A Randomized, Sham-Controlled Trial Investigating Deep Brain Stimulation as a Novel Treatment for Refractory Opioid Use Disorder
Phase: NA
Conditions: Opioid-Related Disorders
Sponsor: West Virginia University

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A Randomized, Sham-Controlled Trial Investigating Deep Brain Stimulation 
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as a Novel Treatment for Refractory Opioid Use Disorder 
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Protocol No: DBS OUD 02 
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IDE Number: G220333  
 
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Approval: 
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Protocol Version 2.0  
 
 
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15 Sep 2023  
 
 
 
Ali Rezai, MD 
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Principal Investigator 
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CONTENTS 
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1 
 
2 
GLOSSARY....................................................................................................................................5 
3 
SCHEMA ........................................................................................................................................6 
4 
1.0 
STUDY OBJECTIVE ........................................................................................................8 
5 
2.0 
INTRODUCTION..............................................................................................................8 
6 
2.1 
Background ..............................................................................................................8 
7 
2.2       Preliminary Data ......................................................................................................9 
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3.0 
STUDY DESIGN ..............................................................................................................13 
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3.1 
Randomization and Blinding Procedures...............................................................13 
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3.2 
Breaking the Blind .................................................................................................13 
11 
4.0 
STUDY POPULATION ..................................................................................................14 
12 
4.1 
Inclusion Criteria ...................................................................................................14 
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4.2 
Exclusion Criteria ..................................................................................................15 
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4.3 
Recruitment Process...............................................................................................16 
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4.4  
Informed Consent...................................................................................................17 
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4.5 
Participant Replacement Guidelines ......................................................................17 
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4.6  
Concomitant Therapy.............................................................................................17 
18 
5.0      STUDY PROCEDURES ..................................................................................................18 
19 
5.1 
Phase I: Screening and Baseline Phase ..................................................................21 
20 
5.2 
Phase II: DBS Surgery ...........................................................................................21 
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5.3 
Phase III: DBS Titration and Stimulation ..............................................................21 
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5.4 
Phase IV:  Primary Endpoint – Follow-up and Monitoring (12 Week Outpatient 
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Phase) .....................................................................................................................22 
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5.5 
Phase V:  Secondary Endpoint – Exploratory Follow-up and Monitoring (Sham 
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Arm – 12 weeks DBS-OFF vs 12 weeks DBS-ON) ..............................................23 
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5.6 
Phase VI:  Tertiary Endpoint – Exploratory Follow-up and Monitoring (52 weeks 
27 
post-active stimulation) ..........................................................................................23 
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5.7 
Long-Term Follow up (> 52 weeks post-active stimulation) ................................24 
29 
5.8 
Study Measures and Assessments ..........................................................................24 
30 
5.9 
Neuroimaging ........................................................................................................30 
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5.10  Potential Benefits ...................................................................................................32 
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5.11 
Potential Risks .......................................................................................................32 
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5.12  Other Risks.............................................................................................................36 
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5.13 Procedures for Minimizing Risks ..............................................................................37 
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6.0 
 SAFETY ENDPOINTS ..................................................................................................41 
36 
7.0  
PLAN FOR REPORTING ANTICIPATED AND UNANTICIPATED PROBLEMS 
37 
AND ADVERSE EVENTS ..............................................................................................41 
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7.1 
Serious Adverse Events .........................................................................................41 
39 
7.2 
Unanticipated Adverse Device Effects ..................................................................42 
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7.3 
Device Malfunction ...............................................................................................42 
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7.4  
Documentation of Adverse Events ........................................................................42 
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7.5 
Reporting of Serious Adverse Events ....................................................................44 
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7.6 
Trial Stopping Rules ..............................................................................................45 
2 
7.7 
Additional Stopping Criteria ..................................................................................46 
3 
8.0  
DATA SAFETY AND MONITORING .........................................................................47 
4 
9.0 
DATA AND STATISTICAL CONSIDERATIONS .....................................................49 
5 
9.1 
Primary Outcomes/Endpoints ................................................................................49 
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9.2 
Secondary Outcomes/Endpoints ............................................................................50 
7 
10.0  REGULATIONS AND ETHICAL CONDUCT OF THE STUDY .............................51 
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11.0  DEVICE DESCRIPTION ...............................................................................................51 
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12.0 
REFERENCES .................................................................................................................54 
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PROTOCOL TEAM
1 
2 
Principal Investigator: 
3 
 
4 
Ali Rezai, MD 
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6 
Co-Investigators: 
7 
 
8 
Sally Hodder, MD 
9 
James J. Mahoney, III, PhD 
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Daisy Thompson-Lake, PhD 
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James Berry, DO 
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Wanhong Zheng, MD 
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Manish Ranjan, MD 
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Daniel Farmer, DO 
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GLOSSARY 
1 
 
2 
ASPD  
Antisocial Personality Disorder 
3 
COAT  
Comprehensive Opioid Addiction Treatment 
4 
CRC  
Chestnut Ridge Center 
5 
CSSRS 
Columbia Suicide Severity Rating Scale 
6 
DA 
 
Dopamine Levels 
7 
DBS  
Deep Brian Stimulation 
8 
DDU  
Dual Diagnosis Unit 
9 
DSMB  
Data Safety and Monitoring Board 
10 
EEG 
 
Electroencephalogram 
11 
FDG  
Fluoro-Deoxy-Glucose 
12 
fMRI  
Functional Magnetic Resonance Imaging 
13 
GSR  
Galvanic Skin Response 
14 
HDE  
Humanitarian Device Exemption 
15 
IDE 
 
Investigational Device Exemption 
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IPG  
 
Implanted Pulse Generator  
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IRB 
 
Institutional Review Board 
18 
LFP 
 
Local Field Potential 
19 
MAT  
Medication Assisted Treatment 
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MRI 
 
Magnet Resonance Imaging 
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NAc 
 
Nucleus Accumbens 
22 
NIH 
 
National Institutes of Health 
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NIDA  
National Institute on Drug Abuse 
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OUD  
Opioid Use Disorder 
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OCD  
Obsessive Compulsive Disorder 
26 
PET 
 
Positron Emission Tomography 
27 
PHI 
 
Personal Health Information 
28 
RMH  
Ruby Memorial Hospital 
29 
SUD   
Substance Use Disorder 
30 
TBI 
 
Traumatic Brain Injury 
31 
VC 
 
Ventral Capsule 
32 
VS 
 
Ventral Striatum 
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WVU   
West Virginia University 
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SCHEMA 
1 
 
2 
PURPOSE 
The overall objective of this study is to assess the safety, tolerability, and 
3 
feasibility of using deep brain stimulation (DBS) to treat opioid use disorder 
4 
(OUD) as well as investigate the potential impact on substance use and risk 
5 
factors associated with drug use recurrence. This study is part of a NIDA 
6 
U01 cooperative agreement award with WVU that will provide critical 
7 
information for planning subsequent clinical trials.  
8 
DESIGN 
This is a randomized, sham-controlled, partial crossover study investigating 
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DBS, targeting the nucleus accumbens (NAc) and ventral internal capsule 
10 
(VC), for participants with severe, treatment refractory OUD. 
11 
DURATION 
Participants are monitored in an inpatient service for approximately 1-2 
12 
weeks to gather screening and baseline data (Phase I) prior to DBS 
13 
placement. Post-implantation they remain for up to 2-3 weeks as inpatients 
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for clinical stabilization (Phase II) and DBS titration (Phase III). Half of the 
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participants are randomized to receive Active DBS (DBS-ON) and half are 
16 
randomized to receive Sham DBS (DBS-OFF). All participants are 
17 
followed twice a week for 12 weeks in the outpatient setting (Phase IV). At 
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12 weeks, participants randomized to DBS-OFF are crossed over to active 
19 
stimulation and re-admitted to the inpatient service for 1-2 weeks to 
20 
complete active titration (weeks 13-14). After titration, these participants 
21 
are discharged to outpatient and followed twice a week for 12 weeks in the 
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outpatient setting (Phase V). All participants remain with the DBS active 
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for one-year post-stimulation (Phase VI), and are monitored weekly for 
24 
safety. At the end of the study, participants may enter a separate long-term 
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safety follow-up for up to five years. 
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SAMPLE SIZE  
Twenty participants will be enrolled in this study to achieve a final sample 
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size of 16 participants who will complete the primary outpatient endpoint 
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(Week 12). 
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POPULATION 
Persons aged 22- 50 years who meet eligibility criteria. 
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OBJECTIVE              The overall objective of this study is to conduct a prospective, randomized, 
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sham-controlled trial of DBS in participants with treatment refractory OUD. 
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Objectives also include an evaluation of the safety and tolerability of 
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NAc/VC DBS and the effect of NAc/VC DBS on opioid use, the brain 
34 
reward circuitry through evaluation of dopamine in the basal ganglia and 
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NAc (18F-fallypride PET), and the effect on prefrontal cortex function 
36 
through the measurement of executive function. 
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PRIMARY/SECONDARY OUTCOME ENDPOINT 
 
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• Between-Subject Comparisons – Participants receiving 12 weeks of Active DBS stimulation 
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will be compared to participants receiving 12 weeks of Sham DBS stimulation. 
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PRIMARY OUTCOMES 
 
1 
1) Safety and tolerability, as measured by all adverse events related to DBS.   
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2) Opioid use as measured by quantitative urine toxicology via gas chromatography/ mass 
3 
spectrometry (GC/MS). 
4 
 
5 
SECONDARY OUTCOMES  
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Impact of Active (DBS-ON) versus Sham (DBS-OFF) NAc/VC DBS on: 
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1) Brain reward circuitry through evaluation of dopamine in the basal ganglia and NAc 
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(18F-fallypride PET) and prefrontal cortex glucose metabolism (FDG PET). 
9 
2) Cognitive functioning, assessed with behavioral scores and/or MRI data. 
10 
3) Quantitative urine toxicology for non-opioid substances (e.g. cannabis, cocaine, 
11 
amphetamine, benzodiazepines) as measured via GC/MS. 
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4) Qualitative urine toxicology for opioids and other substances. Salivary toxicology may be 
13 
conducted as an alternative if the participant is unable to physically present to clinic. 
14 
5) Substance craving, assessed with behavioral scores and/or MRI data. 
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6) Emotional functioning (depression and anxiety). 
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7) Drug overdoses defined according to the National Library of Medicine 
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(www.nlm.nih.gov). 
18 
8) Incidence of serious infectious disease complications (e.g., endocarditis, osteomyelitis, 
19 
septic arthritis, etc.). 
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9) Retention in comprehensive behavioral treatment. 
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10)  Patient survival. 
22 
 
23 
ADDITIONAL OUTCOME ENDPOINTS  
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• Within-Subject Comparisons (Phase V Endpoint) – For those initially randomized to Sham 
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DBS condition (DBS-OFF), following crossover to active stimulation, comparisons of the 
26 
initial 12 weeks of stimulation “OFF” will be made to the 12 weeks of stimulation “ON” for 
27 
the primary and secondary outcomes listed above. 
28 
• Within-Subject Comparisons (Study Completion) – For all participants, comparisons 
29 
following 52 weeks of active stimulation will be made to pre-surgical baseline for the 
30 
primary and secondary outcomes listed above. 
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32 
EXPLORATORY OUTCOMES 
 
 
33 
• Local field potentials (to examine for changes in the neural response in the NAc following 
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DBS of the NAc/VC) 
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• Functional connectivity via resting state and task-based fMRI (to examine for changes in the 
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reward circuitry and associated regions following DBS of the NAc/VC) 
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• Structural brain changes pre- and post-treatment. (e.g., cortical morphometry, subcortical 
38 
volume and white matter integrity) 
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• Exploratory voltammetry analysis recording neural responses to cues from the nucleus 
1 
accumbens 
2 
1.0 
STUDY OBJECTIVE 
3 
 
4 
The overall objective of this study is to assess the safety, tolerability, and feasibility of using deep 
5 
brain stimulation (DBS) to treat opioid use disorder (OUD) as well as investigate the potential 
6 
impact on substance use and risk factors associated with drug use recurrence. This overall objective 
7 
will be attained through completion of the following co-primary specific aims:  
8 
 
9 
• Evaluate safety and tolerability of DBS in 20 participants with treatment refractory OUD. 
10 
• Demonstrate the impact of Active DBS versus Sham DBS on opioid use as measured by 
11 
quantitative urine toxicology via gas chromatography/ mass spectrometry (GC/MS) 
12 
 
13 
2.0 
INTRODUCTION 
14 
 
15 
2.1 
Background 
16 
Novel treatments for OUD are desperately needed. In 2020, there was an estimated 9.5 
17 
million people who misused opioids (Center for Behavioral Health Statistics and Quality, 2021). 
18 
Drug overdose deaths from suicide and unintentional overdose have increased dramatically since 
19 
2017 (Bohnert and Ilgen 2019). In 2021, the documented number of drug overdoses was the 
20 
highest in recorded history; there were >107,000 overdose deaths and >75% of these overdose 
21 
deaths involved opioids many of which were synthetic opioids such as fentanyl (Ahmad et al., 
22 
2022). The toll of this opioid epidemic goes well beyond overdose survivals and deaths. Rates of 
23 
Hepatitis C (HCV) have steadily increased over the past decade and once again future generations 
24 
may be affected as the number of pregnant women with HCV has doubled in recent years and this 
25 
virus may be transmitted by a pregnant woman to her infant (CDC, 2017). The morbidity and 
26 
mortality secondary to the opioid epidemic is clearly one of the greatest public health problems 
27 
that the U.S. currently faces. In addition to the detrimental impact on health, there are significant 
28 
financial consequences, specifically, the total economic burden is estimated to be $78.5 billion for 
29 
opioid overuse and dependence, of which $28.9 billion was only related to increased health care 
30 
cost (Florence et al., 2016). 
31 
Current treatment of OUD is far from ideal. State-of-the-art treatment, which includes 
32 
medically assisted treatment (MAT) combined with psychosocial interventions result in a 50% 
33 
success rate, at best. For example, in a multisite, randomized trial, the rate of unsuccessful 
34 
outcomes following stabilization on MAT over 12 weeks was less than 50% (Weiss, Potter et al. 
35 
2011). A recent review of extended release injectable naltrexone revealed that many patients never 
36 
even start the treatment because of withdrawal symptoms and those who start often discontinue 
37 
(Jarvis, Holtyn et al. 2018). In addition, extended release Naltrexone and buprenorphine have 
38 
unacceptably high relapse rates, with 24-week relapse rates (65% vs. 57%, respectively) (Lee, 
39 
Nunes et al. 2018). Individuals failing standard OUD treatment have a substantial risk of death. 
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Given the enormously increasing socio-economic burden and death risk with OUD, newer and 
1 
innovative treatment modalities are urgently needed. In addition, we need to better understand the 
2 
mechanisms of action for addiction to develop specialized, focused treatments in future.   
3 
In DBS a tiny electrode is placed deep inside the brain at a specific target using a computer 
4 
assisted stereotactic technique. This electrode is connected to a subcutaneous implanted pulse 
5 
generator (IPG) which gives electrical stimulation to the area targeted/implanted. DBS has 
6 
demonstrated safety and efficacy in treatment refractory movement disorders and obsessive-
7 
compulsive disorder (OCD) and is being investigated in a number of other neurobehavioral 
8 
conditions, including but not limited to depression, Tourette’s syndrome, eating disorders, 
9 
traumatic brain injury, Alzheimer’s disease and addiction (Alonso et al., 2015; de Haan, Rietveld, 
10 
Stokhof, & Denys, 2015; Denys et al., 2010; Dougherty et al., 2015; Greenberg et al., 2010; 
11 
Greenberg et al., 2006; Grover et al., 2009; Hamani et al., 2009; Houeto et al., 2005; Kalivas & 
12 
Volkow, 2005; Laxton et al., 2010; Lipsman et al., 2017; Lipsman et al., 2013; Lozano et al., 2016; 
13 
Mayberg et al., 2005; Muller et al., 2009; Rezai et al., 2016, 2018; Smit et al., 2016; Whiting et 
14 
al., 2013). With recent developments in the understanding of the neural basis of addiction (Kalivas 
15 
& Volkow, 2005; Koob & Volkow, 2010, 2016) the Nucleus Accumbens (NAc) emerged as the 
16 
key area of the nodal neural network with robust neural connections through the ventral internal 
17 
capsule (VC). We hypothesize that in treatment refractory OUD, DBS of the NAc/VC will 
18 
modulate the brain reward circuitry by increasing dopamine (DA) levels and thus increasing frontal 
19 
lobe activity.  This will thereby reduce opioid cravings and use and additionally improve inhibition 
20 
and decision making; thus, improving outcomes (e.g., decreased drug overdoses).  
21 
The overarching goal of this study is to further assess the safety, tolerability, and feasibility 
22 
of using DBS to treat OUD as well as investigate the potential impact on substance use and risk 
23 
factors associated with drug use recurrence. There is a high rate of morbidity and death, in addition 
24 
to a huge health care burden associated with OUD (Benumof, 2016; Centers for Disease Control 
25 
and Prevention, 2017; Degenhardt et al., 2014; Florence et al., 2016; Haddy et al., 2017; National 
26 
Center for Health Statistics, 2017; West Virginia Department of Health and Human Resources 
27 
Bureau for Public Health, 2017). Given the life-threatening nature of treatment refractory OUD, 
28 
innovative approaches and more invasive interventions including DBS warrant investigation. 
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The research team led by Dr. Ali Rezai at West Virginia University (WVU) is highly 
30 
experienced in all the elements necessary to conduct this trial: state-of-the-art treatment of OUD, 
31 
NAc/VC DBS surgery, titration and programming, neuroimaging, executive function assessment, 
32 
and clinical trial management.  
33 
 
