Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Alcohol use disorder (AUD) is a major health concern amongst Veterans as it causes poor health, lost days at work, impaired psychosocial functioning, and decreased quality of life. Current treatment options for AUD show limited effectiveness, which is exemplified by high relapse rates. Chronic heavy drinking results in psychological and physical distress during abstinence, including anxiety, irritability, and general discomfort, which increases the urge to drink to relieve these symptoms. The hypothesis of this study is that noninvasive vagal nerve stimulation (nVNS) can modify the perception of such inner bodily sensations of distress, and consequently reduces the drive to drink for relief. The aim of this study is to establish feasibility and acceptability of applying nVNS as a rehabilitative treatment for AUD in Veterans. The study will also evaluate the effect of nVNS on functional outcomes, quality of life, distress, and craving, and if nVNS alters neural activation patterns in brain regions involved in the perception and awareness of distress and pain.
AUD is a serious mental health disorder that affects more than 40% of US military Veterans, presenting a major burden to this population. Relapse rates of AUD are extremely high; over half of Veterans who complete treatment, relapse within 6 months, highlighting the need for improved treatments or differing treatment targets. Chronic, heavy drinking leads to an imbalance in homeostasis resulting in psychological and physical distress during periods of abstinence, and the urge to drink to relieve these symptoms to restore homeostasis.
nVNS is a low-risk form of neuromodulation that has been shown to alleviate anxiety and chronic pain, and to reduce drug and alcohol relapse in animal models. The investigators hypothesize that nVNS attenuates distress-related craving in AUD in humans by modifying the autonomic nervous system and changing the perception of inner bodily sensations of physiological and affective distress. The investigators also hypothesize that nVNS improves functional outcomes and quality of life in Veterans with AUD.
The proposed research will include 16 Veterans who meet for a diagnosis of AUD. Subjects will be randomly assigned to receive nVNS or sham stimulation prior to performing a well-validated functional Magnetic Resonance Imaging task designed to assess neural correlates of physical distress (via a heat stimulus). Subjects will then self-administer nVNS/sham at home twice a day for 7 days and return for a follow-up visit, during which all study components will be repeated. Behavioral assessments of functional disability, quality of life, psychological and physiological distress, and craving will be administered at baseline, after stimulation, and at follow-up.
The aim of the proposed study is to establish feasibility and acceptability of applying nVNS as a rehabilitative treatment for AUD. In addition, the study will evaluate the preliminary effectiveness of nVNS in improving functional outcomes and quality of life, in reducing distress and craving, and in altering neural activation patterns in brain regions involved in the perception and awareness of distress and pain. The proposed work has the potential to lead to innovative, low-risk treatment options with high promise to significantly improve the care and lives of Veterans as there is a need for alternative treatments for AUD. As such, this novel AUD treatment could be particularly beneficial for Veterans who do not tolerate pharmacotherapy, and who have access or cognitive limitations or stigma concerns that act as barriers to psychotherapy.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active cervical transcutaneous vagus nerve stimulation | Active Comparator | Participants will be assigned to active transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. |
|
| Sham cervical transcutaneous vagus nerve stimulation | Placebo Comparator | Participants will be assigned to sham transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cervical transcutaneous vagus nerve stimulation (active comparator) | Device | Active nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that stimulates the vagus nerve. |
| Measure | Description | Time Frame |
|---|---|---|
| Treatment Acceptability Questionnaire (TAQ) | The Treatment Acceptability Questionnaire (TAQ) is a self-rating questionnaire used to assess acceptability of a treatment. The TAQ uses a 7-point rating scale ranging from 1 to 7, with lower scores reflecting lower acceptability and a midpoint of 4 indicating neutral acceptability. A rating above the midpoint of the TAQ (i.e., score between 5 and 7) is the established criterion for "acceptable to highly acceptable". | Measure administered at study completion (i.e., 1 week after baseline) |
| Measurement of Feasibility - Recruitment Goal (Data Reflects the Number of Participants Who Were Successfully Enrolled in the Study) | Treatment feasibility will be evaluated by meeting the proposed recruitment goal of 16 Veterans within 12 months. This aim was measured as the number of study participants who signed the study consent form, completed at least the baseline study visit, and were included in the study analyses. | Baseline |
| Measurement of Feasibility - Treatment Adherence (Number of Times Subjects Self-administered nVNS/Sham Stimulation for 7 Days as Instructed) | Treatment adherence will be assessed via a daily treatment completion log, and calculated by dividing the total number of times subjects were instructed to self-administer the nVNS/sham stimulation (2x/day for 7 days = 14 times) by the number of times the subjects actually self-administered the stimulation. Treatment feasibility will be evaluated by meeting >75% treatment adherence during the 1-week interval. | Baseline to week 1 of 2x daily intervention |
| Measurement of Feasibility - Subject Retention (Number/Percentage of Subjects Who Return for a Follow-up Visit) | Treatment feasibility will be evaluated by meeting >75% subject retention at follow-up as measured by the number/percentage of subjects who return for a follow-up visit and complete primary outcome measures and return the device to the study team. | Baseline to post treatment, up to 21 days post baseline |
| Measure | Description | Time Frame |
|---|---|---|
| Substance Use Recovery Evaluator (SURE) | The Substance Use Recovery Evaluator (SURE) assesses the following domains of AUD-related functional outcomes: self-care (mental and physical health), relationships, material resources (stability of housing and occupational resources), and outlook of life. The SURE has been developed for use in substance use disorder populations. The SURE is comprised of 21 items, rated on a 3-point scale, but scored using a 3-point scale. Scores range from 21-63. A higher score indicates better functional outcomes. |
| Measure | Description | Time Frame |
|---|---|---|
| Neural Response to Heat Pain Stimuli (Measured as Sum of BOLD Beta Coefficients Over Time in Arbitrary Units) | Participants receive brief thermal stimuli (experienced temperature ranging from warm to hot) applied to the leg via a contact thermode during a functional magnetic resonance imaging scan. Neural activation will be measured using the general linear model (GLM) to estimate beta coefficients for the BOLD (blood-oxygen-level-dependent) signal in response to thermal stimulation. Activation in the brain region insula will be summarized by calculating the area under the beta response curve (arbitrary units) over the stimulus duration (i.e., time), reflecting the total magnitude of neural activation. BOLD signal and beta coefficients used to model neural response are in arbitrary units. The area under the curve is the cumulative scaled beta (i.e., cumulative percent signal change) that is most reflective of the activation attributable to the stimulus. Higher numbers indicate more neural activation in the insula in response to painful heat stimuli. |
Inclusion Criteria:
Exclusion Criteria:
Parent study does not enroll women (due to potential sex differences in inflammation-induced alterations of brain response as well as sex differences in prevalence of PTSD), this study will not enroll women either to allow for post-hoc group comparisons. If significant effects are demonstrated with this study, follow-up grant proposals will include females.
