-related. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
 
A serious adverse event will be considered any adverse event temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
1. results in death; 
2. is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
3. requires inpatient hospitalization or prolongation of existing hospitalization; 
4. results in a persistent or significant disability/incapacity; 
5. results in a congenital anomaly/birth defect; or 
6. any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
 

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8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no additional treatment and do not interfere with the 
participant’s daily activities to a greater degree than when enrolled in the study.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning that is somewhat 
greater in degree than when enrolled in the study. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require a modification in 
their current treatment plan external to the study. Severe events are usually potentially life-
threatening or incapacitating. Of note, the term “severe” does not necessarily equate to 
“serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
All adverse events (AEs) will have their relationship to study procedures, including the intervention, 
assessed by the PI, Dr. Aupperle (licensed clinical psychologist) or Dr. Paulus (board-certified 
psychiatrist), based on temporal relationship and his/her clinical judgment. The degree of certainty 
about causality will be graded using the categories below.  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study procedures administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study procedures should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study procedures, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal.  
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of study procedures). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study procedures administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study procedures) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 

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• 
Not Related – The AE is completely independent of study procedures administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
 
8.3.3.3 EXPECTEDNESS  
 
Expected adverse reactions are AEs that are known to occur for the study procedures being studied and 
The PI, Dr. Aupperle (licensed clinical psychologist) or Dr. Paulus (board-certified psychiatrist) will be 
responsible for determining whether an adverse event (AE) is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study procedures. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event may come to the attention of study 
personnel during study visits and interviews or electronic surveys. All AEs, not otherwise precluded per 
the protocol, will be captured on an adverse event form. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study procedures (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 will be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates significantly at any time during the study, it will be recorded as an AE (see above sections 
concerning monitoring of suicidal ideation and mental health symptoms). 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 
The PI will record events with start dates occurring any time after informed consent is obtained until 7 
(for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At each study visit, 
the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed 
for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
Unanticipated, serious adverse events will be reported to the IRB within 24 hours of the time project 
staff become aware of the incident. In addition, at yearly intervals throughout the course of the study, 
the IRB will receive a summary of all other safety-related reports including safety-related protocol 
deviations, treatment retention, and reasons for dropout. Should the protocol or data collection plans 
be amended as a result of adverse events or subsequent data review, the IRB will be notified and the 

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amendment approved prior to study amendment implementation. In addition, the participants will be 
notified of any significant new findings that develop during the course of research (e.g., other potential 
risks) that may affect their wish to continue participation in the study. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
Serious adverse events will be reported to the NIH and the reviewing Institutional Review Board (IRB) as 
soon as possible, but in no event later than 10 working days after the investigator first learns of the 
event. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
Participants will be informed that study personnel are mandated reporters of child, dependent, or elder 
abuse and that confidentiality may be broken in these instances, or in the instance in which the 
participant is considered to be of danger to themselves or others.  
 
8.3.9 REPORTING OF PREGNANCY  
 
Individual participants will be informed of a positive urine pregnancy test and participation in the study 
will be discontinued.  
 
8.4 
UNANTICIPATED PROBLEMS 
No text is to be entered in this section; rather it should be included under the relevant subheadings 
below. 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human 
Research Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or 
others to include, in general, any incident, experience, or outcome that meets all of the following 
criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (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.] 