34 
2.2       Preliminary Data 
35 
2.2.1 Current OUD Treatment Outcomes at WVU 
36 
The Comprehensive Opioid Addiction Treatment (COAT) program was developed at 
37 
WVU in 2004 in response to the emerging opioid epidemic (Zheng et al., 2017). The COAT 
38 
program uses a structured group-based multidisciplinary and multimodal approach including: 1) 
39 
behavioral intervention (both group and individual therapy), 2) required participation in 
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community peer-recovery support groups, and 3) medically assisted treatment with 
1 
buprenorphine/naloxone. A key element of the COAT program includes continued maintenance 
2 
on buprenorphine/naloxone rather than mandatory tapering. Clinic visits consist of a shared group-
3 
based 30-minute medical appointment with the prescribing physician followed by a 90-minute 
4 
group psychotherapy session with a skilled therapist and case manager. In this model of care, 
5 
participants advance through 4 stages of treatment, based on their sustained abstinence and 
6 
program adherence: Stage 1- treatment initiation with weekly sessions, Stage 2 – those 
7 
successfully sustaining abstinence for 90 days progress to attending clinic bi-weekly, Stage 3 – 
8 
after one year of abstinence, monthly clinic sessions with group therapy, and Stage 4 – after two 
9 
years of abstinence, monthly clinic sessions without group therapy. The Intensive COAT program, 
10 
is for those patients who are unable to sustain abstinence in the standard COAT program. These 
11 
patients are prone to relapse and fail to sustain recovery in the weekly group and are thus seen 
12 
thrice weekly. While the WVU COAT program has successfully treated thousands of OUD 
13 
patients, the treatment failure rate remains high, with only half of the patients continuing to be 
14 
engaged in COAT at three months. WVU also has a 30 bed 28-day residential SUD treatment 
15 
program which also includes an additional 12 beds for detoxification services and managements.  
16 
For the current study, participants will be recruited from these locations. 
17 
 
18 
2.2.2 Prior DBS of NAc/VC Investigations 
19 
In the past twenty years, the use of brain pacemakers or DBS, has emerged as a promising 
20 
new therapeutic approach for neuro/psychiatric disorders with over 170,000 DBS implants 
21 
worldwide. DBS has the advantage of being adjustable and reversible since it can be turned off if 
22 
unwanted effects are reported. DBS is an FDA approved and Medicare reimbursed therapy for 
23 
patients with Parkinson’s disease, essential tremor, dystonia and OCD (under a Humanitarian 
24 
Device Exemption [HDE]), and treatment refractory epilepsy. Several clinical investigations have 
25 
explored the utility of DBS to treat a range of neurobehavioral disorders including OCD, 
26 
depression, Tourette’s disease, eating disorders, traumatic brain injury, Alzheimer’s, and addiction 
27 
(Alonso et al., 2015; de Haan et al., 2015; Denys et al., 2010; Dougherty et al., 2015; Greenberg 
28 
et al., 2010; Greenberg et al., 2006; Grover et al., 2009; Hamani et al., 2009; Houeto et al., 2005; 
29 
Kalivas & Volkow, 2005; Laxton et al., 2010; Lipsman et al., 2017; Lipsman et al., 2013; Lozano 
30 
et al., 2016; Mayberg et al., 2005; Muller et al., 2009; Rezai et al., 2018; Rezai et al., 2016; Smit 
31 
et al., 2016; Whiting et al., 2013). For example, patients with OCD undergoing DBS have obtained 
32 
significant improvements in overall functioning, independence, quality of life enhancement, return 
33 
to work or school and resumption of daily activities (Greenberg et al., 2010; Greenberg et al., 
34 
2006) and the same is true for the other medical conditions mentioned above, although they will 
35 
not be reviewed in detail here (Malone et al., 2009; Rezai et al., 2018; Rezai et al., 2016).   
36 
Although the exact mechanism of action of DBS is still unknown, it is clear that the effects 
37 
of DBS are not achieved by a highly localized effect on neurons adjacent to the electrode but by 
38 
modulating effects on neural networks associated with the target region (Benazzouz & Hallett, 
39 
2000; Chiken & Nambu, 2016; McIntyre, Savasta, Kerkerian-Le Goff, & Vitek, 2004; 
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Montgomery & Gale, 2008; Udupa & Chen, 2015). A distributed mechanism of action is supported 
1 
by the findings of a recent study using DBS of NAc to treat OCD (Figee et al., 2013). Using 
2 
functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), the authors 
3 
showed that NAc-frontal network modulation of DBS was able to restore normal NAc function 
4 
and cortico-striatal circuitry connectivity. Dysfunction in cortico-striatal circuitry is postulated to 
5 
be a core feature of OUD, and therefore these findings provide a rationale for the use of DBS in 
6 
the treatment of OUD. 
7 
The PI has extensive experience with DBS surgery in various brain targets with more than 
8 
2000 patients from 1997-2018 with a surgical complication rate of 1% hemorrhage (symptomatic 
9 
0.1%), 2% infection, and 2% device related complications (personal communication-AR), 
10 
consistent with standards in the field.  Dr. Rezai has further participated as a key investigator or 
11 
PI in several NAc/VC DBS clinical trials for neurobehavioral disorders. These studies 
12 
demonstrated 1) safety and efficacy for intractable OCD (Greenberg et al., 2010; Greenberg et al., 
13 
2006), 2) safety but not efficacy in a randomized controlled trial for major depression (Dougherty 
14 
et al., 2015), 3) lack of feasibility in a pilot trial of morbid obesity (Rezai et al., 2018) and 4) safety 
15 
and improved functional outcomes in pilot trials in Alzheimer’s disease (Scharre et al., 2018) and 
16 
traumatic brain injury (Rezai et al., 2016).  Furthermore, Dr. Rezai has experience in neuroimaging 
17 
with DBS, demonstrating impact on brain circuitry (Rauch et al., 2006; Rezai et al., 2016; Scharre 
18 
et al., 2018). Specifically, FDG PET studies of NAc/VC DBS in patients with OCD, and 
19 
Alzheimer’s disease have shown moderation of pathological brain glucose metabolism in the 
20 
frontal cortex (Rauch et al., 2006; Scharre et al., 2018). 
21 
 
22 
2.2.3 Research Studies in Support of the NAc as a DBS Target for Treatment of OUD 
23 
Animal Studies. DBS to the shell of the NAc in drug-seeking rats selectively blocked 
24 
reinstatement of cocaine seeking induced by a priming dose of psychomotor stimulants (Vassoler 
25 
et al., 2008) and conditioned place preference for morphine in rats is attenuated by DBS (Liu et 
26 
al., 2008). Rats trained to self-administer cocaine in the presence of light showed decreased cue-
27 
induced reinstatement of cocaine when they were pretreated with deep brain stimulation of the 
28 
NAc (Guercio et al., 2015). Lesioning the NAc decreased food hoarding and gave rise to sustained 
29 
weight reduction in obese mice (Halpern et al., 2011; Kelley & Stinus, 1985). Similarly, DBS 
30 
stimulation of the NAc decreased caloric intake and also resulted in a sustained weight loss in 
31 
obese mice (Halpern et al., 2013; Ho et al., 2015). Following high frequency DBS of the NAc in 
32 
animals, there is a decrease in the firing rate of the orbitofrontal cortex pyramidal cells and 
33 
enhanced synchronicity of the thalamo-cortical circuit (McCracken & Grace, 2007, 2009). 
34 
Human Studies.  Review of the DBS literature reveals that stimulation of the NAc and VC has 
35 
been performed since 1998 in patients with various neurobehavioral disorders including 
36 
depression, OCD, anxiety disorders, addiction, TBI, Alzheimer’s disease and eating disorders. 
37 
DBS of the NAc/VC is proven safe and beneficial for the treatment of OCD, approved by the FDA 
38 
HDE in 2009 (Greenberg et al., 2010; Greenberg et al., 2006; B. Nuttin, Cosyns, Demeulemeester, 
39 
Gybels, & Meyerson, 1999). A double-blind study involving stimulation of the NAc/VC showed 
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a significant reduction of OCD symptoms (B. J. Nuttin et al., 2003). In addition, DBS was shown 
1 
to be safe and effective in open-label pilot study for major depression (Malone et al., 2009). In a 
2 
recent double blind, phase III sham-controlled trial for depression, stimulation of the NAc/VC was 
3 
found safe, but failed to show a significant difference in outcome between sham and real 
4 
stimulation (Dougherty et al., 2015). Case reports also show that stimulation of the NAc/VC can 
5 
contribute to smoking cessation (Mantione, van de Brink, Schuurman, & Denys, 2010) and to a 
6 
reduction in heroin seeking behaviors (Zhou, Xu, & Jiang, 2011)  
7 
Recently, Figee et al., examined network changes induced by NAc/VC DBS with fMRI 
8 
and EEG in fully implanted patients with OCD (Figee et al., 2013).  Their findings suggest that 
9 
modulation of NAc/VC activity changes frontostriatal connectivity. These changes correlated with 
10 
symptom improvement. Moreover, such a study highlights the fact that DBS effects may not just 
11 
be confined locally, to the relatively small target area, but may be due to a broader modulation of 
12 
several neural circuits and networks. Figee et al. also measured dopamine D2/3 receptor 
13 
availability in the striatum with iodobenzamide single photon emission computed tomography in 
14 
OCD patients. Following NAc/VC DBS there was a decrease in the binding potential in the NAc 
15 
suggesting that DBS induced striatal dopamine release (Figee et al., 2014). One recent study of 
16 
NAc/VC DBS for heroin addiction, done outside USA, was very encouraging with 5 of 8 patients 
17 
achieving abstinence from heroin for more than 3 years (Chen et al., 2018).  
18 
In summary, the reasons to consider DBS of the NAc/VC as an intervention for patients 
19 
with treatment refractory OUD are threefold: 1) The NAc is heavily implicated in both normal and 
20 
drug-induced reward processes and plays a key role in cue-induced craving. Moreover, the NAc 
21 
acts as a ‘motivation gateway’ between the limbic system involved in emotion and systems 
22 
involved in motor control, and is uniquely located to modulate activity in other regions of the brain. 
23 
2) OUD, characterized by dysfunction in several integrated neural pathways, creates the need for 
24 
a treatment that directly targets and normalizes the affected brain circuits. 3) Preclinical studies 
25 
and human case studies report encouraging results for DBS as a treatment for OUD and have 
26 
shown that NAc/VC appears to be a promising and safe target. 
27 
 
28 
2.2.4 WVU/RNI Study Investigating the Safety and Feasibility of NAc DBS for Refractory OUD  
29 
In 2019, we initiated a National Institute on Drug Abuse (NIDA) sponsored single-arm 
30 
clinical trial (ClinicalTrials.gov Identifier; NCT03950492) to evaluate safety and feasibility of a 
31 
neuromodulation approach using DBS of the NAc for treatment-refractory OUD. Four participants 
32 
(all males, ages 20-46) with longstanding history of severe, treatment-refractory OUD and multiple 
33 
overdoses underwent bilateral image-guided stereotactic NAc and internal capsule DBS 
34 
implantation. The study protocol involved the following phases: screening, baseline, DBS 
35 
implantation and titration (all conducted inpatient), and the outpatient follow-up phases. Following 
36 
the baseline phase, bilateral quadripolar DBS electrodes (lead 3387, Medtronic) were implanted 
37 
stereotactically in the NAc and the ventral internal capsule (VC) and connected to the 
38 
neurostimulator in the chest. The DBS parameters of polarity, pulse width, frequency, and intensity 
39 
were optimized during the inpatient titration phase and guided by the participants’ reported 
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anxiety, mood, and substance cravings. Subsequently, participants were discharged to outpatient 
1 
follow-up with the primary outcome endpoint being Outpatient Week 12 as well as a long-term 
2 
follow-up (Outpatient Week 52, primary study completion). Outcomes included safety, substance 
3 
use, cue-induced craving (visual analog scale (VAS); 0 = no craving, 100 = maximum craving), 
4 
anxiety (Brief Scale for Anxiety; BSA), and depression (Montgomery Asberg Depression Rating 
5 
Scale; MADRS).  
6 
DBS surgery was safe in all participants with no complications.  To date, participants #1 
7 
and #3 (both of whom have completed the primary 52-week protocol) have sustained abstinence 
8 
from all substances per urine toxicology (>29 and >12 months respectively). Both evidenced 
9 
significant reductions (p<0.001) in cravings for multiple substances, and reductions in depression 
10 
and anxiety. These two participants remain actively engaged in their treatments showing improved 
11 
functional outcomes including social functioning (e.g. re-establishing relationships with family) 
12 
and employment. Participant #4 (who has also completed the primary 52-week protocol) had 
13 
episodes of substance relapse post-DBS, however importantly, substance use frequency/severity 
14 
are improved relative to pre-surgical baseline and he remains engaged in treatment. Significant 
15 
post-surgical changes in craving were not evident in this participant, but significant post-surgical 
16 
reductions (p<0.001) in anxiety and depression were noted. Participant #2 had DBS explanted 
17 
during Outpatient Week 11 due to persistent non-compliance with the research protocol and 
18 
treatment. There were no safety concerns for Participant #2 through the time of DBS explantation.  
19 
In conclusion, DBS of the NAc is safe and feasible with a potential for reducing substance use, 
20 
craving and relapse among persons with previously treatment-refractory OUD. 
21 
 
22 
3.0 
STUDY DESIGN 
23 
This is a randomized, sham-controlled, partial crossover study investigating DBS targeting 
24 
the NAc and VC for participants with severe, treatment refractory OUD. The major objective of 
25 
this study is to further test safety, tolerability, and feasibility of DBS in this population as well as 
26 
investigate the impact of DBS on opioid use. 
27 
 
28 
3.1 
Randomization and Blinding Procedures 
29 
Randomization will occur after all inclusion criteria have been met and following the 
30 
completion of DBS implantation. Participants will be randomized 1:1 to either the Active (DBS-
31 
ON) or the Sham (DBS-OFF) arm. Details of the procedure will be provided in a randomization-
32 
specification document. The date/time of the randomization will be collected in the electronic Case 
33 
Report Form (eCRF) maintained by a designated team member who is not directly involved in 
34 
study conduct. This study will be performed in a double-blinded manner, with Investigators, study 
35 
staff, and participants unaware of treatment assignment. During the titration phase, there will be 
36 
specified staff performing the active/sham titrations who will be aware of randomization status; 
37 
however, they will play no role in the evaluation of study participants.  
38 
 
39 
3.2 
Breaking the Blind 
40 
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After a participant completes the Outpatient Week 12 visit, that participant’s treatment 
1 
assignment is unblinded. Participants randomized to the “DBS-OFF” arm will be re-admitted to 
2 
the inpatient service for active titration and discharged once active DBS setting are deemed optimal 
3 
by the investigator and study team. Participants initially randomized to the “DBS-ON” arm will 
4 
continue to receive active stimulation and be followed in the outpatient setting.  
5 
Emergency unblinding procedure: Code-breaking and unblinding in the event of medical 
6 
emergencies can be done by the Investigator via the designated team member maintaining the 
7 
randomization eCRF and who is not directly involved in study conduct. Unblinding by the 
8 
Investigator should occur only in the event of an AE/SAE for which it is necessary to know the 
9 
treatment assignment to determine an appropriate course of therapy for the participant. The 
10 
Investigator should first discuss options with the Sponsor and DSMB, if possible; with due 
11 
consideration of the safety of the participant. Participants for whom the code has been broken by 
12 
the Investigator will be encouraged to attend all post-treatment visits as indicated in the Schedule 
13 
of Activities. Code breaking will be documented in the eCRF. 
14 
 
15 
4.0 
STUDY POPULATION 
16 
4.1 
Inclusion Criteria 
17 
A candidate will be eligible if he/she meets all the following criteria: 
18 
• Age 22-50 years at time of enrollment. 
19 
• Fulfills current DSM-5 (American Psychiatric Association diagnostic and statistical 
20 
manual of mental disorders, 5th ed, 2013) diagnostic criteria for severe OUD with at least 
21 
a 5-year history. 
22 
• Participants may have comorbid SUD diagnoses at a mild, moderate or severe level, 
23 
however, OUD must be the primary disorder for which the individual is seeking treatment 
24 
and the other use disorders must occur in the context of relapse. 
25 
• Unsuccessful outcomes (initiated and discontinued/completed treatment with subsequent 
26 
drug recurrence) following at least two levels of treatment (e.g., outpatient Comprehensive 
27 
Opioid Addiction Treatment (COAT), intensive outpatient/intensive COAT, residential, 
28 
inpatient) at least one of which included buprenorphine/naloxone. 
29 
• At least one lifetime overdose survival. Drug overdose criteria and symptoms defined 
30 
according to the National Library of Medicine (www.nlm.nih.gov). 
31 
• Family/Social Support/Involvement (as assessed via the Multidimensional Scale of 
32 
Perceived Social Support). 
33 
• Is able to comprehend the consent form and provide informed consent. 
34 
• Women of reproductive potential must have negative pregnancy test and agree to use 
35 
acceptable forms of contraception.  
36 
• No evidence of systemic infection at time of surgery. The participant will not necessarily 
37 
be excluded if this criteria is met; however, neurosurgical standard of care will be followed 
38 
accordingly (e.g., postponement of surgery until participant is appropriately treated).  
39 
 
