Alcohol Use Disorder
Conditions
Brief summary
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
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.
Interventions
DEVICEDBS
Bilateral DBS electrodes will be implanted into the limbic pallidum of participants with severe alcohol use disorder and advanced but compensated liver disease.
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Khaled Moussawi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Adults (all genders) 21 to 75 years old. 2. Severe primary Alcohol Use Disorder (AUD) (\>= 6 Diagnostic and Statistical Manual-5 AUD criteria) with or without other substance use disorders. 3. Participants are seeking treatment for their AUD (participants receiving medications or other therapy for AUD are eligible). 4. 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)). 5. 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 6. 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. 7. Stated willingness to comply with all study procedures and availability for the duration of the study. 8. 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. 9. 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
1. Pregnancy or lactation. 2. Non-English speaking. 3. AUD treatment with another investigational drug or other intervention within 3 months. 4. 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. 5. 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. 6. Intelligence quotient \<75 as measured by Wechesler Abbreviated Scale of Intelligence (evaluated by a neuropsychologist). 7. History of suicidal attempts in the past 5 years or current suicidal thoughts per psychiatric evaluation and Columbia-Suicide Severity Rating Scale (C-SSRS). 8. 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). 9. Coagulopathy: international normalized ratio (INR) \> 1.4, activated partial thromboplastin time (aPTT) \> 40 s, platelets \< 100,000. 10. Current clinically significant medical or neurologic disease that affects brain function (e.g., recent stroke, myocardial infarction, seizures not due to alcohol withdrawal). 11. Clinically significant abnormality on structural brain MRI scan. 12. Life expectancy less than 18 months per the clinical judgement during medical evaluation (e.g., no terminal cancers). 13. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Completed Assessments (Feasibility) | 4-52 weeks | This will be evaluated based on the average percentage of evaluations completed across participants during the study duration out of total required assessments to measure the participants' adherence to the study protocol. |
| Number of Serious Adverse Events (Safety and Tolerability) | 4-52 weeks | 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). |
| Recruitment (Feasibility) | 0-71 weeks | This will be evaluated based on number of participants recruited and enrolled in the study between study start date and primary completion date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alcohol Use - Percent Days Abstinent | 6 months | assessment of alcohol use will be measured through percent days abstinent (PDA) at baseline (pver preceding 6 months) and at 6 months after DBS activation. PDA at baseline is assessed over the preceding 180 days. PDA at 6 months post-DBS activation is assessed over the preceding 30 days. |
| Alcohol Use - Drinks Per Drinking Day | 6 months | assessment of alcohol use will be measured through drinks per drinking day (DDD) before and after DBS activation. The focus of analysis was limited to the 6-month timepoint. DDD at baseline is assessed over the preceding 180 days. DDD at 6 months post-DBS activation is assessed over the preceding 30 days. |
| Overall Functioning | 6 months | Overall function and disability will be measured using standardized questionnaire World Health Organization Disability Assessment 2.0 (WHODAS2.0) score before and after DBS activation (raw score 0-180, higher is worse). The focus of analysis was limited to the 6-month timepoint. |
| Target Engagement | 6 months | This will be assessed by measuring the percent change in brain metabolism with 18fluoro-Deoxy-Glucose (FDG) PET scans before and after DBS activation. The timepoint 4 weeks post-surgery was excluded because breath alcohol test was positive on that day. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cue Reactivity Craving Score | 6 months | To measure subjective craving after presentation of alcohol or neutral pictorial cues pre and post DBS. Craving is reported using a visual analog scale (VAS) between 0 and 100, where 100 indicates very high craving; the cue reactivity craving score is calculated as the difference in craving scores after alcohol vs. neutral pictures. |
Countries
United States
Participant flow
Recruitment details
224 potential subjects were prescreened. Most prescreened subjects were not eligible. Around fifteen percent of those who were potentially eligible never followed up or were no longer interested.