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8.4.2  UNANTICIPATED PROBLEMS REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• 
A detailed description of the event, incident, experience, or outcome  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB, and to the funding agency 
within 48 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the funding agency within 7 days of the 
investigator becoming aware of the problem. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
See above sections.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
The proposed project would support the final stages of intervention development, including (1) 
incorporating qualitative and quantitative input from AMP-A participants and clinicians and (2) conducting 
a pilot randomized clinical trial (RCT) with the resulting, modified AMP-A intervention with N=60 
individuals with AUD+ANX/DEP. The central hypotheses for the RCT are that (1) AMP-A will enhance 
functioning of the PVS compared to CBT—a first-line treatment for AUD that has small effects on the 
PVS—and (2) PVS improvements will be associated with reductions in alcohol use. 
Aim 1: Further develop and refine AMP-A (Stage 1a) using an iterative process, guided by prior work 
and feedback from AUD+ANX/DEP patients who complete AMP-A (N=8) and clinicians who have 
experience in treating the target population and/or with delivering AMP-A. H1: Participant and clinician 
feedback will reflect a high level of acceptability and satisfaction with AMP-A.  
Aim 2: Determine the effects of AMP-A vs. CBT on the PVS (Stage 1b). Based on preliminary data 
and extant findings, we hypothesize that compared to CBT, AMP-A will result in greater increases in self-
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(secondary outcomes; H1B). Exploratory PVS outcomes expected to improve following AMP-A vs. CBT 
include anticipation, responsiveness, and recall of positive (non-drug) experiences and positive 
reinforcement motives to use alcohol (H1C).  
Aim 3: Relate changes in PVS function to the degree of clinical improvement. Because PVS 
dysfunction is implicated in the maintenance of AUD and ANX/DEP, we hypothesize that increases in the 
PVS (e.g., positive affect) will be associated with reductions in alcohol use (primary clinical outcome; 
H2A) and anxiety and depression symptoms (secondary clinical outcomes; H2B).  
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Because this project focuses initially on the development of an intervention, sample size determination 
(N=60 randomized) was primarily guided by appropriateness for pilot study objectives and ability to inform 
future fully powered studies93 94. Our proposed N=60 conforms to guidelines in the literature for pilot 
studies (typical recommendation is 30/group93 94) and should provide (a) useful data regarding 
intervention feasibility and (b) data characteristics/distributions appropriate to examining data- and 
analysis-related procedures, variability, and potential effect sizes. The minimum effect size detectable in 
the proposed study was calculated based on a 2-sample, 2-sided t-test to compare differences in mean 
change in positive affect by treatment arm (alpha=0.05). Assuming N=52 evaluable participants (26 per 
group; assuming 10% lost to follow-up; i.e., subjects who provide no post-randomization outcomes), we 
have 80% power to detect a Cohen’s d=0.79 effect size of change between the treatment arms. Our 
ability to detect medium to large effect sizes in the proposed study is supported by observations that prior 
CBT trials for AUD found small within-CBT improvements in positive affect (d range = 0.10-0.14)95 96, 
whereas our preliminary work in ANX/DEP samples found large within-AMP improvements in positive 
affect (d range = 0.89-1.16). 
9.3 
POPULATIONS FOR ANALYSES 
 
Both intent-to-treat analyses (including all participants with baseline and at least one post-baseline time 
point completed) and completer anlaysis (including all participants who completed the AMP-A or CBT 
interventions) will be completed. 
 
9.4 
STATISTICAL ANALYSES 
 
Aim 1: Protocol Development and Acceptability.  
For focus groups, analysis will be conducted as has been done in Co-I Dr. Wolitzky-Taylor’s prior 
treatment development studies with co-occurring substance use and ANX/DEP97. Themes described in 
the focus groups will be identified in transcripts98. After separately examining portions of the transcripts 
for examples that suggest processes, actions, assumptions, and consequences to extract these themes98 
99, we will reach consensus about which themes to examine in detail and a codebook will be 
developed100. Text management software will be used to mark instances where each theme occurs.101 
To increase confidence that all instances of a theme have been identified, 2 independent coders will 
read the material and mark codes102. Once themes have been marked, all text that pertains to each 