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4.2 
Exclusion Criteria 
1 
A candidate will be excluded if he/she meets any of the following criteria: 
2 
• Medical problems requiring intensive medical or diagnostic management. 
3 
• Diagnosis of acute myocardial infarction or cardiac arrest within the previous 6 months. 
4 
• History of a neurosurgical ablation procedure. 
5 
• Any medical contraindications to undergoing DBS surgery. 
6 
• History of hemorrhagic stroke. 
7 
• Life expectancy of <3 years. 
8 
• Past or present diagnosis of schizophrenia, psychotic disorder, bipolar disorder, or 
9 
untreated depression other than one determined to be substance induced (assessed via 
10 
SCID-5). Any treated depression considered to be non-substance induced must have been 
11 
in remission for one year. 
12 
• Baseline assessment on the Hamilton Depression Rating Scale (HAMD) of > 17. 
13 
• Increased risk of suicide based upon any positive response regarding passive or active 
14 
suicidal ideation with or without intent over the past three months or history of active 
15 
suicidal ideation with intent within the past three years on the Columbia Suicide Severity 
16 
Rating Scale (CSSRS). 
17 
• History of medically verified suicide attempt within the past three years 
18 
• Parental history of completed suicide. 
19 
• Meet the criteria for Cluster A or B Personality Disorders (assessed via SCID-5-PD).  
20 
• Diagnosis of dementia or any other disorder which has led to clinically significant 
21 
cognitive impairment. 
22 
• Personal history of any clinically defined neurological disorder, including organic brain 
23 
disease, medically uncontrolled epilepsy, stroke, brain lesions, or multiple sclerosis.  
24 
• Personal history of previous neurosurgery (brain), severe TBI, or head trauma that resulted 
25 
in loss of consciousness (>24 hours) which was not medically/substance induced. 
26 
• Abnormal coagulation lab studies, defined as INR >1.4, abnormal PT/PTT deemed 
27 
clinically significant (repeat labs for confirmation at discretion of investigator) 
28 
• Platelet count < 75×109/L (repeat labs for confirmation at discretion of investigator). 
29 
• Medically uncontrolled hypertension (systolic > 185 mmHg and/or diastolic > 110 
30 
mmHg), demonstrated on each of three repeated measurements taken within one hour 
31 
regardless of whether the patient is taking antihypertensive medications. 
32 
• Implanted neurostimulators (e.g., vagus nerve stimulator, spinal cord stimulator, DBS) 
33 
• Any current Central Nervous System infection or infection with the Human 
34 
Immunodeficiency Virus.  
35 
• Unable to undergo MR-imaging because of implanted pacemakers, medication pumps, 
36 
aneurysm clips, metallic prostheses (including metal pins and rods, heart valves or 
37 
cochlear implants), shrapnel fragments, permanent make-up or small metal fragments in 
38 
the eye that welders and other metal workers may have, or if candidates are uncomfortable 
39 
in small spaces (have claustrophobia) or cannot lie comfortably on their back for up to 
40 
one hour. 
41 
• Documentation of MRI abnormality indicative of a neurological condition that may 
42 
jeopardize the participant’s safety, study conduct, or confound the participant’s diagnostic 
43 
assessments. 
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• Substance use treatment mandated by court of law. 
1 
• Known destruction and/or damage to the NAc, ventral striatum, or VC region as 
2 
determined by MRI. 
3 
• Pregnant or planning to become pregnant. 
4 
• History of medically uncontrolled epilepsy. Participants with documented febrile seizures 
5 
will not be excluded. Seizures which are secondary to substance use and/or withdrawal 
6 
and/or provoked seizures will not be exclusionary if they occurred more than one year 
7 
ago.   
8 
• Conditions requiring repeated MRI scans. 
9 
• Conditions requiring diathermy. 
10 
• Uncorrectable coagulopathy; patients on anticoagulant/antiplatelet medications who 
11 
cannot be off these medications during the standard perioperative care period  
12 
• Unable to speak, read and understand English fluently.  
13 
• Any evidence of cutaneous bacterial infection (e.g., impetigo, cellulitis, etc.). The 
14 
participant will not necessarily be excluded if this criteria is met; however, neurosurgical 
15 
standard of care will be followed accordingly (e.g., postponement of surgery until 
16 
participant is appropriately treated). 
17 
In the event that there is a discrepancy between medical records and other sources of information, 
18 
members of the clinical study team will conduct a thorough investigation to reconcile these 
19 
differences. Other sources of information include self-reported information provided by the 
20 
subject, collateral information provided by others (e.g., members of the subject’s support system), 
21 
and clinical impressions of the treatment team. Similar reconciliation will be performed if 
22 
conflicting documentation is present within medical records (e.g., inconsistent historical 
23 
information documented in separate notes). Findings from this reconciliation will be presented to 
24 
the study team and will be reviewed by the DSMB (if consensus across the study team cannot be 
25 
reached), and the designated external independent eligibility reviewer. Eligibility will be 
26 
determined after review of their recommendations. 
27 
 
28 
4.3 
Recruitment Process 
29 
Participants will be recruited internally from WVU Behavioral Medicine and Psychiatry 
30 
(BMED) programs which includes outpatient (COAT, Intense Outpatient Program (IOP)), 
31 
residential (CHH), and acute inpatient (Dual Diagnosis Unit) programs. The primary recruitment 
32 
program will be COAT, a comprehensive treatment program that combines medication assisted 
33 
treatment with psychosocial treatment for OUD.  The program has been recognized by Substance 
34 
Abuse and Mental Health Services Administration (SAMHSA) as “The West Virginia Model”. 
35 
There are currently multiple training sites throughout the state and practitioners across the nation 
36 
come to learn about program to implement this treatment in their own region.  COAT utilizes a 
37 
multidisciplinary 
and 
multimodal 
approach including medication assisted treatment 
38 
(buprenorphine/naloxone), behavioral intervention (both group and individual therapy) and case 
39 
management services. There is ongoing enrollment in the COAT program with up to 700 active 
40 
participants at any given time.  As 50% of participants admitted into the COAT program are 
41 
retained, there is a sufficient recruitment pool and experience suggests that study recruitment will 
42 
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Page 17 of 59 
not be a barrier to the conduct of this clinical trial. If a participant is deemed eligible and is enrolled, 
1 
continued active participation and engagement in the WVU BMED treatment program, as 
2 
clinically indicated, will be required throughout the duration of the proposed study. Participants 
3 
will also be recruited externally from non-WVU sites after thorough consultation with the external 
4 
treatment providers. These participants will have the same requirements regarding continued 
5 
treatment during enrollment, either via transferring care to WVU or collaboration and consultation 
6 
with their external treatment providers.  
7 
 
8 
4.4  
Informed Consent   
9 
Informed consent will be obtained by the PI or their designee with documented specific 
10 
knowledge of the study. The informed consent form will be reviewed with the participant and all 
11 
questions will be addressed before the participant signs the consent form. Participants will be 
12 
explained the study, including the screening process and required testing; and educated on the 
13 
possible risks and benefits to participating. It will be explained that the results of the screen will 
14 
determine if they will be invited to participate in the next phases of the study. It will also be 
15 
explained that even after passing the initial screen and entering the study phase, subsequent 
16 
assessments may determine that they are not a suitable candidate and be discontinued from the 
17 
study. The specific procedures will be outlined and the risks and benefits clearly described. The 
18 
participant will be given a copy of the signed consent, and a copy of the consent will be placed in 
19 
the patient’s medical record as well as the research file. Participants will have the option to consent 
20 
to videotaping throughout the study. The videotapes will be used for educational purposes. 
21 
 
22 
4.5 
Participant Replacement Guidelines 
23 
Participants who have signed the informed consent document and have been enrolled in 
24 
the trial may withdraw that consent at any time during the trial.  Data collected up to the time of 
25 
consent withdrawal will remain in the database as part of the study. Participants withdrawing 
26 
consent before DBS implantation will not have any collected data relevant to the safety or 
27 
tolerability of the device or other study endpoints. Additional participants may be recruited to the 
28 
study for each participant withdrawing consent prior to DBS placement or failing to reach the 
29 
primary 12-week endpoint, thereby assuring the required number of participants from whom study 
30 
endpoints are collected. The DBS device may be explanted for participants who are discontinued 
31 
from the study for any reason. If a participant withdraws consent before the 12-week outpatient 
32 
endpoint, the designated team member maintaining the randomization eCRF and who is not 
33 
directly involved in study conduct will ensure that the randomization schema is adjusted to ensure 
34 
that there are an equitable number of participants enrolled in each Sham and Active arm. 
35 
 
36 
 
37 
4.6  
Concomitant Therapy 
38 
For this study, a prescription medication is defined as one that can be prescribed only by a 
39 
properly authorized/licensed clinician. All supportive care is allowed, there are no restrictions on 
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Page 18 of 59 
the medications allowed concomitantly during participation on the trial. Likewise, medications 
1 
may be added, tapered, or withdrawn as determined by the clinical treatment team and/or study 
2 
investigators. Medications to be reported in the eCRF for the duration of the study, from the time 
3 
of informed consent to the end of follow-up, are concomitant prescription medications related to 
4 
buprenorphine/naloxone maintenance. All other concomitant medication may be abstracted from 
5 
medical records as needed during data analysis or adverse event reporting. During the conduct of 
6 
the trial, shortwave/ultrasound/microwave therapy and implantation of metallic items or other 
7 
neurostimulators are not allowed as concomitant therapy, however, there are no other restrictions 
8 
on procedures during participation on the trial.  Procedures to be reported in the eCRF for the 
9 
duration of the study, from the time of informed consent to the end of follow-up, include all 
10 
medical and surgical procedures including elective ones.  
11 
 
12 
5.0      STUDY PROCEDURES 
13 
 
14 
The study design will consist of the following six study phases with the corresponding schedule 
15 
of events related to testing and procedures:  
16 
 
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Phase 
I1 
II 
III2 
IV 
V3 
VI 
 Screening/ 
Baseline 
Surgery/ 
Recovery 
Titration 
Outpatient Follow-Up 
Inpatient/ Outpatient 
Inpatient 
Outpatient 
Duration 
2 weeks 
1 week 
Up to 2 
weeks 
12 weeks 
12 weeks 
40 weeks 
 
Page 19 of 59 
Assessment 
 
 
 
 
 
 
Medical History/Physical 
Examination 
x 
 
 
 
 
 
Neurological Examination 
x 
 
 
 
 
 
Psychiatric Examination 
x 
 
 
 
 
 
ECG 
x 
 
 
 
 
 
Demographic & 
Drug/Alcohol Use 
Inventory 
x 
 
 
 
 
 
MR Checklist 
x 
 
 
 
 
 
X-Ray 
x 
 
 
 
 
 
MRSA Nasal Swab 
x 
 
 
 
 
 
Lab Tests (blood work) 
x 
 
 
x 
x 
 
NIH Stroke Scale 
x 
x 
x 
x 
x 
x 
Urine/Salivary Toxicology 
(Qualitative) 
x 
x 
x 
x 
x 
x 
Urine Toxicology 
(Quantitative - HPLC) 
x 
 
 
x 
x 
x 
Pregnancy (Qualitative) 
x 
x 
x 
x 
x 
x 
Pregnancy (Serum) 
x 
x 
x 
x 
x 
x 
Vital Signs 
x 
x 
x 
x 
x 
x 
Adverse Events/Adverse 
Device Events 
x 
x 
x 
x 
x 
x 
Con Meds 
x 
x 
x 
x 
x 
x 
SCID-5 
x 
 
 
 
 
 
SCID-5-PD 
x 
 
 
 
 
 
MSPSS 
x 
 
 
 
 
 
BPRS 
x 
x 
x 
x 
x 
x 
HAM-D 
x 
x 
x 
x 
x 
x 
CSSRS 
x 
x 
x 
x 
x 
x 
YMRS 
x 
x 
x 
x 
x 
x 
CPRS 
x 
x 
x 
x 
x 
x 
BIS 
x 
x 
x 
x 
x 
x 
DVPRS 
x 
x 
x 
x 
x 
x 
SURE 
x 
x 
x 
x 
x 
x 
NIH Quality of Life 
Measures  
x 
x 
x 
x 
x 
x 
TLFB 
x 
x 
x 
x 
x 
x 
Cue Presentation/Cue 
Induced Craving VAS 
x 
x 
x 
x 
x 
x 
WRAT-IV 
x 
 
 
 
 
 
WASI-2 
x 
 
 
x 
x 
x 
Standard Cognitive 
Battery4 
x 
 
 
x 
x 
x 
NIH Cognition Toolbox 
x 
 
 
x 
x 
x 
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Phase 
I1 
II 
III2 
IV 
V3 
VI 
 Screening/ 
Baseline 
Surgery/ 
Recovery 
Titration 
Outpatient Follow-Up 
Inpatient/ Outpatient 
Inpatient 
Outpatient 
Duration 
2 weeks 
1 week 
Up to 2 
weeks 
12 weeks 
12 weeks 
40 weeks 
 
Page 20 of 59 
Eriksen Flanker 
x 
x 
x 
x 
x 
x 
N-Back 
x 
x 
x 
x 
x 
x 
Balloon Analogue Risk 
Task 
x 
x 
x 
x 
x 
x 
Delay Discounting 
x 
x 
x 
x 
x 
x 
Structural MRI 
x 
x 
 
x 
x 
x 
Functional MRI 
x 
x 
 
x 
x 
x 
CT Scan   
 
x 
 
 
 
 
FDG PET/CT 
x 
x 
 
x 
x6 
x6 
18F-fallypride PET/CT 
(Placebo) 
 
x 
 
x 
 
 
18F-fallypride PET/CT 
(Methylphenidate) 
 
x 
 
x 
 
 
LFP Capturing 
 
x 
x 
x 
x 
x 
EEG5 
x 
x 
x 
x 
x 
x 
 
1 
1 Screening and Baseline procedures will occur over a two-week inpatient phase and/or while the 
2 
subject is outpatient (within 3 weeks of inpatient admission). 
3 
2 Those randomized to Sham will complete an Active Titration session (Phase IIIb) following 
4 
Phase IV after cross over from Sham to Active stimulation conditions 
5 
3 Phase V will only apply to those participants randomized to Sham initially. Procedures will be 
6 
identical to Phase IV so that within-subject comparisons (12 weeks “DBS-OFF” versus 12 weeks 
7 
“DBS-ON”) can be made. 
8 
4 The standard neuropsychological battery includes the following: California Verbal Learning 
9 
Test-Second Edition, Short Form (CVLT-II-Short), Brief Visuospatial Memory Test-Revised  
10 
(BVMT-R), Trails Making Test Parts A and B (TMT-A, TMT-B), Controlled Oral Word 
11 
Association Test (COWAT) and Animal Fluency, Stroop Color-Word Interference Task (SCWT). 
12 
5 EEG may be measured during screening/baseline and post-surgical phases while the subject is at 
13 
rest and/or during specific tasks 
14 
6   Optional
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5.1 
Phase I: Screening and Baseline Phase  
1 
After providing informed consent, study participants will complete an inpatient stay at a 
2 
WVU facility (e.g., Chestnut Ridge Center (CRC); the inpatient psychiatric hospital of WVU or 
3 
the Center for Hope and Healing (CHH) a residential treatment program at WVU) for 
4 
approximately 1-2 weeks where they will undergo screening and baseline assessments to 
5 
determine study eligibility prior to DBS placement. Alternatively, screening assessments may be 
6 
initiated prior to their inpatient admission to the CRC. If performed prior to inpatient admission, 
7 
screening assessments will be conducted within 3 weeks of the admission date.  
8 
 
9 
5.2 
Phase II: DBS Surgery 
10 
After completion of the screening period, if the participant is assessed as being appropriate 
11 
for the surgery, the participant will then undergo the DBS placement (Phase II) at Ruby Memorial 
12 
Hospital (RMH), which includes approximately 1-2 weeks recovery period at RMH and 
13 
CRC/CHH. On the day of surgery, standard clinical care requires a head CT with the stereotactic 
14 
head frame and merging of the CT and MRI images for targeting the NAc/VC. DBS surgery 
15 
involves FDA approved standard stereotactic implantation of DBS electrodes (Medtronic 
16 
Neurological Model 3387S) bilaterally in the NAc/VC in each participant using anatomical and 
17 
physiological guidance and single cell microelectrode recording. The specific target can be directly 
18 
visualized on axial, coronal, and sagittal T1, T2, and inversion-recovery MRI scans, obtained 
19 
approximately one week prior to the surgery (but no more than 2 weeks prior to the surgery date). 
20 
The trajectory planning will be based on avoidance of vasculature while maximizing the approach 
21 
through the internal capsule to the ventral striatum and the NAc. The anatomical target will 
22 
correspond to the stereotactic targets coordinates of approximately 5 to 10mm lateral to the 
23 
midline, 1 to 5 mm anterior to the anterior commissure, and 2 to 5mm ventral to the anterior 
24 
commissure. Single-cell micro-electrode recording will be performed to verify the anatomical 
25 
target traversing the internal capsule white matter with white matter recordings and cells in the 
26 
NAc. The DBS electrodes implanted to the target will be connected to pulse generators (Medtronic 
27 
Percept PC, Activa RC or Activa PC) in the chest wall in the usual fashion as for all DBS 
28 
procedures. After DBS placement, patients will undergo a post-operative CT scan on the same day 
29 
as surgery to rule out hemorrhage. The participants will be followed on the neurosurgical step-
30 
down unit and patient ward until deemed clinically stable, at which point they will be transferred 
31 
to our inpatient addiction psychiatry service for a up to two weeks post DBS surgery.  
32 
 