Pre-assignment details
3 subjects consented and were enrolled. One subject was a screen-fail and was not implanted with the device.
Participants by arm
| Arm | Count |
|---|---|
| AUD DBS 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. | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | AUD DBS |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 2 |
| other Total, other adverse events | 1 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Number of Serious 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).
Time frame: 4-52 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AUD DBS | Number of Serious Adverse Events (Safety and Tolerability) | Serious Adverse Events | 1 Adverse Events |
| AUD DBS | Number of Serious Adverse Events (Safety and Tolerability) | Other Adverse Events | 1 Adverse Events |
Primary
Proportion of Completed Assessments (Feasibility)
This will be evaluated based on the average percentage of evaluations completed across participants during the study duration out of total required assessments to measure the participants' adherence to the study protocol.
Time frame: 4-52 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AUD DBS | Proportion of Completed Assessments (Feasibility) | 100 Percent of total assessments |
Primary
Recruitment (Feasibility)
This will be evaluated based on number of participants recruited and enrolled in the study between study start date and primary completion date.
Time frame: 0-71 weeks
Population: 224 potential participants were pre-screened for recruitment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AUD DBS | Recruitment (Feasibility) | 3 Participants |
Secondary
Alcohol Use - Drinks Per Drinking Day
assessment of alcohol use will be measured through drinks per drinking day (DDD) before and after DBS activation. The focus of analysis was limited to the 6-month timepoint. DDD at baseline is assessed over the preceding 180 days. DDD at 6 months post-DBS activation is assessed over the preceding 30 days.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AUD DBS | Alcohol Use - Drinks Per Drinking Day | Baseline | 10.49 drinks per drinking day |
| AUD DBS | Alcohol Use - Drinks Per Drinking Day | 6 months | 5 drinks per drinking day |
Secondary
Alcohol Use - Percent Days Abstinent
assessment of alcohol use will be measured through percent days abstinent (PDA) at baseline (pver preceding 6 months) and at 6 months after DBS activation. PDA at baseline is assessed over the preceding 180 days. PDA at 6 months post-DBS activation is assessed over the preceding 30 days.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AUD DBS | Alcohol Use - Percent Days Abstinent | Baseline | 14.6 percentage of days |
| AUD DBS | Alcohol Use - Percent Days Abstinent | 6 months | 81 percentage of days |
Secondary
Overall Functioning
Overall function and disability will be measured using standardized questionnaire World Health Organization Disability Assessment 2.0 (WHODAS2.0) score before and after DBS activation (raw score 0-180, higher is worse). The focus of analysis was limited to the 6-month timepoint.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AUD DBS | Overall Functioning | Baseline | 1.61 score on a scale |
| AUD DBS | Overall Functioning | 6 months | 1.5 score on a scale |
Secondary
Target Engagement
This will be assessed by measuring the percent change in brain metabolism with 18fluoro-Deoxy-Glucose (FDG) PET scans before and after DBS activation. The timepoint 4 weeks post-surgery was excluded because breath alcohol test was positive on that day.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AUD DBS | Target Engagement | Limbic pallidum change in activity at 6 months relative to baseline | -7 percentage of cerebellar activity |
| AUD DBS | Target Engagement | Ventral striatum change in activity at 6 months relative to baseline | -13 percentage of cerebellar activity |
| AUD DBS | Target Engagement | OFC change in activity at 6 months relative to baseline | -14 percentage of cerebellar activity |
Other Pre-specified
Cue Reactivity Craving Score
To measure subjective craving after presentation of alcohol or neutral pictorial cues pre and post DBS. Craving is reported using a visual analog scale (VAS) between 0 and 100, where 100 indicates very high craving; the cue reactivity craving score is calculated as the difference in craving scores after alcohol vs. neutral pictures.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AUD DBS | Cue Reactivity Craving Score | Baseline | 73.06 score on a scale |
| AUD DBS | Cue Reactivity Craving Score | 6 months | -3 score on a scale |