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theme will be summarized. For survey data (“End of Session” Questionnaires, AAS, DEVS), total and 
subscale scores will be summarized using descriptive statistics. 
Aim 2: Outcome Analysis of PVS Outcomes.  
Analyses will incorporate the modified intent-to-treat (mITT) principle. Participants who are randomized 
and attend at least one treatment session will be included in the mITT population. We expect missing 
data will be minimal for our primary outcomes, which will be assessed during each visit (<10% lost to 
follow-up), but higher (15-20%) for outcomes assessed only at pre- and post-treatment in the event that 
subjects who discontinue early are lost to follow-up or decline to complete post-assessments.  Missing 
data will be evaluated. If the missingness is not random (non-ignorable), multiple imputation and/or 
propensity weighting will be considered, but will not be applied without extensive sensitivity analysis 
(for more details see Section 4.3 of the Clinical Trials Protocol Synopsis: Statistical Design and Power). As 
a sensitivity analysis we will report associations from complete- and imputed-data analyses. All results 
will be reported as point estimates (means and standard deviations) and interval estimates (95% 
confidence intervals). All tests of significance will be 2-sided. A p-value of 0.05 will be considered 
statistically significant. Analysis will be conducted using R statistical package. Demographic and baseline 
characteristics will be compared between study arms using Fisher’s exact test for categorical variables, 
and a 2-sample t-test for continuous variables. Non-parametric alternatives will be considered, if 
parametric assumptions fail. 
We will employ longitudinal modeling to measure trajectories over time, namely the MMRM 
approach. The primary dependent variable in the MMRM model is change from baseline in positive 
affect at each post-baseline visit. Independent variables in the MMRM model include treatment arm, 
visit (as a categorical variable), arm-by-visit interaction, positive affect at baseline and potential 
covariates of clinical interest (e.g., sex) that are simultaneously unbalanced at baseline (univariate 
p<0.10) and associated with the outcome (univariate p<0.15). To avoid inflation of Type I error, we will 
use permutation tests for inference. Hypothesis: Participants assigned to AMP-A will display greater 
increases in positive affect compared to CBT. Analagous methods will be applied to secondary and 
exploratory positive valence outcome measures, including NIH Toolbox Loneliness and PROMIS Meaning 
and Purpose (secondary) and TEPS, and SBI, MNRQ Positive Reinforcement from Alcohol, SHAPS, NIH 
Toolbox Friendship, and PROMIS General Life Satisfaction, (exploratory), to compare AMP-A vs. CBT 
from baseline to post-treatment. We will use Holm’s adjustment to correct for multiple testing of 
secondary outcomes. There will be no correction for exploratory outcomes. 
Aim 3: Relate changes in PVS function to Changes in Alcohol Use.  
The primary clinical outcome of interest is alcohol use (TLFB number of drinking days in the past month). 
Linear regression models will be performed within the full sample to examine the association between 
change in positive affect (primary target engagement outcome) and change in alcohol use from baseline 
to post-treatment. We will explore whether the magnitude of the correlation differs by treatment arm - 
i.e., if the clinical outcomes of AMP-A seem to have a stronger relationship to changes in PVS as has 
been seen in our prior work in ANX/DEP103. Secondary clinical measures include TLFB average drinks per 

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drinking day (past month), PROMIS anxiety and depression; exploratory measures include TLFB percent 
of heavy drinking days (past month), PROMIS Alcohol Use, MNRQ Negative Reinforcement from Alcohol, 
ACQ-SF, and SDS. Methods analogous to the primary analysis will be applied to examine the association 
between change in primary (positive affect) and secondary target engagement outcomes (NIH Toolbox 
Loneliness; PROMIS Meaning and Purpose measures) and change in anxiety and depression, and 
secondary alcohol use outcomes.  
 