33 
5.3 
Phase III: DBS Titration and Stimulation  
34 
Up to a two-week time-period will be allocated for initial programming, titration, and 
35 
safety check/follow-up, while inpatient for safety.  Titration will be based on stimulation 
36 
parameters used in previous studies examining the role of DBS of the NAc in the treatment of 
37 
OCD and depression as well as the parameters utilized in the initial pilot study conducted by the 
38 
team. Since it is difficult to titrate stimulation parameters for efficacy in OUD the optimum 
39 
stimulation will be based first on the absence of adverse effects and second, on whether the 
40 
stimulation parameters help to improve craving, mood, and/or physiological responses; or at the 
41 
discretion of the research team with regards to behavioral addiction features. 
42 
The DBS system is turned on with a standard monopolar or bipolar setting, as deemed 
43 
necessary per the medical team, after reviewing each contact setting while the participants are 
44 
being monitored for adverse effects. Stimulation will be delivered initially at 90-185 Hz, in pulse 
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widths ranging from 90 - 210 µsec. The polarity, frequency, pulse width and intensity will be 
1 
adjusted using the standard range used for OCD and depression based on previous experience with 
2 
NAc/VC DBS. Stimulation will be used on the electrode contact, unless side effects at that contact 
3 
preclude any stimulation. During this phase, the Percept PC neurostimulator may be accessed to 
4 
obtain local field potentials recorded from the patient’s brain during initial adjustments and 
5 
programming. 
6 
Amplitude of stimulation will be increased slowly in small increments while the patient is 
7 
monitored for immediate side effects. These can include sensory changes, motor symptoms, 
8 
immediate mood changes, non-specific drowsiness, discomfort, or eye deviation. The stimulation 
9 
will not exceed the 30 µcoulomb/cm² charge density safety limit. After the programming session 
10 
and safety follow-up (up to two weeks) participants will be discharged from inpatient/residential 
11 
setting and monitored via outpatient visits and with the behavioral medicine program as per the 
12 
protocol.  
13 
For participants randomized to the “DBS-ON” arm, in the event that no adjustments are 
14 
needed, there may be sessions conducted similar to a typical titration session with the exception 
15 
that no changes are made to the stimulation parameters. These sessions are performed in an attempt 
16 
to decrease any anticipatory bias on behalf of the subject (e.g., knowing an adjustment is being 
17 
made and subsequently anticipating an effect).  After completion of the titration and stimulation 
18 
phases, participants may have their stimulation parameters adjusted to maintain or improve 
19 
efficacy at the discretion of the treatment team during the follow up phase of the study. There may 
20 
also be sessions conducted where no changes are made to the parameters to decrease the potential 
21 
of anticipatory bias as mentioned above.  
22 
For participants randomized to the “DBS-OFF” condition, titration sessions will be 
23 
conducted identically to the “DBS-ON” arm, the only difference is that no stimulation is delivered 
24 
and therefore, no actual adjustments made. Following outpatient Week 12, the participants 
25 
randomized to the “DBS-OFF” condition will be re-admitted to the hospital for 1-2 weeks to 
26 
receive the active titration and stimulation sessions as described above. 
27 
Before the DBS unit is implanted, participants will be given a copy of the Medtronic Patient 
28 
Therapy Guide, which describes the DBS unit and its care (e.g., avoiding magnetic fields) and 
29 
receive individual teaching regarding the contents of the Guide.  Participants will also receive a 
30 
smaller pocket-size Quick Guide reference. At discharge, the participants may be given the 
31 
Medtronic patient controller for safety. The access will be set to “limited: view battery status only”. 
32 
In this setting, the participants can confirm that the stimulator is on and working correctly, but they 
33 
cannot see the programmed voltage. They will also be able to mark events (e.g. increased craving) 
34 
with the device (see section 5.4 for further details). If severe side effects are experienced and the 
35 
stimulator needs to be turned off, they will be able to do so with their patient controller; however, 
36 
it will be recommended that the participant contact the study team first before doing so. 
37 
Participants will be instructed to carry their DBS controller with them when attending medical 
38 
appointments and emergency visits (for the rare event that the DBS unit must be turned off). 
39 
Participants will be given a wallet ID card describing the DBS unit. 
40 
5.4 
Phase IV:  Primary Endpoint – Follow-up and Monitoring (12 Week Outpatient 
41 
Phase) 
42 
The primary study endpoint is 12 weeks post-discharge to the outpatient phase. All 
43 
participants (regardless of randomization condition) will return to the clinic twice weekly during 
44 
the first 12 weeks, any further requirements for inpatient treatment related to OUD will follow the 
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WVU BMED program standard of care. See Table 1 for detailed assessments to be performed at 
1 
Week 12.  
2 
The impedance of each DBS electrode will be assessed at every outpatient visit to ensure 
3 
the device is functioning properly and connected. DBS settings will be maintained at previously-
4 
set levels unless adverse effects are noted, in which case the settings will be adjusted back to the 
5 
previous level at which the participant had no adverse effect or a different setting at the discretion 
6 
of the investigative team. Participants may have their stimulation parameters adjusted at the 
7 
discretion of the treatment team to maintain or improve efficacy during the follow up phase of the 
8 
study. There may also be sessions conducted where no changes are made to the parameters to 
9 
decrease the potential of anticipatory bias. 
10 
The Percept PC device allows recording of local field potentials non-invasively from the 
11 
implanted DBS system. The Percept PC can also record and stream local field potential data in 
12 
real time. This feature may be used during the planned behavioral (e.g., cue-induced craving) and 
13 
cognitive assessments (e.g., delay discounting, balloon analog risk task). The Percept PC device 
14 
will also record averaged local field potentials continuously and these will be obtained from the 
15 
Percept PC device at programming sessions to be evaluated later. Patients with an implanted 
16 
Percept PC will be able to have events marked either in clinic or in the community (by themselves 
17 
using the patient controller or the care/investigative team in the clinic). For example, these events 
18 
could include increased cravings or feelings of wellness.  
19 
 
20 
5.5 
Phase V:  Secondary Endpoint – Exploratory Follow-up and Monitoring (Sham Arm 
21 
– 12 weeks DBS-OFF vs 12 weeks DBS-ON) 
22 
At 12 weeks, participants randomized to DBS-ON already have active stimulation which 
23 
will continue; therefore, Phase V applies to only those participants initially randomized to the 
24 
sham arm (i.e., DBS-OFF). Following completion of Phase IV (the 12-week outpatient primary 
25 
endpoint), participants randomized to DBS-OFF are crossed over to active stimulation and re-
26 
admitted to the inpatient service for up to two weeks to complete active titration (Phase IIIb). They 
27 
are then discharged as outpatients where they will, again, be followed twice weekly for 12 weeks 
28 
in the outpatient setting. The secondary analysis is a within-subject analyses of 12 weeks DBS-
29 
OFF vs 12 weeks DBS-ON within these participants.  
30 
 
31 
5.6 
Phase VI:  Tertiary Endpoint – Exploratory Follow-up and Monitoring (52 weeks 
32 
post-active stimulation) 
33 
Once DBS is activated and titrated, all participants are followed weekly up until 52 weeks 
34 
post-activation. For the Active arm this will be study weeks 13-52, for the Sham arm this will be 
35 
weeks 26-66, (the shift in weeks accounts for 12 weeks of DBS-OFF stimulation and the two-week 
36 
readmission for active titration).  Final safety assessment and analyses will occur at 52 weeks post-
37 
active DBS titration.  
38 
We will post the results on ClinicalTrials.Gov no later than 24 weeks after the last 
39 
participant has completed follow up or hastened to within 12 weeks if at any point the trial is 
40 
stopped for safety by WVU IRB or the FDA. The results of this study will be specifically 
41 
generalizable to those individuals with OUD who are disabled from their life-threatening condition 
42 
and/or are Medicare beneficiaries. 
43 
 
44 
 
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5.7 
Long-Term Follow up (> 52 weeks post-active stimulation) 
1 
After the completion of 52-weeks with active DBS stimulation, patients may be eligible to 
2 
participate in a separate long-term follow-up study. During these long-term follow-up visits, 
3 
battery replacement, stimulation adjustments and DBS impedances will be checks to ensure that 
4 
the device is working properly. Participants who do not consent to be in the long-term follow up 
5 
study will have the device explanted as there is no mechanism to ensure the safety of these 
6 
participants when not under regular observation. UADEs and SAEs that are attributable to the 
7 
device and/or stimulation will be reported according to FDA and IRB reporting criteria 
8 
 
9 
5.8 
Study Measures and Assessments 
10 
The study will utilize various medical procedures/assessments along with established 
11 
behavioral, 
neuropsychological, 
cognitive, 
neurological, 
and 
neuroimaging 
12 
assessments/measures/tasks to evaluate the status of the participant. These measures are employed 
13 
to determine eligibility and/or support the primary and secondary objectives of the study. 
14 
  
15 
5.8.1 Medical Procedures/Assessments 
16 
 
Participants 
Phase Endpoint 
DBS status 
Phase I 
All 
Screening/Baseline 
All: Pre-implantation 
Phase II 
All 
Recovery after surgery 
All: Implanted at surgery 
Phase IIIa 
 
Active only 
 
Successful titration 
(~1-2 weeks post-surgery) 
Active arm: Titrated to active stimulation 
Sham arm: Sham titrations (inactive stim) 
Phase IV 
All 
Outpatient Week 12 
Active arm: DBS On 
Sham arm: DBS Off 
Phase IIIb 
Sham only 
Successful titration 
(~1-2 weeks) 
All: Active Stimulation 
Phase V 
Sham only 
12 weeks post-activation 
Sham: Active, post-unblinding and titration 
Phase VI 
All 
52 weeks post-activation 
All: Active Stimulation 
 
17 
Blood collection to be performed for the following analyses at Phase I, endpoint of Phase IV/V. 
18 
• CBC with Differential 
19 
• BMP (Na, K, Cl, CO2, BUN, Creatinine, Glucose) 
20 
• PT/INR 
21 
• PTT 
 
22 
• Type and Screen (Only collecting during Phase I) 
 
23 
• HIV1/HIV2 
24 
• Hepatitis C 
25 
• Liver function panel 
26 
• Serum pregnancy test (if applicable) 
27 
Urine collection will be performed for the following analyses: 
28 
• Urinalysis – Completed during Phase I and at the completion of Phase IV and V).  
29 
• Qualitative Urine Toxicology – Completed at least once during outpatient screening (if 
30 
applicable), twice weekly during inpatient phases (Phases I-III), twice weekly during Phase 
31 
IV and V, and once weekly throughout Phase VI. Salivary toxicology may be completed if 
32 
participant is unable to physically present to clinic. 
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• Quantitative Urine Toxicology (GC/MS) – Completed during Phase I, every four weeks of 
1 
Phase IV and V, and once at the completion of Phase VI.  
2 
o Analyses on the following substances and substance metabolites will be performed: 
3 
Cocaine, 
Amphetamine, 
Delta-9 
tetrahydrocannabinol, 
Benzodiazepines, 
4 
Morphine, Heroin, Buprenorphine, Fentanyl, Opioids/opioid analogs 
5 
• Urine pregnancy test (if applicable) – Completed twice weekly during inpatient phases 
6 
(Phases I-III), twice weekly during Phase IV and V, and once weekly during Phase VI.  
7 
 
8 
The following medical procedures will also be performed during screening/baseline (Phase I): 
9 
• MRSA screening by nasal swab 
10 
• History and physical examination, neurological examination, psychiatric examination 
11 
• Electrocardiogram 
12 
• Chest x-ray 
13 
• Vital signs (also monitored daily during inpatient phases and weekly during the outpatient 
14 
phases) 
15 
 
16 
5.8.2 Behavioral Assessments 
17 
Demographic and Drug and Alcohol Use Inventory: Demographic information including age, sex, 
18 
education, ethnicity and characterizes years, recent (days in the past 30) (Mahoney, 2017), and 
19 
daily drug use for opioids and other illicit substances. Completed at Screening/Baseline (Phase 
20 
I) and takes approximately 20 minutes to administer. 
21 
Structured Clinical Interview for DSM-5 Axis I Disorders (SCID-5) (First et al., 2016a): The 
22 
SCID-5 is a semi-structured interview guide for making DSM-5 diagnoses and uses an 
23 
algorithmic approach to scoring, assessing, and diagnosing DSM-5 disorders. It is administered 
24 
by a clinician or trained mental health professional that is familiar with the DSM-5 
25 
classification and diagnostic criteria. Guide covers the DSM-5 diagnoses most commonly seen 
26 
in clinical settings including depressive/bipolar disorders, schizophrenia spectrum and other 
27 
psychotic disorders, substance use disorders, anxiety disorders, obsessive-compulsive 
28 
disorder, posttraumatic stress disorder, attention-deficit/hyperactivity disorder. Completed at 
29 
Screening/Baseline (Phase I) and takes approximately 45 minutes to administer. 
30 
Structured Clinical Interview for DSM-5 Axis II Personality Disorders (SCID-5-PD) (First et al., 
31 
2016b): The SCID-5-PD is a semi-structured interview guide for making DSM-5 diagnoses to 
32 
assess the 10 DSM-5 Personality Disorders across Clusters A, B, and C as well as Other 
33 
Specified Personality Disorder. This measure is designed to build rapport, the SCID-5-PD can 
34 
be used to make personality disorder diagnoses, either categorically or dimensionally. 
35 
Completed at Screening/Baseline (Phase I) and takes approximately 45 minutes to administer. 
36 
Multidimensional Scale of Perceived Social Support (MSPSS) (Zimet, Dahlem, Zimet, & Farley, 
37 
1988): The MSPSS is a brief research tool designed to measure perceptions of support from 3 
38 
sources: Family, Friends, and a significant Other.  The scale is comprised of a total of 12 items, 
39 
with 4 items for each subscale. Completed at Screening/Baseline (Phase I) and takes 
40 
approximately 5 minutes to administer. 
41 
Depression and Suicidal Ideation Assessment and Monitoring 
42 
(Completed at least once during outpatient screening, three times weekly during the inpatient 
43 
phases (Phase I-III), post each titration session, up to twice weekly during Phase IV and V, 
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and once monthly during Phase VI. During the inpatient titration phase, these required post-
1 
titration assessments will count toward the three-time weekly inpatient assessment 
2 
requirement as long as they remain within normal limits following the titration session. If a 
3 
titration session is performed during the outpatient phase, these required post-titration 
4 
assessments will count towards the outpatient assessment requirement as long as they remain 
5 
within normal limits following the titration session.)  
6 
Hamilton Depression Rating Scale (HAM-D) (Hamilton, 1960): The HAM-D is a multiple item    
7 
questionnaire used to assess depression and has been clinically validated. Depression is rated 
8 
based on the responses and takes about 10 minutes to complete. 
9 
Columbia–Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2011): The C-SSRS is a suicidal 
10 
ideation and behavior rating scale and has been clinically validated. It is assessed through a 
11 
series of questions for suicidal risk and takes about 5-10 minutes to complete. 
12 
Brief Psychiatric Rating Scale (BPRS) (Overall, Gorham, 1988): The BPRS is a clinician 
13 
administered instrument which assesses the level of 18 symptom constructs such as hostility, 
14 
suspiciousness, hallucination, and grandiosity. The rater enters a number for each symptom 
15 
construct that ranges from 1 (not present) to 7 (extremely severe). Completed at 
16 
Screening/Baseline (Phase I), pre/post DBS surgery, and post each titration session at 
17 
Investigator discretion and takes approximately 10 minutes to administer. 
18 
Comprehensive Psychopathological Rating Scale (CPRS) (Asberg, Montgomery, Perris, 
19 
Schalling, & Sedvall, 1978): The CPRS assesses symptoms of anxiety and depression via 
20 
participant’s self-reported responses. Completed up to three times weekly during the inpatient 
21 
phases (Phase I-III), up to twice weekly during Phase IV and V, and once monthly during 
22 
Phase VI.  This assessment takes approximately 5 minutes to complete. 
23 
Young Mania Rating Scale (YMRS) (Young, Biggs, Ziegler, & Meyer, 1978): The YMRS scale 
24 
consists of 11 items to monitor the development of hypomanic/manic symptoms during the 
25 
study.  The YMRS total score ranges from 0 to 60. Completed up to three times weekly during 
26 
the inpatient phases (Phase I-III), up to twice weekly during Phase IV and V, and once monthly 
27 
during Phase VI.  During the inpatient titration phase, this required post-titration assessment 
28 
will count toward the three-time weekly inpatient assessment requirement as long as it remains 
29 
within normal limits following the titration session. If a titration session is performed during 
30 
the outpatient phase, this required post-titration assessment will count towards the once or 
31 
twice weekly outpatient assessment requirement as long as it remain within normal limits 
32 
following the titration session. This assessment takes approximately 5 minutes to complete. 
33 
Barratt Impulsiveness Scale (BIS) (Patton, 1995): The BIS is a 30-item self-report questionnaire 
34 
assessing impulsive personality traits. Each item is rated on a 4-point scale ranging from 1 
35 
(never) to 4 (always) with a range from 30–120. Completed up to three times weekly during 
36 
the inpatient phases (Phase I-III), up to twice weekly during Phase IV and V, and once monthly 
37 
during Phase VI. This assessment takes approximately 5 minutes to complete. 
38 
Defense & Veterans Pain Rating Scale (DVPRS) (Polomano, 2016): The DVPRS 2.0 is a pain 
39 
assessment tool that utilizes a numerical rating scale enhanced by functional word descriptors, 
40 
color coding, and pictorial facial expressions matched to pain levels. Four supplemental 
41 
questions measure how much pain interferes with usual activity and sleep, and affects mood 
42 
and contributes to stress. Completed up to three times weekly during the inpatient phases 
43 
(Phase I-III), up to once weekly during Phase IV and V, and once monthly during Phase VI. 
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This assessment takes approximately 5 minutes to complete. 
1 
Timeline Follow-back (TLFB): The TLFB is an assessment method that obtains estimates of daily 
2 
opioid and other substance use.  Using a calendar, the participants provide a retrospective 
3 
estimate of daily substance use since their previous self-report. Completed up to three times 
4 
weekly during the inpatient phases (Phase I-III), up to twice weekly during Phase IV and V, 
5 
and once weekly during Phase VI. This assessment takes approximately 5 minutes to complete. 
6 
Cue Reactivity and Craving Visual Analog Scale (VAS): A set of substance-related stimuli (e.g., 
7 
photos, computer images) will be presented to the participant. Prior to and immediately after 
8 
viewing the cues, participants will complete paper- or computer-based assessment VAS 
9 
designed to assess craving and mood. Cue presentation and VAS Measurements may be 
10 
conducted more frequently at the investigator’s discretion. Completed up to three times weekly 
11 
during the inpatient phases (Phase I-III), every four weeks during Phase IV, V and VI. 
12 
Substance Use Recovery Evaluation (Neale, 2016): The SURE is a 21-item (five factors) 
13 
psychometrically valid, self-report measure which assesses recovery from drug and alcohol 
14 
dependence. Completed up to once weekly during the inpatient phases (Phase I-III), once 
15 
weekly during Phase IV and V, and once monthly during Phase VI. This assessment takes 
16 
approximately 5 minutes to complete. 
17 
Quality of Life in Neurological Disorders Measures (Neuro-QoL) (Cella, 2012): The Neuro-QoL 
18 
is self-administered by the participant on an iPad, available through the NIH Toolbox app with 
19 
trained staff providing guidance and scoring. The Neuro-QOL includes validated measures that 
20 
evaluate and monitors physical, mental, and social functioning. Domains assessed include 
21 
anxiety, depression, emotional/behavioral dyscontrol, stigma, and sleep disturbance. The 
22 
primary QoL outcome measure will be composite score for each domain. Completed up to once 
23 
weekly during the inpatient phases (Phase I-III), once weekly during Phase IV and V, and once 
24 
monthly during Phase VI. This assessment takes approximately 5 minutes to complete. 
25 
 
