Deep Brain Stimulation for Alcohol Use Disorder

Study Overview
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Brief Summary
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The purpose of this clinical study is to investigate the safety, tolerability, and feasibility of Deep Brain Stimulation (DBS) of the limbic pallidum in participants with severe alcohol use disorder (AUD) who have advanced but compensated liver fibrosis.

Detailed Description
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Participants with severe AUD will undergo baseline medical and psychiatric assessments, cognitive and behavioral testing, and positron emission tomography (PET) imaging. One to two weeks later, participants will undergo neurosurgical implantation of DBS electrodes in the limbic pallidum and a neurostimulator. Four weeks after DBS system implantation, the DBS system will be turned ON and the stimulation parameters optimized. Participants will be followed biweekly then monthly for repeated comprehensive assessments.

Official Title
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Limbic Pallidum Deep Brain Stimulation for the Treatment of Severe Alcohol Use Disorder

Conditions
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Alcohol Use Disorder

Intervention / Treatment
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* Device: DBS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (all genders) 21 to 75 years old. Severe primary Alcohol Use Disorder (AUD) (>= 6 Diagnostic and Statistical Manual-5 AUD criteria) with or without other substance use disorders. Participants are seeking treatment for their AUD (participants receiving medications or other therapy for AUD are eligible). Participants have insight into their alcohol use disorder (score >26 on the recognition subscale of the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES V.8)). Participant has advanced compensated alcohol-associated liver disease (ALD). Compensated is defined as asymptomatic per clinical evaluation (by hepatologist or internist). Advanced is defined as fibrosis stage >= 3; if not previously diagnosed, fibrosis stage >= 3 will be diagnosed with liver elastography using a liver stiffness cutoff >=15kiloPascal AUD is treatment refractory: unable to achieve sustained remission (>12 months) over the past 5 years, despite treatment attempts, with at least one treatment attempt involving completed residential or outpatient treatment program with pharmacotherapy, behavioral therapy, or both. Stated willingness to comply with all study procedures and availability for the duration of the study. Social support system and stable living arrangement to provide assurances that the subject will adhere to study requirements: family or friends who live with or near the subject, and can provide collateral information, monitor the subject's behavior, support, and encourage the subject to participate in follow-up visits and evaluations. This is evaluated by a neuropsychologist. For females of reproductive potential: use of highly effective contraception for at least 4 weeks prior to DBS surgery and agreement to use such a method during study participation, and after study completion if they elect to keep the DBS system implanted and ON. Exclusion Criteria: Pregnancy or lactation. Non-English speaking. AUD treatment with another investigational drug or other intervention within 3 months. History of primary psychosis or Bipolar I disorder per the psychiatric evaluation or Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders-5 measure. History of severe personality disorder that could interfere with study participation (e.g., antisocial personality disorder) per the psychiatric evaluation, neuropsychological evaluation, or Structured Clinical Interview for the Diagnostic and Statistical Manual-5 measure. Intelligence quotient <75 as measured by Wechesler Abbreviated Scale of Intelligence (evaluated by a neuropsychologist). History of suicidal attempts in the past 5 years or current suicidal thoughts per psychiatric evaluation and Columbia-Suicide Severity Rating Scale (C-SSRS). Decompensated ALD: clinically obvious ascites, hepatic encephalopathy, jaundice episodes, large esophageal varices with or without variceal bleeding, hepatorenal syndrome, per the clinical evaluation (by hepatologist or internist). Coagulopathy: international normalized ratio (INR) > 1.4, activated partial thromboplastin time (aPTT) > 40 s, platelets < 100,000. Current clinically significant medical or neurologic disease that affects brain function (e.g., recent stroke, myocardial infarction, seizures not due to alcohol withdrawal). Clinically significant abnormality on structural brain MRI scan. Life expectancy less than 18 months per the clinical judgement during medical evaluation (e.g., no terminal cancers). Any labeled DBS contraindication or inability to have brain MRI: certain pacemakers, metal in body, inability to undergo awake operation, significant cardiac or other medical risk factors for surgery, infection, and coagulopathy.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AUD DBS<br>This is a single arm study. Participants will undergo baseline medical and psychiatric assessments, cognitive and behavioral testing, and positron emission tomography (PET) imaging. One to two weeks later, participants will undergo neurosurgical implantation of DBS electrodes in the limbic pallidum and a neurostimulator. Four weeks after DBS system implantation, the DBS system will be turned ON and the stimulation parameters optimized. Participants will be followed biweekly then monthly for repeat comprehensive assessments. | Device: DBS<br>* Bilateral DBS electrodes will be implanted into the limbic pallidum of participants with severe alcohol use disorder and advanced but compensated liver disease.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse events (Safety and Tolerability) | This will be evaluated based on number and seriousness of adverse events associated with DBS implantation and stimulation (e.g., infection, bleeding, cognitive or behavioral side effects). | 4-52 weeks | 
| Recruitment (Feasibility) | This will be evaluated based on number of participants recruited and enrolled in the study | 4-52 weeks | 
| Completed assessments (Feasibility) | This will be evaluated based on number of evaluations conducted during the study duration and participants' adherence to the study protocol. | 4-52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall functioning | Overall function and disability will be measured using standardized questionnaire World Health Organization Disability Assessment 2.0 (WHODAS2.0) score before and monthly after DBS activation (raw score 0-180, higher is worse) | 4-52 weeks | 
| Alcohol use - percent days abstinent | assessment of alcohol use will be measured through percent days abstinent before and monthly after DBS activation | 4-52 weeks | 
| Alcohol use - drinks per drinking day | assessment of alcohol use will be measured through drinks per drinking day before and monthly after DBS activation | 4-52 weeks | 
| Target engagement | This will be assessed by measuring change in brain metabolism with 18fluoro-Deoxy-Glucose (FDG) PET scans before and after DBS activation | baseline, 4 weeks post surgery and 6 months post DBS. |