Exploratory Aim: Explore the potential impact of training on neural reactivity during reward processing 
and alcohol cue processing. 
Hypothesis 1a: Participants will have increased striatal responses during the MID task, from pre to post 
intervention. Hypothesis 1b: Participants will have decreased striatal responses during the processing of 
alcohol cues, from pre to post intervention. Analyses will include linear mixed models to investigate the 
time*treatment effects on average percent signal change in regions of interest (striatuma, vmPFC, 
anterior insula, anterior cingulate cortex, amygdala, and dorsolateral prefrontal cortex). 
9.4.1 SAFETY ANALYSES 
 
Acceptability and tolerability of the intervention will be assessed using the Adherence and Acceptability 
Scale78 104 and on the Endorsement and Discomfort Scale79 and symptom rating scales described above. 
Spontaneously reported adverse events will also be documented by study staff. Adverse events will be 
recorded on the Adverse Event Form. 
 
9.4.2 BASELINE DESCRIPTIVE STATISTICS 
 
N/A 
 
9.4.3 PLANNED INTERIM ANALYSES  
9.4.4  
 
N/A, other than the interim safety analysis described above.  
9.4.5 SUB-GROUP ANALYSES 
 
The impact of age and sex will be considered during analyses; given the small sample size, this will be 
evaluated more qualitatively than through specific subgroup analyses.  
 
9.4.6 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be listed by measure and time point. 
 
9.4.7 EXPLORATORY ANALYSES 

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Exploratory analyses will be conducted to examine changes on the self-report measures, brain 
activation and connectivity, being collected that are not specified in the aims and hypotheses. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to 
the participant and written documentation of informed consent will be completed prior to starting the 
study intervention.  The consent materials are submitted with this protocol, along with a 
“communication methods preferences form” that all participants will be asked to complete immediately 
after consent. 
 
10.1.1.2 PROCESS AND DOCUMENTATION OF CONSENT. 
 
Informed Consent will be obtained by members of the research team that have received training 
from the PI to obtain consent for this study. All participant interactions including consenting will be 
conducted in private interview/exam rooms.  
Documented Consent: If the individual appears eligible, we schedule the documented informed 
consent process in order to conduct the Clinical Interview. Documented informed consent will be 
obtained once the consent has been reviewed and the individual agrees to participate using the 
appropriate approved informed consent document. Participants are provided a copy of the consent. 
All volunteers are of legal age and will be asked to give fully informed documented consent following 
consent procedures already approved. Care is taken to appropriately describe IRB-approved consent 
forms as documented by signature of the person giving permission and person obtaining informed 
consent. We review consents for completeness and file them in a locked file cabinet in a locked 
office. Consent may be obtained electronically using tablet computers, in which case a full copy of the 
informed consent will still be provided to the participant. 
Measures to decrease coercion of participants: The researcher will remind the subject that 
participation is strictly voluntary and remind them that they have the right to withdraw at any time 
without penalty. In addition, it will be emphasized that their decision to participate or not participate 
in the research study will have no impact on their treatment and care provided by external treatment 
providers. Family members will be allowed to be present and discuss the consenting process with the 
participant if requested.  

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Subject Capacity: All subjects enrolled in this study will have the capacity to consent. 
Subject/Representative Comprehension: During written informed consent, subject’s understanding 
of the study protocol will be assessed using open-ended questions (e.g., Q: “Approximately how long 
will you be followed for the purposes of this study?” A: “approximately 10-16 weeks”). If they are 
unable to communicate understanding of the protocol, they will not be enrolled in the study. 
Debriefing Procedures: None of the procedures used in this study involve withholding 
information from the subject. 
 
 
10.1.1.3 CONSENT PROCEDURES AND DOCUMENTATION 
 
See previous section. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor/funding 
agency and will provide the reason(s) for the termination or suspension. Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Demonstration of efficacy that would warrant stopping    
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
Determination of futility 
 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the funding agency, sponsor, and IRB. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Strategies to manage and protect the privacy of participants and confidentiality of research data: 
We have instituted the following measures to protect the privacy of participants and confidentiality 
of research data: 
 Data will be collected by LIBR staff who completed training in human subjects’ research, HIPAA, 
and research integrity, on research data management, confidentiality and mandatory reporting, 
and project specific training on the protocol.   
 To protect confidentiality, no personally identifying information will be coded on questionnaires, 
interviews, brain imaging data, or other study records. Further, subjects will not be identified in 