26 
5.8.3 Cognitive Assessments 
27 
 
28 
Wide Range Achievement Test-Fourth Edition, Reading Subtest (Wilkinson, 2006): The WRAT-
29 
4 is an individually administered test of word reading. The participants read the words and the 
30 
examiner determines whether the word is pronounced correctly. The total number of correctly 
31 
pronounced words is transformed into a Standard Score with age-corrective normative data. 
32 
The test is used to roughly approximate the participant's general ability (IQ). Completed during 
33 
screening/baseline (Phase I). This assessment takes approximately 10 minutes to complete. 
34 
Wechsler Abbreviated Scale of Intelligence – Second Edition (WASI-II) (Wechsler, 2011) 
35 
Provides an index of estimated intellectual functioning via the Vocabulary, Similarities, Block 
36 
Design, and Matrix Reasoning subtests. Estimated administration time is 30 minutes. 
37 
Completed during Phase I and at Phase IV-VI endpoints. This assessment takes approximately 
38 
45 minutes to complete. 
39 
NIH Toolbox Cognition Battery (NIHTB-CB) (Gershon et al., 2013): The NIHTB-CB consists of 
40 
assessments designed to yield different measures of cognitive performance. The NIHTB-CB 
41 
tasks include the following which generates a Fluid Cognition Composite Score: 1) 
42 
Dimensional Change Card Sort Test; 2)  Flanker Inhibitory Control and Attention Test; 3) 
43 
Picture Sequence Memory Test; 4) List Sorting Working Memory Test; 5) Pattern Comparison 
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Processing Speed Test; and includes the following tests which generate a Crystalized 
1 
Cognition Composite score: 6) Picture Vocabulary Test; 7) Oral Reading Recognition Test. 
2 
Supplementary measures including the Auditory Verbal Learning Test and Oral Symbol Digit 
3 
Test will also be administered. The NIHTB-CB automatically generates age-corrected and 
4 
fully corrected t-scores, allowing for comparison to average scores from a nationally 
5 
representative sample. Completed during Phase I and at Phase IV-VI endpoints. This 
6 
assessment takes approximately 45 minutes to complete. 
7 
Standard Neuropsychological Battery: This includes validated neurocognitive measures which 
8 
cover several domains to yield a comprehensive assessment of functioning.  This battery 
9 
includes the following measures described below. Completed during Phase I and at Phase IV-
10 
VI endpoints. This assessment takes approximately 60 minutes to complete. 
11 
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) – Digit Span Subtest (Wechsler, 
12 
2008): The Digit Span subtest will assess focused auditory attention and concentration.  
13 
California Verbal Learning Test-Second Edition, Short Form (CVLT-II-Short) (Delis D.C., 2000): 
14 
The CVLT-II-Short measures verbal learning and memory.  It includes 9 words across a series 
15 
of 4 trials, free recall following a short delay, free and cued recall following a delay, 
16 
recognition, and forced choice. This test will provide information on the effects of DBS on 
17 
verbal learning and memory.  
18 
Brief Visuospatial Memory Test-Revised (BVMT-R) (Benedict, Schretlen, Groninger, Dobraski, 
19 
& Shpritz, 1996):  Assess visual learning and memory (outcome variables: the number of figure 
20 
details recalled across the three learning trials, number recalled following a 25-minute delay, 
21 
and number correct when presented in recognition format).  
22 
Trails Making Test Parts A and B (TMT-A, TMT-B) (Reitan, 1958)): The TMT provides a 
23 
measure of visual scanning and mental flexibility. It involves drawing lines between letters 
24 
and numbers, in sequential order.  
25 
Controlled Oral Word Association Test (COWAT) and Animal Fluency (Lezak, 1995): The 
26 
COWAT provides a measure of verbal fluency. The timed task measures include phonemic 
27 
fluency, which requires the participant to name as many words as possible that begin with a 
28 
specified letter in one minute. Also includes semantic fluency which requires the participant 
29 
to name as many animals as the can in one minute.  
30 
Stroop Color-Word Interference Task (SCWT) (Stroop, 1935): Assess information processing and 
31 
inhibition (outcome variables: total number of words read, and colors named in 45 seconds).  
32 
 
33 
5.8.4 Measures of Executive Function 
34 
 
35 
The proposed study will employ a series of experimental cognitive tests focused on elements 
36 
of executive function that supplement the clinical neuropsychological measures. The following 
37 
tasks will be administered to participants via a smartphone/tablet to capture day-to-day 
38 
variability in measures of response inhibition, working memory, cognitive flexibility, and 
39 
attention. In addition to the analysis of performance scores that data will be integral for the 
40 
development of a machine learning model to predict recovery and relapse.  
41 
Eriksen Flanker Task (Eriksen, 1974): The Flanker task is a response inhibition test to assess the 
42 
participant’s ability to suppress a response that is inappropriate based on the task rules. 
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Participants respond either left or right based on the direction of the middle arrow (target) of 
1 
five aligned items. The task consists of congruent stimulus (the direction of the target and 
2 
flanker arrows are the same), incongruent stimulus (the direction of the target is opposite of 
3 
the flanker arrows), and neutral stimulus (flanker items are different shape e.g., a square than 
4 
the target arrow). Completed up to once weekly during the inpatient phases (Phase I-III), up to 
5 
once weekly during Phase IV and V, and up to once monthly through Phase VI. This assessment 
6 
takes approximately 5 minutes to complete. 
7 
N-Back Task (Kirchner, 1958): The N-Back task is a working memory measure where participants 
8 
monitor a series of stimuli and respond whenever a stimulus is presented that is the same as 
9 
one presented in a predefined previous trial. For example, items that are 1, 2, or 3 items back 
10 
from the current stimulus whereas 1-back is less difficult then then 3-back since less 
11 
information is needed in working memory to correctly respond. Completed up to once weekly 
12 
during the inpatient phases (Phase I-III), up to once weekly during Phase IV and V, and up to 
13 
once monthly through Phase VI. This assessment takes approximately 5 minutes to complete. 
14 
Balloon Analogue Risk Task (BART) (Lejuez, Read, Kahler, Richards, Ramsey, Stuart, Strong, 
15 
Brown, 2002): The BART is a computerized measure of risk-taking behavior which models 
16 
real-world risk behavior through the conceptual frame of balancing the potential for reward 
17 
versus loss. In the task, the participant is presented with a balloon and offered the chance to 
18 
earn money by pumping the balloon up by clicking a button. Each click causes the balloon to 
19 
incrementally inflate and money to be added to a counter, up until some threshold at which 
20 
point the balloon is over inflated and explodes. Thus, each pump confers greater risk, but also 
21 
greater potential reward. If the participant chooses to cash-out prior to the balloon exploding 
22 
then they collect the money earned for that trial, but if balloon explodes earnings for that trial 
23 
are lost. Participants are not informed about the balloons’ breakpoints; the absence of this 
24 
information allows for testing both participants' initial responses to the task and changes in 
25 
responding as they gain experience with the task contingencies. Risk taking is a related, but 
26 
phenomenologically distinct process from impulsivity. Completed up to once weekly during 
27 
the inpatient phases (Phase I-III), up to once weekly during Phase IV and V, and up to once 
28 
monthly through Phase VI. This assessment takes approximately 5 minutes to complete. 
29 
Delayed Discounting Task (Richards, Zhang, Mitchell, de Wit, 1999): The Delayed Discounting 
30 
Task assesses cognitive functions which are often impaired in substance users including: 
31 
decision-making, impulsivity, and inhibitory control. This task presents subjects with 
32 
hypothetical choice of a smaller immediate reward or a larger delayed reward, for example, 
33 
“Would you rather have $2 now or $10 in 30 days?”  The delay of the larger amount varies as 
34 
a function of time e.g., a delay of 1, 2, 30, 180 or 365 days. The primary outcome measure is 
35 
an indifference value calculated at each delay time point. This value reflects the smallest 
36 
amount of immediate money (smaller sooner) an individual chooses over a delayed larger 
37 
amount (larger later).  Completed up to once weekly during the inpatient phases (Phase I-III), 
38 
up to once weekly during Phase IV and V, and up to once monthly during Phase VI. This 
39 
assessment takes approximately 12 minutes to complete. 
40 
 
41 
5.8.5 Neurological Assessments 
42 
National Institutes of Health Stroke Scale (NIHSS): In the long-term follow up period, the NIHSS 
43 
will be performed after any stimulation adjustments. The Stroke Scale (NIHSS) is a systematic 
44 
assessment tool that provides a quantitative measure of stroke-related neurologic deficit.  The 
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NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute 
1 
cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, 
2 
extraocular movement, motor strength, ataxia, dysarthria, and sensory loss.  A trained observer 
3 
rates the patient’s ability to answer questions and perform activities.  Ratings for each item are 
4 
scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items.  
5 
Completed during Phase I, once post-surgery, post each titration session, and then once 
6 
monthly through endpoint of Phase VI. This assessment takes approximately 10 minutes to 
7 
complete. 
8 
 
9 
5.9 
Neuroimaging 
10 
5.9.1 PET/CT Scans 
11 
The study will utilize PET imaging to demonstrate the physiological changes associated with 
12 
NAc/VC DBS. FDG PET/CT will be used to assess changes in brain metabolism with DBS. FDG 
13 
PET/CT will be collected at WVU. 18F-fallypride PET/CT will be conducted to measure changes 
14 
in dopamine brain metabolism, through the measurement of dopamine binding, associated with 
15 
NAc/VC DBS.  
16 
There will be a total of 2 PET/CT sessions performed for each participant during this study: 
17 
1) Session one includes three scans at the end of the surgical recovery period and prior to the DBS 
18 
titration and programming 2) Session two includes three scans at the 12-week outpatient primary 
19 
endpoint (end of Phase IV).   
20 
Each of these sessions above will consist of three PET scans: 1) FDG PET/CT to assess 
21 
brain glucose metabolism, 2) 18F-fallypride/CT placebo (no methylphenidate challenge) and 3) 
22 
18F-fallypride PET/CT (with methylphenidate challenge) to determine binding potential of 
23 
dopaminergic D2/D3 receptors and dopamine release. Methylphenidate will be administered orally 
24 
at a dose of 60 mg prior to the scan per the standard protocol developed at NIDA. FDG PET/CT 
25 
may also be completed following 52 weeks of active stimulation as well as 12 weeks following 
26 
active stimulation for the group initially randomized to receive sham DBS. 
27 
 
28 
5.9.2 CT Scans 
29 
Two high resolution CTs of the head will be obtained, one prior to surgery and one post-operatively 
30 
to verify placement of electrodes. The patient will require a CT scan of the head after application 
31 
of the Leksell stereotactic frame on the morning of surgery, co-registered to pre-operative MRI 
32 
scans, for intra-operative anatomic localization per standard care. The patient will also require a 
33 
CT scan, co-registered to pre-operative images, immediately after implantation of intracranial 
34 
leads to confirm placement of the electrodes and to evaluate for intracranial hemorrhage and air. 
35 
The participant may require an additional CT scan post-operatively for clinical reasons, for 
36 
example to identify intracranial bleeding. 
37 
 
38 
5.9.3 MRI Scans 
39 
High resolution MRI of the brain will be obtained approximately one week prior to surgery (but 
40 
no more than 2 weeks prior to the surgery date) and may be completed at the end of the surgical 
41 
recovery period prior to the DBS titration and programming, at the endpoint of Phase IV, and V 
42 
and endpoint of Phase VI. Additional structural MRI may be completed at investigator’s discretion, 
43 
if clinically indicated, prior to or after DBS surgery. Structural (e.g., T1-weighted, Diffusion 
44 
weighted imaging) and functional MRI (resting state and task-based paradigms) may be performed 
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prior to DBS surgery, at the end of the surgical recovery period, at the endpoint of Phase IV, Phase 
1 
V, and Phase VI. Scans may also be acquired in conjunction with LFP acquisition. 
2 
MR-imaging uses a strong magnetic field and radio waves to take pictures of the brain. The 
3 
MR-scanner is a metal cylinder surrounded by a strong magnetic field.  During the MR-imaging, 
4 
the patient will lie on a table that can slide in and out of the cylinder.  The patient will be in the 
5 
scanner about 30-40 minutes. The patient may be asked to lie still for up to 15 minutes at a time.  
6 
During the task-based fMRI, if time allows, neurocognitive or craving assessments similar to those 
7 
described above may be presented to the participant via a computer monitor and the participant 
8 
will be able to complete the task by responding using a response box. While in the scanner the 
9 
patient will hear loud knocking noises and will be fitted with earplugs or earmuffs to muffle the 
10 
sound. The patient will be able to communicate with the MR-staff at all times during the scan and 
11 
may ask to be moved out of the machine at any time. During part of the MR-imaging a contrast 
12 
agent (Gadolinium) will be given through an IV catheter. A needle will be used to guide the 
13 
catheter into an arm vein. The needle will be removed, leaving only the catheter in the vein. The 
14 
catheter will be taped to the skin to hold it in place. 
15 
 
16 
5.9.4  Micro-electrode Recording 
17 
The microelectrode recording (MER) is a standard process for DBS surgery. During DBS surgery 
18 
a microelectrode is inserted into the brain to record and map the neural structure and to plan/modify 
19 
the final DBS stimulating electrodes placement. In addition to standard MER recording, to record  
20 
electrochemical measurements of neural activity, an electrochemical probe will be lowered into 
21 
the cannula through the same track used for the microelectrode recording prior to inserting the 
22 
DBS electrode.  A behavioral task will be performed by the patient while electrochemical data is 
23 
recorded. Our goal is to take the opportunity to record of electrochemical measurements of neural 
24 
activity during behavioral tasks (described above) without significantly prolonging or 
25 
compromising any aspect of the surgical procedure. The tasks take less than 15 minutes for each 
26 
DBS placement to complete, thus adding no more than 30 minutes total to the procedure. The 
27 
electrochemical probe will pass through the same tissues for the microelectrode recordings, and 
28 
no other sites. 
29 
 
30 
5.9.5 Local Field Potential Recording 
31 
To observe the functioning of the NAc in association with DBS therapy and symptom severity 
32 
over time, local field potentials (LFP) will be measured using by recording functionality of the 
33 
Medtronic Percept PC stimulator device. During recordings, patients will sit quietly in a chair with 
34 
the data receiver positioned nearby, either at rest (to acquire a baseline or “resting state” 
35 
measurement) or performing one the computer-based tasks listed above. An EEG cap or a 
36 
transcutaneous electrical nerve stimulator (TENS) device will be used to synchronize the electrical 
37 
artifacts produced by DBS pulses. This allows the LFP recordings from the Percept PC to be 
38 
synchronized to the events produced from the task computer during data analysis. 
39 
 
40 
Additionally, patients may be provided with a juice reward system. Juice rewards are an 
41 
effective way of stimulating NAc activity and will facilitate the use of LFP data in understanding 
42 
the effects of DBS on reward processing. Juice is given via a straw-like mouthpiece via food-safe 
43 
tubing, gated by a computer-controlled solenoid valve. The task computer briefly opens the valve 
44 
to give an immediate, pleasant outcome that drives NAc activity. When used, patients may be 
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provided with the option to select a juice flavor from among a few commercially available options. 
1 
The entire juice reward system will be sanitized before and after each use, and a new unused 
2 
mouthpiece will be provided for each session. 
3 
 
4 
5.9.6 Electroencephalogram 
5 
Electroencephalogram (EEG) will be used to evaluate the electrical activity in the brain during 
6 
pre- and post-surgical phases of the study. EEG may be performed while the subject is at rest or 
7 
while completing specific tasks (e.g., delayed discounting). 
8 
 
9 
5.10  Potential Benefits 
10 
Patients may not receive any health benefit from participating in this study. NAc/VC DBS may 
11 
suggest a novel therapeutic approach for individuals with treatment refractory OUD and to learn 
12 
about the effects of DBS in the modulation of brain networks in patients with OUD. This 
13 
knowledge may lead to new clinical insights that will improve treatment for OUD. 
14 
 
15 
5.11 
Potential Risks 
16 
General Risks Associated with DBS 
17 
The general risks associated with DBS for OUD are similar as with DBS applications involving 
18 
Parkinson’s disease, dystonia, essential tremor, chronic pain, Tourette’s, epilepsy, OCD, major 
19 
depression, and TBI. The potential risks for any DBS procedure are divided into three categories. 
20 
These include risks associated with the actual surgical implantation of the DBS lead and pulse 
21 
generator, risks associated with the implantable device, and risks associated with the programming 
22 
of the device. The surgical risks for DBS implantation are the same as for any intracranial 
23 
stereotactic procedure. This includes hemorrhages (intraparenchymal, subdural or epidural 
24 
hematoma), paralysis, coma and/ or death, stroke, leaking of cerebrospinal fluid, seizures, 
25 
infection, allergic reaction, temporary or permanent neurological complications, confusion or 
26 
attention problems, pain at the surgery sites and headaches.  
27 
The risk of a seizure due to DBS is less than 1%. The risk of a seizure associated with DBS 
28 
in this study may be no different than when DBS is used for other medical conditions. If a seizure 
29 
occurs while participant is an inpatient at WVU, immediate actions will be taken by qualified 
30 
medical personnel to reduce the risk of injury and prolonged seizure activity. These actions will 
31 
be in accordance with WVU Medicine approved patient care protocols and latest American 
32 
Epilepsy Society guidelines for treatment of seizures that occurs in a hospital or inpatient setting. 
33 
All outpatient medical emergencies including seizures will follow standard 911 protocol.  The 
34 
risks associated with the devices include mechanical, electrical, software, and others device related 
35 
system failures. Additional risks include battery failure, electric shock and reactions to the 
36 
components of the device. The lead or lead extension connector may move, which would require 
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surgical intervention to readjust. 
1 
Stimulation related side effects are most commonly reversible by adjusting the stimulation 
2 
parameters and re-programming. In addition to re-programming, the system can be turned OFF 
3 
and the intensity placed at 0V. A recent summary of the risks profile for DBS in movement 
4 
disorders is reviewed in Rezai et al. (Rezai et al., 2008). These include suicidal ideation, 
5 
depression, gastrointestinal disturbances, nausea, muscle weakness or partial paralysis, jolting or 
6 
shocking sensation, numbness, paresthesia, facial flushing and motor contraction, dizziness, 
7 
headaches pain, changes in vital signs, hyperactivity or euphoria, pain or discomfort, dry mouth, 
8 
itching at the surgical site, insomnia, increased fatigue, cognitive disturbance, restlessness, weight 
9 
gain or loss, speech and visual difficulties, blurred or double vision, unusual smell and taste 
10 
sensations, cognitive and/or behavioral changes, mood changes, and energy level changes.  
11 
A list of potential titration and programming related side effects include: 
12 
• Depression (feeling sad, down, or blue, and/or a loss of interest in things usually enjoyed) 
13 
• Changes in mood (positive and negative) 
14 
• Anger, aggression 
15 
• Gastrointestinal disturbances (changes in digestion) or nausea 
16 
• Tingling sensation (paresthesia) 
17 
• Dizziness or lightheadedness (disequilibrium) 
18 
• Facial and limb weakness or partial paralysis (inability to move arms or legs) (paresis) 
19 
• Facial flushing (red or rosy facial color) or facial muscle contractions 
20 
• Jolting or shocking sensation (sudden movements) 
21 
• Hypomania 
22 
• Numbness (hypoesthesia) 
23 
• Increased heart rate 
24 
• Increased respiratory rate 
25 
• Increased blood pressure 
26 
• Hyperactivity or euphoria (hypomania) 
27 
• Pain or discomfort 
28 
• Headaches 
29 
• Dry mouth 
30 
• Itching at the surgical site(s) 
31 
• Irritability 
32 
• Increased fatigue (feeling exhausted or moving slower than usual) 
33 
• Cognitive disturbance (“cloudy” thinking) 
34 
• Restlessness 
35 
• Weight gain or weight loss 
36 
• Insomnia/Sleep disturbance 
37 
• Speech and visual difficulties 
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• Blurred/Double vision 
1 
• Unusual smell and taste sensations 
2 
• Changes in mood, memory, thinking and energy level 
3 
There are potential adverse events that could be related to the non-surgical procedures.  
4 
Risks associated with the DBS device. The risks associated with the device include mechanical, 
5 
electrical, software, and others device related system failures. Additional risks include battery 
6 
failure, electric shock and reactions to the components of the device. The lead or lead extension 
7 
connector may move, which would require surgical intervention to readjust. The brain stimulation 
8 
system may affect the operation of other surgically placed devices, such as cardiac pacemakers, 
9 
and implantable defibrillators, which may interfere with the device function. Electrocautery, 
10 
external defibrillators, radiation therapy, ultrasonic devices may interfere with the function of the 
11 
neurostimulator and may even cause some damage to it. In addition, the electrical signal from the 
12 
neurostimulator may interfere with the function of an external defibrillator. The safety of external 
13 
defibrillators on patients with this surgically placed system has not been established. 
14 
Electromagnetic interference (EMI) is a field of energy (electrical, magnetic or a combination of 
15 
both) that is generated by various equipment found in medical, work, and home environments.  
16 
This equipment can create enough interference to do the following: 
17 
• Turn the neurostimulator off or on 
18 
• Cause stimulation that can result in an uncomfortable sensation 
19 
• Reset the neurostimulator to factory settings, which will require reprogramming 
20 
The neurostimulator is designed to protect against most EMI. However, strong electromagnetic 
21 
fields and permanent magnets can interfere with the system. Even when the DBS is turned off, 
22 
interference can affect the lead(s). Subjects will be instructed on the risks and potential sources of 
23 
EMI, and what to do if EMI is suspected. They will be instructed to move away from the source 
24 
of the EMI or if possible, turn off the suspected source of EMI. They will be instructed to use the 
25 
control magnet to turn the DBS unit on or off. 
26 
Additional Concerns.  There may be pain, lack of healing, or infection where the brain stimulation 
27 
system parts are surgically placed. 
28 
• The parts of the brain-stimulation system may wear through the participant’s skin, which 
29 
can cause an infection or scarring. 
30 
• The lead or lead/extension connector may move. Participants may need surgery to re-adjust 
31 
the location. 
32 
• Components or parts of the brain-stimulation system may break or fail to work properly. 
33 
Participants may need surgery to replace the system parts. 
34 
• The brain-stimulation system could stop because of mechanical or electrical problems. 
35 
Either of these would require surgery. DBS service life depends on individual use. 
36 
• The participant may have an allergic reaction to the brain stimulation system. The system 
37 
materials coming in contact with tissue include titanium, polyurethane, silicone, and nylon. 
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The body could also reject the system (as a foreign body). 
1 
• There is the possibility of tissue damage resulting from the programming parameters or a 
2 
malfunction of one of the parts of the brain stimulation system. 
3 
DBS systems have a battery life of approximately 2-9 years, depending upon the uses and the 
4 
model; WVU Medicine will provide follow up care (at no cost to the participant) related to battery 
5 
replacement, as well as any other related follow-up DBS care. 
6 
Using the different configurations of the Percept PC device may lower battery life. The 
7 
minimum expected battery life, even with maximal use, is well within the 2-9 years of current 
8 
DBS systems and use of the Percept PC device is, on average, not expected to significantly alter 
9 
battery life of the system. We estimate an average time of live streaming LFP data to be 180 hours 
10 
or on average 3 hours per week (as clinically indicated). This use will result in an estimated average 
11 
loss of battery life of less than six months (1 hour of live streaming = loss of 20 hours of battery 
12 
life). We estimate the typical battery life lost from live streaming to be approximately 165 days 
13 
over the course of a 52 week follow up (which equates to a 5-6% loss of the 2-9 year battery life). 
14 
As an example, we will obtain live streaming LFP during tasks involving experimental measures 
15 
of executive function listed above and cue reactivity (assesses cue induced craving). The extent of 
16 
live streaming will be variable, subject dependent and may be far less than estimated.  
17 
Risks of DBS System Revision.  There is a possibility that the DBS system may need to be revised 
18 
(removed, replaced, or repositioned) before the end of the research study. Possible reasons for 
19 
revision might be infection, malfunction, or other reasons. If revision is necessary, the participant 
20 
will need to have surgery similar to when the system was put in. There might be a “buildup” of 
21 
scar tissue (related to the original surgery) that may make replacement of the leads unsafe. In some 
22 
cases, it may not be possible to remove the leads. If the electrodes or stimulator need to be 
23 
removed, then the operation to remove them may be associated with additional risks of bleeding, 
24 
infection, pain, and surgical or anesthesia complications. Replacement with the Percept PC 
25 
neurostimulator will be possible for those participants who received the Activa neurostimulator 
26 
during initial placement. 
27 
 
28 
Risks of Electrochemical Electrode. The risks from recording brain activity during research tasks 
29 
are no greater than the risks associated with the DBS procedure, as placement of the electrodes is 
30 
a standard component of the surgical procedure. The risks from using the chemical-sensing probe 
31 
are believed to be of equal risk to placement of the standard DBS electrodes. Of concern in any 
32 
surgery is the effect of additional surgical time on exposed tissues. Participation in this type of 
33 
study in the past has not been found to increase the risk of complications or adverse events. The 
34 
neurosurgeon will be considering the safety and well-being of the patient at all times and has the 
35 
authority to stop the research procedures or not allow them to be performed. There is a possible 
36 
increased chance of infection because of the research probe but, like the regular surgery electrodes, 
37 
the probe will be sterilized and kept in sterile packaging. 
38 
 
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5.12  Other Risks 
1 
Blood Sample Risks.   The risks of drawing blood include temporary pain from the needle stick, 
2 
bruising, bleeding, and rarely, infection. 
3 
X-ray Risks. X-ray technology uses radiation. The average amount of radiation that the average 
4 
person would receive from the x-rays for the research study is less than that received from 
5 
natural sources of radiation in a year. At this level, no harmful effects of radiation have been 
6 
demonstrated and the risk, if any, is minimal. 
7 
Medication-Related Risks.  During the study, participants will be asked to continue the same 
8 
medications they were taking before the surgery. As a result, they may experience the side effects 
9 
associated with these medications. Some neurologic medications cause withdrawal reactions if 
10 
they are stopped suddenly. Withdrawal reactions can include anxiety, feeling dizzy, headaches, 
11 
and possibly seizures. For this reason, participants should not stop taking any medications 
12 
suddenly without specifically discussing it with the study doctors. 
13 
Risks of MRI.  People are at risk for injury from the MRI magnet if they have pacemakers or other 
14 
implanted electrical devices. Medtronic DBS systems are MRI Conditional and safe in the MRI 
15 
environment as long as certain conditions are met. If the conditions are not met, a significant risk 
16 
is tissue lesions from component heating, especially at the lead electrodes, resulting in serious and 
17 
permanent injury including coma, paralysis, or death. DBS of the NAc is off label and therefore 
18 
there are unknown risks in general. 
19 
Other mental implants e.g., types of dental implants, aneurysm clips (metal clips on the 
20 
wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and 
21 
cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments.  Welders 
22 
and metal workers are also at risk for injury because of possible small metal fragments in the eye 
23 
of which they may be unaware.  Participants will be screened for these conditions before having 
24 
any scan, and if they have any, they will not receive an MRI scan.  If participants have a question 
25 
about any metal objects being present in their body, they should inform the staff.  In addition, all 
26 
magnetic objects (for example, watches, coins, jewelry, and credit cards) must be removed before 
27 
entering the MRI scan room. 
28 
It is not known if MR-imaging is completely safe for a developing fetus.  Therefore, all 
29 
women of childbearing potential will have a pregnancy test performed no more than 24 hours 
30 
before each MRI scan.  The scan will not be done if the pregnancy test is positive.  People with 
31 
fear of confined spaces may become anxious during an MR-imaging.  Those with back problems 
32 
may have back pain or discomfort from lying in the scanner.  The noise from the scanner is loud 
33 
enough to damage hearing, especially in people who already have hearing loss. Everyone having 
34 
a research MRI scan will be fitted with hearing protection.  If the hearing protection comes loose 
35 
during the scan, the participants will let MR-imaging staff know right away. Participants will 
36 
notify staff of any hearing or ear problems.  Participants will be asked to complete an MR-
37 
screening form for each MRI scan.  There are no known long-term risks of MRI scans. 
38 
Risks of an IV catheter include bleeding, infection, or inflammation of the skin and veins 
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with pain and swelling.  Symptoms from the contrast infusion are usually mild and may include 
1 
coldness in the arm during the injection, a metallic taste, headache, and nausea. In an extremely 
2 
small number of patients, more severe symptoms have been reported including shortness of breath, 
3 
wheezing, hives, and lowering of blood pressure.  People with kidney disease are at risk for a 
4 
serious reaction to gadolinium contrast called “nephrogenic systemic fibrosis” which has resulted 
5 
in a very small number of deaths.  If participants have diabetes, kidney disease or liver disease, a 
6 
blood test of kidney function will be done within 4 weeks before any MR-scan with gadolinium 
7 
contrast.  Participants will not receive gadolinium if their kidney function is not normal.   
8 
 
9 
Risks of Radiation Exposure from Positron Emission Tomography (PET), Computer-assisted 
10 
Tomography (CT), chest radiograph, and intra-operative fluoroscopy.   
11 
This research study involves exposure to radiation from six 18F-Fallypride PET/CT scans (if 
12 
conducted), three FDG PET/CT scans, two CT scans, one chest x-ray, and intra-operative 
13 
fluoroscopy.  The participant may require another CT to evaluate for the development of a blood 
14 
clot while the electrodes are in place (for clinical care reasons).  The amount of radiation 
15 
participants will receive in this study is estimated at 4.2 rem, which is below the guideline of 5 
16 
rem per year allowed for research participants by the NIH Radiation Safety Committee.  The 
17 
average person in the United States receives a radiation exposure of 0.3 rem per year from natural 
18 
sources, such as the sun, outer space, and the Earth's air and soil.  
19 
The MRI, CT, PET, fluoroscopy, and chest radiograph used in this study can be harmful to 
20 
a developing fetus.  Therefore, sexually active women able to get pregnant must use effective 
21 
methods of contraception (birth control) from the time of screening until the end of the study in 
22 
order to avoid exposure to the radiation required in by procedures this study.  Everyone receives a 
23 
small amount of unavoidable radiation each year. Some of this radiation comes from space and 
24 
some from naturally occurring radioactive forms of water and minerals. This research gives the 
25 
participant’s body the equivalent of about 11.8 extra years' worth of this natural radiation. A 
26 
possible health problem seen with radiation exposure is the development of a second cancer later 
27 
in life. This extra cancer risk is higher at younger ages and for girls and women. The extra lifetime 
28 
risk of dying of a fatal cancer due to the radiation exposure from this research may range from 
29 
about one in 700-2,000.  At such low radiation exposures, scientists disagree about the amount of 
30 
risk. These estimates are very uncertain, and there may be no extra risk at all. 
31 
 
32 
5.13 Procedures for Minimizing Risks 
33 
Participants, after screening for eligibility, will be recruited for participation in the study. Consent 
34 
will be conducted by members of the study team, and all risks and benefits will be described to the 
35 
participants in written and oral presentation. Participants will be made to understand that their 
36 
participation is voluntary, and that they will be provided with any new information that develops 
37 
during the study that might affect their decision to continue with the study. A sixth-grade reading 
38 
level will be considered when developing the consent materials, and the informed consent will be 
39 
on file with the WVU IRB. Participants will be pre-screened for decision-making capacity prior to 
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the consenting process. A clinical determination will be made at the time of the consent by a WVU 
1 
Medicine Behavioral Medicine Clinician to determine if participants are competent for consenting. 
2 
All evaluation forms, assessment results, and other records that leave the site will be 
3 
identified by coded number only to maintain participants’ confidentiality. All study records will 
4 
be kept locked at the WVU Rockefeller Neuroscience Institute. All computer entry and networking 
5 
programs will be done with coded numbers only. Clinical information will not be released without 
6 
written permission of the participants, except as necessary for monitoring by the IRB. If serious 
7 
adverse events become evident, the study will be terminated after review and recommendation by 
8 
the DSMB. All participants previously enrolled will be immediately contacted regarding findings. 
9 
Vulnerable subjects: We consider participants in this study to be vulnerable due to the presence of 
10 
OUD and the resultant stigma engendered by this diagnosis. Special protections for participants 
11 
include a full-time patient navigator on call to address emergent issues as well as a Certificate of 
12 
Confidentiality that is extended to participants in all NIH-supported trials. 
13 
Women of reproductive potential must use acceptable forms of contraception from the time of 
14 
enrollment through the completion of study participation. Acceptable effective methods of 
15 
contraception for this study include: 
16 
• Hormonal contraception (birth control pills, injected hormones, hormonal implants, or 
17 
vaginal ring). 
18 
• Intrauterine device. 
19 
• Barrier methods (condom or diaphragm) combined with spermicide. 
20 
• Surgical sterilization (hysterectomy, tubal ligation, or vasectomy) 
21 
It is important for the participant to know that no method of birth control is totally effective in 
22 
preventing pregnancy except for surgical sterilization (hysterectomy or tubal ligation) and total 
23 
abstinence from sexual relations. The long-term effects of DBS on pregnancy and a fetus are not 
24 
known. The MR-imaging, CT scans, PET scans, and surgery used in this study can be harmful to 
25 
a developing fetus. At a minimum, pregnancy testing will be performed on all women of 
26 
childbearing potential at screening, monthly, and before MR-imaging, CT scan, PET scans, and 
27 
surgery. Presence of confirmed pregnancy will result in study discontinuation if DBS surgery has 
28 
not yet been done. If pregnancy occurs after DBS placement, imaging studies will not be 
29 
performed, however, the participant will be followed through the duration of the study, and 
30 
pregnancy outcome will be assessed. 
31 
The investigators involved with this study have a great deal of expertise with the 
32 
conduction of DBS surgeries. The surgical team has over 20 years of experience with DBS with 
33 
over 2000 DBS implants for various indications. The study inclusion/exclusion criteria have been 
34 
developed to select those who would most likely benefit from this study as well as excluding those 
35 
with higher risks. Study participants will be monitored after DBS implantation in neurosurgical 
36 
and physiological monitoring units with personnel experienced in the care of complex 
37 
neurosurgical participants and monitoring neurological status. After surgical stabilization, 
38 
participants will be monitored on an inpatient addiction service, which is staffed by personnel 
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experienced in monitoring psychiatric and addiction care. 
1 
 