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any reports or publications. All de-identified hard-copy data will be stored in locked file cabinets 
in a locked office. A unique subject identification number is assigned to each participant, and 
linked to the study participant name in an electronic file managed in accordance with ISO 2700 
standards as specified below with access limited the PI, Study Psychiatrist or Physician, and 
designated Study Coordinator.   
 The original signed consents, screening form, locator form with contact information, the 
Research Privacy Form, and any other forms or papers containing personally identifiable 
information (PII) will be stored in a secured medical records room with access granted only to 
authorized study personnel. 
 Electronic data will be stored securely on servers and databases accessible only to study 
personnel. 
 
The Life Chart application, developed by LIBR, is accessed only within the LIBR network by participants 
and members of LIBR’s research team. Life Chart data is stored behind a firewall through a password 
protected database on a secure server managed by LIBR that undergoes weekly security dynamic and 
static analysis scans through Veracode’s platform under the HIPAA/Omnibus Act/HITECH/HITRUST 
policy. Veracode is used by over 2000+ companies in the world in making secure software 
(www.veracode.com). 
 
A Certificate of Confidentiality will be obtained from NIH to further protect the subject. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
N/A 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator
Robin Aupperle, PhD, licensed clinical psychologist
Laureate Institute for Brain Research
6655 S. Yale Ave., Tulsa, OK
918-502-5744
raupperle@libr.net
 
Co-investigators include: Martin Paulus, MD (LIBR Scientific Director and board-certified psychiatrist), 
Jennifer Stewart, PhD (LIBR Principal Investigator), Charles Taylor, PhD (collaborator and Associate 
Professor, University of California – San Diego), Kate Wolitzky Taylor, PhD (collaborator and Associate 
Professor, University of California – Los Angeles), and Evan White, PhD (LIBR Associate Investigator).  
 
10.1.6 SAFETY OVERSIGHT 
 
Given the low level of risk involved in this study, safety oversight will be under the direction of the PI 
and co-investigator and LIBR Scientific Director, Dr. Martin Paulus.  

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10.1.7 CLINICAL MONITORING 
Clinical site monitoring will be conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Council on Harmonisation Good Clinical Practice (ICH GCP), and with applicable 
regulatory requirement(s).  
 
The Project PI and Dr. Martin Paulus (board-certified psychiatrist, LIBR Scientific Director) will have 
primary responsibility for monitoring the safety of the study and complying with the reporting 
requirements. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process as well 
as a percentage of the completed consent documents.  This review will evaluate compliance with GCP, 
accuracy, and completeness.  Feedback will be provided to the study team to ensure proper consenting 
procedures are followed.  
 
Protocol Deviations – The study team will review protocol deviations on an ongoing basis and will 
implement corrective actions when the quantity or nature of deviations are deemed to be at a level of 
concern. 
 
The PI will be responsible for ensuring the quality of data collected. As needed, the PI will provide direct 
access to all trial related sites, source data/documents, and reports for the purpose of monitoring and 
auditing by the sponsor/funding agency, and inspection by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection will be the responsibility of the study staff at the site under the supervision of the site 
investigator. The investigator will be responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents will be completed in a neat, legible manner to 
ensure accurate interpretation of data. Hardcopies of the any measures or study visit worksheets will be 
provided for use as source document worksheets for recording data for each participant 
consented/enrolled in the study.  Data recorded in the electronic database (RedCAP) will be consistent 
with the data recorded on the source documents. The RedCAP data system in which information is 
entered and securely stored 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. 
10.1.9.2 STUDY RECORDS RETENTION  

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Per NIH policies, study records will be retained records for a period of at least three years from the date 
of final Federal Financial Report (FFR) submission.   
 
10.1.10 
PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
International Council on Harmonisation Good Clinical Practice (ICH 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. As a result of deviations, corrective actions will be developed by the site and 
implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3  
• 
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1  
• 
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2.  
 
It will be the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations. All deviations will be addressed in study source documents, reported to the NIH program 
official. Protocol deviations will be sent to the reviewing Institutional Review Board (IRB).  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY  
 
This study will comply with the NIH Data Sharing Policy and Policy and as such, this trial will be 
registered at ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.   
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, 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 design and conduct of this trial.  
 
10.2 ADDITIONAL CONSIDERATIONS 
 
N/A 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
AAS
Adherence and Acceptability Scale
ACC
Anterior Cingulate Cortex

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ACQ-SF
Alcohol Craving Questionnaire Short Form
AE
Adverse Events
AMP-A
Affective Modulation of Positivity for Alcohol Use Disorder
CBT
Cognitive-Behavioral Therapies
CDDR
Customary Drinking and Drug Use Record
CFR
Code of Federal Regulations
CM
Contingency Management
CNS
Central nervous system
COPES
Community Outreach Psychiatric Emergency Services
DAST
Drug Abuse Screening Test
DCR
Alcohol Cue Reactivity
DEVS
Distress/Endorsement Validation Scale
dlPFC
Dorsolateral prefrontal cortex
DSM-5
Diagnostic and Statistical Manual of Mental Disorders – 5th Edition
EPI
Echo-planar imaging
FFR
Federal Financial Report
FLAIR
Fluid-attenuated inversion recovery
fMRI
Functional magnetic resonance imaging
GAD
Generalized Anxiety Disorder
HIPAA
Health Insurance Portability and Accountability Act of 1996
HITECH
Health Information Technology for Economic and Clinical Health Act
IAPS
International Affective Picture System
ICH GCP
International Council on Harmonisation Good Clinical Practice
IRB
Institutional Review Board
ISO 
International Organization for Standardization
KSS
Karolinska Sleepiness Scale
LIBR
Laureate Institute for Brain Research
MASQ
Mood and Anxiety Symptom Questionnaire-Short Form
MDD
Major Depressive Disorder
MI
Motivational interviewing
MID
Monetary Incentive Delay Task
MINI
Mini International Neuropsychiatric Inventory
MP-RAGE
Magnetization prepared rapid gradient-echo
MR
Magnetic resonance
MRI
Magnetic resonance imaging
NAPS
Normative Appetitive Picture System
NCT
National Clinical Trial
NIH
National Institutes of Health
NIST 
National Institute of Standards and Technology
OASIS
Overall Anxiety Severity and Impairment Scale
OCD
Obsessive-Compulsive Disorder
OFC
Orbitofrontal Cortex
OHRP
Office for Human Research Protections
PACS
Picture archiving and communication systems
PANAS
Positive and Negative Affective Schedule
PCL
Posttraumatic Stress Disorder Checklist

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PD
Panic Disorder
PHQ-9
Patient Health Questionnaire
PI
Primary Investigator
PII
Personally identifiable information
PLUS
Participant Last Use Summary
PROMIS
Patient-Reported Outcomes Measurement Information System 
PTSD
Posttraumatic stress disorder
QC
Quality control
QIDS
Quick Inventory of Depressive Symptomatology
REDCap
Research Electronic Data Capture
SAD
Social Anxiety Disorder
SAE
Serious adverse events
SCS-R
Social Connectedness Scale - Revised
SDS
Sheehan Disability Scale
SHAPS
Snaith-Hamilton Pleasure Scale
SoA
Schedule of Activities
SP 
Special publication
SPSRQ
Sensitivity to Punishment and Sensitivity to Reward Questionnaire
SUD
Substance Use Disorder
TENS 
Transcutaneous electrical nerve stimulation
TEQ
Traumatic Events Questionnaire
UP
Unanticipated problems
US
United States
USB
Universal serial bus
VPN
Virtual private network
WIR
Women in recovery
WIRB
Western Institutional Review Board
 
 
 

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