2 
We plan a number of measures to mitigate occurrence of adverse events.  Patients will be 
3 
carefully examined for presence of infection prior to DBS placement.  Specifically, patients with 
4 
any evidence of cutaneous bacterial infection (e.g., impetigo, cellulitis, etc.) will need to be treated 
5 
accordingly before surgery and neurosurgical standard of care processes will be followed.  As 
6 
surgical -site infections occur with increased frequency among nasal carriers of Staphylococcus 
7 
aureus, we screen all potential DBS candidates for staph nasal carriage and, if present, treat with 
8 
mupirocin to eliminate the carrier state prior to DBS implantation.  We also instruct all patients to 
9 
use chlorhexidine wash prior to the surgery.   
10 
Our standard of care for all DBS surgeries includes meticulous surgical techniques, 24 
11 
hours of peri-operative prophylactic IV antibiotics after implantation of the DBS lead and 5-7 days 
12 
of prophylactic oral antibiotics after the pacemaker battery implantation. Patients will additionally 
13 
be carefully followed for evidence of implant/hardware infection, not only in the post-operative 
14 
period but throughout the subsequent year.  Any evidence of possible hardware infection will be 
15 
pursued for definitive diagnosis and treatment for which infectious diseases consultation will be 
16 
sought. 
17 
The risk of infection will be further mitigated chiefly by careful and meticulous surgical 
18 
technique.  Should the patient present with signs or symptoms consistent with wound breakdown 
19 
or infection, contrast enhanced imaging will be obtained to ensure there is no intracranial 
20 
involvement.  The most conservative reports give a risk of infection around 1/20 over the lifetime 
21 
of the device, with about 1/40 requiring lead explantation over the life of the device.  Treatment 
22 
will then consist of a combination of antibiotics, wound cultures, surgical exploration and wound 
23 
revision, and if the implanted system is deemed to be unsalvageable, explantation.  Multiple reports 
24 
have shown that up to 50% of infections/wound breakdowns associated with deep brain stimulation 
25 
can be successfully treated without lead explantation. Should explantation become necessary after 
26 
an infection, it will almost always lead to a rapid resolution of both wound healing and infection 
27 
issues.  The risk of explantation will be mitigated by using meticulous surgical technique and a 
28 
very experienced implanting surgeon.  Also, the risk will be mitigated by utilizing conservative 
29 
strategies if appropriate to avoid DBS explantation.  
30 
Some individuals, such as those with a history of intravenous drug use (IVDU), may be at a higher 
31 
risk of infection than others. All patients will be hospitalized as inpatients for at least one week 
32 
prior to surgery and for approximately 2-4 weeks post-surgery during the recovery and 
33 
stimulation/titration phases. As mentioned above, they will be regularly assessed for infection in 
34 
the weeks surrounding implantation. Moreover, during their inpatient hospitalization, patients will 
35 
reside in a locked unit and are monitored 24 hours per day/7 days per week, thus significantly 
36 
reducing the possibility of acute infection secondary to IVDU during hospitalization. Once 
37 
discharged to the outpatient phase, patients are monitored twice weekly for the first 12-26 weeks 
38 
(depending on whether they were randomized to active/sham conditions) and then once weekly 
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throughout 52 weeks of active stimulation.  Monitoring of infection will occur routinely during all 
1 
follow-up visits and AE assessments. In addition, urine toxicology will be performed during this 
2 
visit and there will be routine medical examinations to assess whether relapse has occurred. If the 
3 
patient experiences a relapse, especially via the intravenous route, the investigator will determine 
4 
whether antibiotics should be prescribed prophylactically. If there is any suggestion or proven 
5 
infection at any point pre- or post-surgically, the patient will be treated aggressively per standard 
6 
of care including appropriate antibiotics in consultation with team, including but not limited to 
7 
neurosurgery and infectious disease, and the patient will be followed up with regularly until 
8 
infection resolves.   
9 
The risk of intracranial hemorrhage will be mitigated by meticulous surgical planning and 
10 
stereotactic techniques.  Hemorrhage will also be evaluated with post-operative CT scans obtained 
11 
on every patient to ensure that if a hemorrhage occurs, it is diagnosed early and treated early as 
12 
well.  Prevention of hardware damage is chiefly done with good surgical technique in applying 
13 
strain relief loops of the wire at the cranial and pectoral sites of the implant as well as keeping 
14 
wires away from pressure points, where skin wearing can cause breakdown.   Other risks associated 
15 
with the surgery are much rarer than hemorrhage, infection/wound breakdown, and hardware 
16 
damage.  These will be managed according to the best evidence and experience of the surgeon.  
17 
The risk of explantation after a DBS surgery is about 1 in 40 over the lifetime of the device 
18 
when implanted for movement disorders. Reasons for explantation are usually wound 
19 
breakdown/infection or damage to cranial DBS lead wire or other portion of the system.  This risk 
20 
can be minimized by using meticulous surgical technique and ensuring adequate healthy scalp/skin 
21 
coverage over the implanted device.  Should explantation become necessary, it carries a similar 
22 
risk profile to the implantation surgery, although these risks, especially brain hemorrhage, are less 
23 
likely to occur. Risks are minimized in all of the non-surgical procedures including phlebotomy as 
24 
well as the neuroimaging procedures by having trained and highly experienced personnel 
25 
performing all those tasks/procedures.  
26 
After the surgery, the DBS system will be interrogated and monitored by individuals who 
27 
have expertise in programming of neurostimulators. In the event that after titration is complete, 
28 
symptoms develop that affect the safety or quality of life of the patient, stimulation parameters 
29 
first will be adjusted.  If these symptoms persist, stimulation will be discontinued. Symptoms that 
30 
would necessitate divergence from the protocol would include any condition or occurrence that 
31 
would be deemed serious and significantly divergent from typical clinical symptoms seen with 
32 
OUD patients. Examples might include any unexplained sudden or severe cognitive and functional 
33 
loss or severe behavioral disturbances out of the ordinary for this population that is profoundly 
34 
affecting quality of life of the participants.  
35 
Participants may terminate from the study or discontinue stimulation at any time and for 
36 
any reason. DBS systems will also be removed if the participant/representative asks for removal. 
37 
Subjects who prematurely withdraw from the study due to an adverse event will be followed (e.g. 
38 
telephone contact, and/or follow-up visits, etc.) until resolution of the event. In addition, a 
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designated investigator/programmer will have access to treatment status at all times and provide 
1 
that information to appropriate medical personnel in the event of medical emergencies. The DBS 
2 
device may be explanted for participants who are discontinued from the study for any reason. 
3 
Risks to confidentiality are negligible in this protocol, since participants will not be 
4 
identified by name, or by any personal data, in any summary reports or publications. CRFs will be 
5 
maintained in locked files and password-protected databases. Subject identification codes will be 
6 
used in place of names, with the key linking data to names kept separate from the data. Data and 
7 
safety monitoring activities for this study will continue until all subjects have completed their 
8 
participation in the study.  
9 
  
10 
6.0 
 SAFETY ENDPOINTS 
11 
The study safety endpoints will include a characterization of all adverse events (AE) for all 
12 
participants, including those related to the implant surgical procedure, the implantable device, and 
13 
stimulation of the NAc/VC in patients with OUD.  In addition, these safety profile elements will 
14 
be compared across the various phases of the study. Patients with clinically significant 
15 
complications related to surgery (hemorrhage, stroke, infection) will not undergo DBS 
16 
implantation or further participation in the study.  
17 
 
18 
7.0  
PLAN FOR REPORTING ANTICIPATED AND UNANTICIPATED PROBLEMS 
19 
AND ADVERSE EVENTS 
20 
All serious unanticipated problems, major protocol deviations, serious adverse events (SAEs) and 
21 
unanticipated device effects will be reported to the IRB as soon as possible, but not more than 5 
22 
days after the PI first learns of the event. As is required for device research, the PI will report to 
23 
the IRB any deviation from the investigational plan to protect the life or physical well-being of a 
24 
subject in an emergency as soon as possible, but no later than 5 working days after the emergency 
25 
occurred. All SAEs will be reported to NIDA within 72 hours of the PI being aware of the event. 
26 
At the time of continuing review, the PI will provide the WVU IRB with an aggregated 
27 
summary of all unanticipated problems and all protocol deviations. The PI is responsible for 
28 
detecting, documenting, and reporting unanticipated problems, adverse events (AEs), including 
29 
serious adverse events (SAEs), and deviations in accordance with IRB requirements, and federal 
30 
regulations. Relatedness to the research of all adverse events will be determined by the PI or 
31 
designated co-investigator. 
32 
 
33 
7.1 
Serious Adverse Events 
34 
An adverse event or suspected adverse reaction is considered serious if, in the view of the 
35 
investigator or the sponsor, it results in any of the following: 
36 
• Death 
37 
• A life-threatening adverse experience 
38 
• Prolongation of existing hospitalization or new hospitalization 
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• Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
1 
life functions 
2 
• A congenital anomaly/birth defect 
3 
• Required intervention to prevent permanent impairment or damage 
4 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
5 
may be considered a serious adverse device experience when, based upon appropriate medical 
6 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
7 
intervention to prevent one of the outcomes listed in this definition.  
8 
 
9 
7.2 
Unanticipated Adverse Device Effects 
10 
An unanticipated adverse device effect (UADE) is any serious adverse effect on the health and/or 
11 
safety or any life-threatening problem or death caused by or associated with the device and/or 
12 
stimulation if that effect, problem, or death was not previously identified in nature, severity, or 
13 
degree of incidence in the investigational plan; or any other unanticipated serious problem 
14 
associated with a device that relates to the rights, safety, or welfare of participant.   
15 
Unanticipated adverse device effects will be categorized as they related to: 
16 
• The implanted components (lead, extension, neurostimulator) 
17 
• The lead/extension tract or neurostimulator pocket 
18 
• The burr hole site. 
19 
An event will not be considered related to the device when it is the result of: 
20 
• A preexisting medical condition 
21 
• A medication. 
22 
 
23 
7.3 
Device Malfunction  
24 
A device malfunction is the failure of a device to meet its performance specifications or other 
25 
performance as intended.  Performance specifications include all claims made in the labeling for 
26 
the device.  The intended performance of a device refers to the intended use for which the device 
27 
is labeled or marketed (21 CFR 803.3). The PI will report UADEs as soon as possible, but no more 
28 
than 10 working days after the PI first learns of the event.  For IDE research, the PI will report 
29 
deviations from the investigational plan that were intended to protect life or physical well-being 
30 
of a subject in an emergency to the IRB within five days.  Unanticipated adverse device effects 
31 
will be reported to the IRB and not more than five days after the PI first learns of the event. 
32 
 
33 
7.4  
Documentation of Adverse Events 
34 
The study PI and co-investigators will be responsible for the evaluation, monitoring, and 
35 
documentation of events meeting the criteria and definition of an adverse event (AE) or serious 
36 
adverse event (SAE) as provided in this clinical investigation.  The study participants will be 
37 
evaluated for any possible AEs from the time written study informed consent is obtained until 
38 
study closure or the subject exits the study. Please note that the following will not be considered 
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an AE: 
1 
• Reprogramming of the DBS system due to lack of efficacy. 
2 
• Transient undesirable stimulation-produced effects that occur during programming 
3 
sessions that resolve with or without programming changes prior to the subject leaving a 
4 
study follow-up visit and do not require follow-up medical care.  
5 
• Any normal expected postoperative complaints or symptoms, unless the event involves a 
6 
clinically significant change in a patient’s severity or duration of symptoms, or that requires 
7 
clinical intervention other than the ordinary postoperative care. The following are some 
8 
expected postoperative outcomes that may occur: headache, incision pain, nausea, 
9 
vomiting, low grade fever, dizziness, sleepiness, nervousness, insomnia, constipation, 
10 
urinary retention, confusion, etc.  
11 
• Any pre-existing condition, unless a worsening of that condition in terms of nature, 
12 
severity, or frequency develops.  
13 
• Medical or surgical procedure unrelated to the clinical protocol (i.e., dental or elective 
14 
cosmetic procedure) 
15 
• Routine neurostimulator replacement for battery depletion (will be documented as a system 
16 
modification) Replacement with the Percept PC neurostimulator will be possible for those 
17 
participants who received the Activa neurostimulator during initial placement.  
18 
• Technical observation or a device event that does not result in a medically undesirable 
19 
situation for the participant. 
20 
 
21 
All AEs from the time the study informed consent is signed through the final study visit will be 
22 
recorded as AEs on the study event log, each event being documented separately.  All AEs and 
23 
SAEs will be followed until: 
24 
• AE is resolved, has returned to normal/baseline, or has stabilized. 
25 
• Participant has withdrawn from the study. 
26 
• AE is judged by the investigator to be no longer clinically significant 
27 
• Study closure. 
28 
 
29 
In the long-term follow up period, only UADEs and SAEs that are attributable to the device and/or 
30 
stimulation will be reported according to FDA and IRB reporting criteria. All non-serious adverse 
31 
events will be reported to the FDA and IRB during the continuing review.  All adverse events, 
32 
which include serious adverse events, will be categorized unrelated, unlikely, possibly, probably, 
33 
or definitely related as follows: 
34 
Not related: Temporal relationship of the onset of the event, relative to administration of the 
35 
product, is not reasonable or another cause can by itself explain the occurrence of the event. 
36 
Unlikely related: Temporal relationship of the onset of the event, relative to administration of the 
37 
product, is likely to have another cause, which can by itself explain the occurrence of the event. 
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Possibly related: Temporal relationship of the onset of the event, relative to administration of the 
1 
product, is reasonable but the event could have been due to another, equally likely cause. 
2 
Probably related: Temporal relationship of the onset of the event, relative to administration of the 
3 
product, is reasonable and the event is more likely explained by the product than any other cause. 
4 
Definitely related: Temporal relationship of the onset of the event, relative to administration of the 
5 
product, is reasonable and there is no other cause to explain the event. 
6 
As applicable, relationship may also be categorized as related to: 
7 
• Surgical/Procedure-Related: associated with surgical implantation of the DBS system; 
8 
• Device-Related: caused by the implanted system; 
9 
• Stimulation-Related: caused by the electrical stimulation of the nervous system while 
10 
treating the participant’s symptoms; 
11 
• Disorder-Related: an event that might reasonably be attributed to the patients underlying 
12 
disease state. 
13 
• NA = Not related. 
14 
 
15 
If considered at least possibly related, multiple relationship(s) could also be associated with 
16 
each adverse event. 
17 
 
18 
For those events that are determined to be at least possibly related to stimulation or the DBS 
19 
device, the sponsor/investigator will report the strength of the relatedness using the following 
20 
definitions: 
21 
Definite: The event is resolved with reprogramming of the stimulation parameters and is 
22 
confirmed by the reappearance of the event when the device settings are returned to the settings 
23 
programmed at the time the event was observed; 
24 
Probable: The event resolves upon reprogramming of the stimulation parameters and cannot 
25 
be reasonably explained by the participant’s current clinical state; 
26 
Possible: The event may have been produced by the study participant’s clinical state; however, 
27 
the effect of stimulation cannot be ruled out. 
28 
In addition, the relationship between the device/procedure and the occurrence of each adverse 
29 
event may be assessed and categorized using the criteria above in addition to clinical 
30 
judgement. Alternative causes, such as natural history of the underlying diseases, concomitant 
31 
therapy, and other risk factors may also be considered.  
32 
 
33 
7.5 
Reporting of Serious Adverse Events 
34 
Adverse events (AE) will be monitored by direct questioning and examination at each study visit 
35 
and by patient self-report.  NCI Common Toxicity Criteria (NCI-CTCAE v.5.0) grade 3 or higher 
36 
in the neurology domain will be considered as severe AE prompting evaluation of the cause. Any 
37 
grade 4 or higher in any other NCI-CTCAE domain will also be considered a severe AE, prompting 
38 
evaluation of cause. Any subject withdrawal due to a severe or serious AE will be submitted orally 
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immediately and in writing within 15 working days to the Data and Safety Monitoring Board 
1 
(DSMB) and the IRB for evaluation, and an assessment of the safety of continuing the entire study 
2 
protocol will be made.  Care will be provided to attempt stabilization of the patient's condition and 
3 
an investigation will be initiated for possible concurrent conditions causing the deterioration, 
4 
including imaging, urine and blood tests.  The DBS leads and unit can be removed at the patient's 
5 
request, or with the patient's consent if judged necessary by the investigators.  Similarly, new 
6 
persistent neurologic deficit(s) or worsening of previous deficit(s) causing intolerable patient 
7 
distress will prompt changing the DBS paradigm and if needed termination of DBS and subject 
8 
withdrawal.  The same measures described above will be employed. 
9 
The PI will make a preliminary determination of whether the SAE is related to the DBS 
10 
system or therapy.  The DSMB will make the final determination of relatedness. The sponsor 
11 
/investigator will report the available information on all SAEs to the FDA within 10 working days 
12 
of learning of the event.  Any SAE which occurs during the study, whether related to the DBS-
13 
system or not, will be reported to the DSMB.  Any SAE related to the DBS system will be reported 
14 
to the device manufacturer. 
15 
The inpatient screening/baseline, DBS surgery, and DBS titration phases, and 
16 
hospitalization for DBS battery replacement and period of DBS-off state for washout to collect 
17 
LFPs, will not be considered an SAE. Likewise, if the participant is admitted to the hospital during 
18 
follow up Phase 4 or 5 through the COAT clinic standard of care, the hospitalization will not be 
19 
considered an SAE if it was related to pre-existing conditions (e.g. inpatient hospitalization for 
20 
substance use treatment and/or deemed not related to the study intervention by the PI, co-
21 
investigators and/or study team (consultation will be made with consultants, DSMB, and NIDA as 
22 
appropriate in making this determination. 
23 
7.6 
Trial Stopping Rules 
24 
If repeated (more than 2) SAE or 2 patients develop SAE that are probably or definitely related to 
25 
the DBS implantation or stimulation, this will trigger a review by the DSMB and the FDA. DSMB 
26 
will meet within two weeks of every SAE. At the time of the review by the DSMB and the FDA, 
27 
enrollment, and/or treatment if indicted, will be paused until a determination is made.  The DSMB 
28 
and the FDA will recommend to the PI to resume or stop the protocol.  The following specific 
29 
conditions will result in a pause and review by the DSMB and the FDA for final determination of 
30 
stopping the study: 
31 
• Any participant with a symptomatic intraparenchymal hemorrhage or acute subdural 
32 
hematoma. (The expected incidence of symptomatic intracranial hemorrhage with DBS 
33 
surgery is 1-3%). 
34 
• Confusion lasting more than 2 weeks after surgery in 2 patients. 
35 
• Postoperative edema or symptoms that do not resolve with a month of onset in 2 patients.  
36 
• Infection from surgery requiring hospitalization or extend the post-operative period for 
37 
more than a week in 2 patients.   
38 
• 2 patients that develop post-operative seizures without a preoperative diagnosis of seizure 
39 
disorder. 
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• Worsening neurological status due to study related procedures according to a change on 
1 
the NIH Stroke Scale of a least 5 for greater than one week in 2 patients. 
2 
• A single death deemed definitely related to study procedure. 
3 
 
4 
7.7 
Additional Stopping Criteria 
5 
The assessments described below will be administered to establish baseline measurements of 
6 
psychosis, mania, depression, and/or suicidality prior to DBS surgery and following DBS surgery 
7 
before the first titration session. The symptoms noted above may emerge following surgery and/or 
8 
titration. If the clinician or study staff observes any of these symptoms clinically/behaviorally, 
9 
these assessments will be re-administered.  In addition, following the titration sessions, these 
10 
measures will be administered and compared to the baseline assessments to monitor changes. 
11 
While the primary objective of the titration sessions is to determine the optimal DBS settings in 
12 
achieving the desired outcome (e.g., reduced craving), these potential side effects will be 
13 
monitored during the process of optimizing the DBS settings. Assessing the resolution of these 
14 
potential side effects, if present and necessary, will be performed as described below. If any of 
15 
these symptoms arise and do not remediate, this will trigger DSMB consultation.  
16 
  
17 
Symptom: Psychosis 
18 
• Assessment: Brief Psychiatric Rating Scale (BPRS) 
19 
• Stopping Criteria: If patient endorses moderate scores or higher (raw score ≥4) on items 
20 
related to psychosis post-surgery or post-titration sessions for >24 hours and if symptoms 
21 
do not resolve with further titration. 
22 
Symptom: Mania 
23 
• Assessment: Young Mania Rating Scale (YMRS) 
24 
• Stopping Criteria: If patient endorses moderate scores or higher (raw score of >25) 
25 
persistently for one-week post-surgery or during titration and if symptoms do not resolve 
26 
with further titration. 
27 
 
28 
Symptom: Depression 
29 
• Assessment: Hamilton Rating Scale for Depression (HAM-D) 
30 
• Stopping Criteria: If patient endorses severe scores or higher (raw score of >17) persistently 
31 
for one-week post-surgery or during titration and if symptoms do not resolve with further 
32 
titration. 
33 
Symptom: Suicidality 
34 
• Assessment: Columbia Suicide Severity Rating Scale (C-SSRS) 
35 
• Stopping Criteria: If patient endorses active thoughts of self-harm post-surgery or post-
36 
titration sessions for >24 hours and if symptoms do not resolve with further titration. 
37 
 
38 
In addition, if an annual review indicates that the study is not likely to be completed within a 
39 
reasonable timeframe the protocol will be stopped.  Finally, other SAE and unanticipated problems 
40 
will be reported to and discussed with the DSMB prior to continuing protocol enrollment. If the 
41 
adverse events are not of a higher incidence than expected, enrollment may continue. If adverse 
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events are of a higher incidence than expected, then additional analysis of causal effects will be 
1 
performed.  All DSMB reports will be sent to the PI who will forward copies to the IRB and FDA 
2 
and may request discussion with the IRB and FDA regarding the need for an amendment.  
3 
 
4 
8.0  
DATA SAFETY AND MONITORING 
5 
To ensure ensures that the trial is conducted, recorded and reported in accordance with the 
6 
protocol, SOPs, GCP and applicable regulatory and ethical requirements, this study will be 
7 
monitored by an independent monitor and a DSMB.  
8 
The independent monitor will be selected qualified by training and experience to monitor 
9 
the progress of the investigation. The monitoring plan will be tailored to minimize the risks 
10 
identified based on considerations such as the objective, purpose, design including patient 
11 
population and intervention, complexity, blinding, size and endpoints of the trial. Following are 
12 
the key responsibilities of a monitor: 
13 
Verify that the investigator(s) have adequate qualification, expertise and the resources to carry out 
14 
the trial. The monitor should also ensure that the investigator will be available for the proposed 
15 
duration of the trial. 
16 
Ascertain that the required institutional facilities (laboratories, equipment, staff, space for storage, 
17 
etc.) are available throughout the trial. 
18 
Verify or make provisions to ensure the following: 
19 
Only eligible participants are enrolled in the trial. 
20 
Sufficient amount of IP is available at the site, and is stored in appropriate conditions. 
21 
IP is supplied to only to eligible participants at the specified dose(s) and time(s). 
22 
The receipt, use, return and disposal of IP at the site is controlled and documented as 
23 
prescribed. 
24 
The protocol and all approved amendments (if any) are followed. 
25 
The investigator(s) has received the current version of Investigators Brochure and the trial 
26 
supplies, as required. 
27 
All essential documents are maintained by the investigator at site. 
28 
All parties involved in the trial are adequately informed of the trial and its various aspects, 
29 
and follow the GCP guidelines and prescribed SOPs. 
30 
The monitor should ensure that the site staff have been adequately trained and comply with the 
31 
protocol, SOPs, and other aspects of the trial. 
32 
The monitor should also assist with providing guidance on Case Record Form (CRF) completion. 
33 
The monitor must ensure that all CRFs are completed accurately in accordance with original 
34 
observations (source data verification), entries are legible, complete and dated. The monitor should 
35 
verify the following: 
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Critical data, required by the protocol is reported accurately on the CRFs and is consistent with 
1 
the source documents. 
2 
Any modification(s) with the dose and/or therapy are documented for each trial participant. 
3 
Ensure that the investigational product is retrieved and disposed or returned to the sponsor, in 
4 
accordance to the protocol. 
5 
The DSMB will be composed of 5 individuals, 2 with collective expertise in addiction and 
6 
behavioral medicine, 1 with neurosurgical expertise, 1 with expertise of neurologic critical care, 
7 
and 1 with statistical expertise.  
8 
Prior to the review of the protocol, each member of the DSMB discloses in writing to the sponsor 
9 
any potential conflicts of interest, actual or implied by appearance. Should an unanticipated 
10 
situation arise that the Board member feels represents a conflict of interest, the Board member 
11 
should recuse themselves. 
12 
Ongoing Study Meetings: During study conduct the DSMB will meet prior to the start of 
13 
enrollment and every six months or more frequently as needed (details regarding meeting time 
14 
frames following key events can be found below). The DSMB may meet in person or via 
15 
teleconference. During these meetings the DSMB will be assigned to review study data, including 
16 
all adverse events, patient withdrawals, and baseline and any re-evaluation data. 
17 
• Interim data review: The DSMB will review interim data to detect evidence of or trending 
18 
of adverse effects and determines if the trial should continue as originally designed, or 
19 
whether it should be changed or stopped.  
20 
• Progress evaluation: The DSMB may also evaluate the progress of the trial, including 
21 
assessments of data quality/completeness, achievement of recruitment goals, protocol 
22 
adherence, accrual and retention of participants, and other factors that may affect the study 
23 
outcome. 
24 
• Protection of confidentiality: Study participant confidentiality will be maintained by 
25 
providing only de identified data to the DSMB. All source data will be stripped of 
26 
identifiers and given a study assigned number before providing to the board. The DSMB 
27 
will protect the confidentiality of study participants, trial data and the results of the 
28 
monitoring. 
29 
• For each participant, the DSMB will meet within 2 weeks following the completion of the 
30 
titration phrase, review AEs, and provide a go/no-go vote before enrolling the next 
31 
participant. 
32 
• DSMB will meet within 2 weeks of every SAE. 
33 
• DSMB will meet biannually after all patients titrated. 
34 
The DSMB will evaluate the safety of the subjects as pre-specified in the protocol, and the DSMB 
35 
will make recommendations to researchers to continue, to amend, or to terminate a clinical trial. 
36 
The DSMB will be assigned to review study data, including all adverse events, patient 
37 
withdrawals, and baseline and any re-evaluation data. Each SAE and significant medical event will 
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prompt a review by the DSMB, and the study will be suspended until it is determined whether the 
1 
SAE is study-related or unrelated.  DSMB analysis of safety data will be performed after the first 
2 
participant has completed 12 weeks of ON stimulation. During the long-term follow-up, the DSMB 
3 
will review any UADEs and SAEs that are attributable to the device and/or stimulation within 2 
4 
weeks. 
5 
The data management for this study will maintain a level of data integrity and 
6 
confidentiality that will provide optimum adherence to all 21 CFR regulations, while providing a 
7 
standardized method of data collection and recording to enable the investigators, sponsors and 
8 
regulatory agencies to accurately reconstruct the events of a study, confirm protocol compliance, 
9 
and produce data that is accurate and appropriate in demonstrating study results.  
10 
• Study coordinators at the RNI will perform primary data collection based on source 
11 
documents following good documentation practices (GDP) at all times. Source data for the 
12 
study may be paper based surveys and questionnaires, EMR or a copy of the CRF labeled 
13 
clearly as SOURCE may also be used as source to collect data not captured in the EMR. 
14 
• Paper or electronic CRFs that have been validated by a Quality control check will be used 
15 
to collect study data.  
16 
• Compliance of regulatory documents and study data accuracy and completeness will be 
17 
maintained through an internal quality control and quality assurance process. 
18 
• Internal Quality Control: All data collected (CRF Pages) will be source verified on an 
19 
ongoing basis (as data becomes available) by a qualified clinical research team member.  
20 
 
21 
9.0 
DATA AND STATISTICAL CONSIDERATIONS 
22 
 
23 
9.1 
Primary Outcomes/Endpoints 
24 
Co-primary outcomes for the proof-of-concept study include: 1) safety and tolerability and 2) 
25 
impact on opioid use among participants. Participants receiving 12 weeks of Active DBS 
26 
stimulation will be compared to participants receiving 12 weeks of Sham DBS stimulation. 
27 
 
28 
1) The safety/tolerability primary endpoint will be assessed comparing Grade 3 and 4 adverse 
29 
events between the Active (DBS-ON) and Sham (DBS-OFF) arms throughout Phase IV 
30 
(Outpatient Week 12). We will provide a list of all adverse events and their grading. We 
31 
will also categorize adverse events by organ system and assess relatedness to any aspect of 
32 
this proof-of-concept study. Statistical tests will be performed at the request of the Data 
33 
and Safety Monitoring Board (DSMB). 
34 
2) Opioid use will be evaluated through the use of quantitative urinary toxicology using gas 
35 
chromatography/mass spectrometry. For each subject, quantitative urine toxicology will be 
36 
collected at baseline (during screening) and during Outpatient Follow-Up Week 4, 8, and 
37 
12. We will evaluate the area under the curve (AUC) as the primary endpoint for each 
38 
subject, using the functional data analysis method to fit a smoothing curve for each 
39 
individual data over time. The AUC data can be standardized by the divided time interval 
40 
as the mean urine drug concentration over the period. For the descriptive purpose, we will 
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plot those individual AUC curves with a mean-curve based on such functional data analysis 
1 
for each treatment group. The statistical inference on the AUC data as a continuous variable 
2 
is based on Wilcoxon’s rank-sum test between the DBS-ON and DBS-OFF arms 
3 
throughout Phase IV. 
4 
 
5 
9.2 
Secondary Outcomes/Endpoints  
6 
1) Brain reward circuitry through evaluation of prefrontal cortex glucose metabolism (FDG 
7 
PET) and dopamine in the basal ganglia and NAc (18F-fallypride PET). 
8 
• The metabolic images (normalized to whole-brain metabolism) will be analyzed using 
9 
the Statistical Parametric Mapping (SPM) (Friston et al., 1995) package SPM12 
10 
(Wellcome Trust Centre for Neuroimaging) or other appropriate image processing tool 
11 
as appropriate. Specifically, the PET images will be spatially normalized to the 
12 
stereotactic space of the MNI using a 12-parameter affine transformation. The SPM2 
13 
FDG template (PET.mnc) was used to normalize the metabolic images, which were 
14 
then normalized to their mean signal intensity. These normalized and transformed 
15 
images will be used for comparisons between baseline (pre-titration) and 12 weeks 
16 
following titration to examine increases in the prefrontal cortex metabolism.   
17 
• 
18F-fallypride PET images will be analyzed according to procedures described by 
18 
Volkow et al. (Volkow et al., 2013). We will estimate the distribution volume (DV) for 
19 
each voxel, and a custom MNI template, which was previously developed using DV 
20 
images from 34 healthy subjects that were acquired with 11C Raclopride (similar to 18F-
21 
fallypride) and the same PET scanning sequence (Wang et al., 2012), will be used for 
22 
the spatial normalization of the DV images. Data will be analyzed via SPM 12, 
23 
confined to ROIs in the basal ganglia and NAc, to evaluate changes at baseline (pre-
24 
titration) and Outpatient Week 12 with and without methylphenidate to determine 
25 
binding potential of dopaminergic D2/D3 receptors. 
26 
2) Performances on the NIH Toolbox Cognition Battery (NIHTB) and the standard 
27 
neuropsychological battery will be assessed and analyzed using repeated measures 
28 
ANOVA. In addition, experimental measures of executive function will be assessed and 
29 
analyzed using repeated measures ANOVA. These measures include the following: 
30 
• Eriksen Flanker Task (Eriksen, 1974): response inhibition. 
31 
• N-Back task (Kirchner, 1958): working memory. 
32 
• Balloon Analogue Risk Task (Lejuez, 2002): risk-taking behavior. 
33 
• Delayed Discounting Task (Richards, 1999): decision-making, impulsivity, and 
34 
inhibitory control. 
35 
3) Similar to Primary Outcome #2, gas chromatography/mass spectrometry will be utilized 
36 
to assess exposure to non-opioid substance use (e.g., cannabis, cocaine, amphetamine, 
37 
benzodiazepines) at baseline (during screening) and at 4, 8, and at 12 weeks of outpatient 
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follow-up. AUC Comparisons will be made between baseline (pre-DBS implantation) and 
1 
post-surgery follow-up, measured at Outpatient Week 4, 8, and 12 weeks.  
2 
4) Qualitative urine toxicology will be obtained twice weekly Phase IV and until 24 weeks 
3 
post-activation and once weekly until 52 weeks post-activation (salivary toxicology may 
4 
be conducted as an alternative if the participant is unable to physically present to clinic). 
5 
Chi-square analyses will be used to determine differences in total number of positive results 
6 
between sham and active arms. 
7 
5) Substance craving will be assessed within two contexts: a) without substance related cues 
8 
and b) with substance related cues during a cue reactivity paradigm. 
9 
a) Substance craving without cues: Baseline craving ratings prior to initiating the cue 
10 
reactivity task will be assessed and analyzed using repeated measures ANOVA.  
11 
b) Substance craving with cues (via a cue reactivity task): Cue-induced craving ratings 
12 
will be assessed and analyzed using repeated measures ANOVA.  
13 
6) Mood (depression and anxiety) assessed via the Comprehensive Psychopathological 
14 
Rating Scale (CPRS) will be assessed and analyzed using repeated measures ANOVA.  
15 
7) Drug overdoses, serious infectious disease complications, retention in comprehension 
16 
behavioral treatment, and patient survival will be assessed weekly throughout the 
17 
Outpatient phase and chi-square analyses will be utilized to determine differences (Yes/No) 
18 
between active and sham arms. 
19 
The outcomes listed above will be evaluated in the following contexts: 
20 
• Between-Subject Comparisons (Primary Endpoint) – Participants receiving 12 weeks of 
21 
Active DBS stimulation will be compared to participants receiving 12 weeks of Sham 
22 
DBS stimulation. 
23 
• Within-Subject Comparisons (Secondary Endpoint) – For those initially randomized to 
24 
Sham DBS condition (DBS-OFF), following crossover to active stimulation, comparisons 
25 
of the initial 12 weeks of stimulation “OFF” will be made to the 12 weeks of stimulation 
26 
“ON” for the primary and secondary outcomes listed above. 
27 
• Within-Subject Comparisons (Tertiary Endpoint) – For all participants, comparisons at 52 
28 
weeks of active stimulation will be made to pre-surgical baselines in line with the 
29 
primary and secondary outcomes listed above. 
30 
 
31 
10.0  REGULATIONS AND ETHICAL CONDUCT OF THE STUDY 
32 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
33 
Clinical Practice (ICH GCP) and the following:  
34 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
35 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR 21 CFR Part 812) 
36 
This protocol will be reviewed/approved by the WVU IRB responsible for oversight of the study. 
37 
 
38 
11.0  DEVICE DESCRIPTION 
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The devices to be used in this study are the standard Medtronic devices which are FDA approved 
1 
for movement disorders such as Parkinson’s disease, essential tremor, dystonia, OCD and 
2 
recently epilepsy. The device consists of a lead, a neurostimulator, and an extension that 
3 
connects the lead to the neurostimulator.  The Medtronic leads used in this study include the 
4 
Model B33005(M) or Model B33015(M) (primary), the Medtronic DBS implanted pulse 
5 
generator (IPG)/neurostimulator include the Model B35200 Percept PC (primary), Model 37612 
6 
Activa RC, or Model 37601Activa PC, and the Medtronic extensions include the Model B34000 
7 
(primary) or Model 37086. Specific details of the lead, neurostimulator, and extension, as well as 
8 
other DBS accessories/components, are described below.   
9 
Model B33005(M) or Model B33015(M) (DBS Lead). The DBS lead consists of a polyurethane 
10 
protective sheath with four platinum/iridium electrodes near the tip of each lead that deliver 
11 
stimulation to the target site.  The leads are stereotactically introduced into the target and fixed at 
12 
the skull with a burr hole cap and ring. The primary leads used in this study (Model B33005(M) 
13 
or Model B33015(M)) use the Medtronic developed SensightTM technologies which combines the 
14 
benefits of directionality with the power of sensing LFPs from the implanted brain 
15 
electrodes. The following SenSightTM components are also included: Lead Test Cable (Model 
16 
B31040), Lead Cap Kit (Model B31020), Burr Hole Device (Model B31000), Burr Hole Device 
17 
Kit (Model B32000), and Extension Tunneler Kit (Model B31030) 
18 
Model B35200 Percept PC, Model 37612 Activa RC, or Model 37601 Activa PC 
19 
(Neurostimulators). The neurostimulator is implanted subcutaneously in the subclavicular or 
20 
upper abdominal region.  It is comprised of a battery and integrated circuits that are hermetically 
21 
sealed within an oval-shaped titanium enclosure. The neurostimulator delivers electrical 
22 
stimulation pulses with a variety of parameters, modes, and polarities.  The electrical pulses are 
23 
carried from the neurostimulator to an implanted deep brain stimulation lead by means of a lead 
24 
extension. The Percept PC Neurostimulator also has the ability to record and export LFPs from 
25 
the implanted brain electrodes. 
26 
Model B34000 or Model 37086 (Extension). The extension is a set of wires within silicone 
27 
tubing that connects the lead to the neurostimulator, providing an electrical path that allows 
28 
stimulation to be delivered to the target site.  The extension is subcutaneously passed from the 
29 
scalp area, where it connects to the lead, through to the subclavicular area or upper abdominal 
30 
region, where it connects to the neurostimulator.  The primary extension used in this study 
31 
(Model B34000) will be utilized in combination with the SensightTM leads referenced above. 
32 
Model 37651 (Recharger). The Activa RC is a rechargeable neurostimulator and is charged 
33 
externally for the internally implanted IPG in subclavicular or upper abdominal region with the 
34 
Medtronic charger for Activa DBS Therapy - Medtronic, Inc. Model 37651. It has 3 components; 
35 
the AC power supply and its cord, the charger and an antenna. The antenna establishes 
36 
communication with the subcutaneously implanted Activa RC IPG, which can be used over a 
37 
belt or the strap. The Therapy screen of the patient therapy controller (Model 37642 RC therapy 
38 
controller), supplied with the patient or caregiver, shows the neurostimulator battery status and 
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charging requirements can be tailored for the individual patients. While charging, the charging 
1 
status is displayed on the neurostimulator charging screen and when the neurostimulator battery 
2 
is fully charged, the Neurostimulator Charge Complete screen appears and the charger stops. 
3 
Model CT900A (Clinical Programmer). The clinical programmer is an FDA approved device, 
4 
which is a tablet-based programming device and works wirelessly. It has an encrypted Bluetooth 
5 
connection from the programmer to the communicator and has a proprietary, proximal telemetry 
6 
from the communicator to the implanted device. The Medtronic Clinical Programmer Model 
7 
CT900A contains the necessary software and options to program neurostimulator. 
8 
Model 8880T2 (Communicator). The communicator is a telemetry head and connects wirelessly 
9 
through an encrypted Bluetooth connection to the clinician programmer model no. CT900A. The 
10 
device is kept close to the IPG and once establishes the connection with the clinical programmer, 
11 
DBS setting is programmed as per the requirement. 
12 
Model 37642 (RC Therapy Controller) or Model A620 (Percept PC Patient Programmer). The 
13 
therapy controller is designed for use by a patient or caregiver.  Using the therapy controller, the 
14 
patient or caregiver can turn therapy on or off, check whether the therapy is on or off, and check 
15 
the condition of the neurostimulators battery. The Percept PC patient programmer also has the 
16 
ability to mark events based on patient perceptions. 
17 
The Medtronic Deep Brain Stimulation components have been commercially approved as 
18 
components of the Medtronic Activa Tremor Control System (PMA P960009, and all associated 
19 
amendments) Medtronic Activa Parkinson’s Control Therapy (P960009) and Medtronic HDE 
20 
H050003 (S001). 
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12.0 
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