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Ruth Klaming, PhD | VA San Diego Healthcare System, San Diego, CA | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VA San Diego Healthcare System, San Diego, CA | San Diego | California | 92161-0002 | United States |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Active Cervical Transcutaneous Vagus Nerve Stimulation | Participants will be assigned to active transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. Cervical transcutaneous vagus nerve stimulation (active comparator): Active nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that stimulates the vagus nerve. |
| FG001 | Sham Cervical Transcutaneous Vagus Nerve Stimulation | Participants will be assigned to sham transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. Cervical transcutaneous vagus nerve stimulation (sham comparator): Sham nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that does not stimulate the vagus nerve. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Active Cervical Transcutaneous Vagus Nerve Stimulation | Participants will be assigned to active transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. Cervical transcutaneous vagus nerve stimulation (active comparator): Active nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that stimulates the vagus nerve. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Treatment Acceptability Questionnaire (TAQ) | The Treatment Acceptability Questionnaire (TAQ) is a self-rating questionnaire used to assess acceptability of a treatment. The TAQ uses a 7-point rating scale ranging from 1 to 7, with lower scores reflecting lower acceptability and a midpoint of 4 indicating neutral acceptability. A rating above the midpoint of the TAQ (i.e., score between 5 and 7) is the established criterion for "acceptable to highly acceptable". | TAQ ratings for two subjects (both in the sham group) were not included in the analyses because they were not treatment adherent (i.e., did not self-administer nVNS/sham as instructed). One subject was lost to follow-up. | Posted | Mean | Standard Deviation | score on a scale | Measure administered at study completion (i.e., 1 week after baseline) |
|
7 days
[Not Specified]
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active Cervical Transcutaneous Vagus Nerve Stimulation | Participants will be assigned to active transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. Cervical transcutaneous vagus nerve stimulation (active comparator): Active nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that stimulates the vagus nerve. |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lip pulling | Product Issues | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ruth Klaming, PhD | VA San Diego Healthcare System, San Diego, CA | 858-552-8585 | rklaming@health.ucsd.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 29, 2024 | May 1, 2025 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 8, 2023 | May 22, 2024 | ICF_000.pdf |
Not provided
| ID | Term |
|---|---|
| D000437 | Alcoholism |
| D000428 | Alcohol Drinking |
| D001008 | Anxiety Disorders |
| ID | Term |
|---|---|
| D019973 | Alcohol-Related Disorders |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
Not provided
Not provided
Devices include a sham and an active noninvasive vagal nerve stimulator (nVNS). Devices are identical in appearance, and both produce reliable sensation on the skin when applied to the neck area (transcutaneous cervical stimulation). Stimulation duration is approximately 120 seconds for both sham and active devices. Subjects receive the same instructions to self-administer stimulation twice a day for 120 minutes on each side (right and left).
Not provided
Not provided
Both the research team involved in data collection and subjects will be blinded (double-blind study design). Subjects will be randomly assigned to receive either active or sham stimulation. Devices will be marked with an identification number to mask treatment condition. An unblinded Co-Investigator, not involved in data collection and subject contact, will assign randomization, provide device identification number, and keep the key linking condition to identification numbers.
| Cervical transcutaneous vagus nerve stimulation (sham comparator) | Device | Sham nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that does not stimulate the vagus nerve. |
|
| Measurement of Feasibility - Serious Adverse Side Effects | Treatment feasibility will be evaluated by no occurrence of serious adverse side effects (as documented in checklist/daily log, interview at study completion, or otherwise reported by the participant). | Baseline to week 1 of 2x daily intervention |
| Baseline to week 1 of 2x daily intervention |
| WHO Quality of Life Assessment (WHOQOL-BREF) - Psychological Domain | The WHO Quality of Life assessment (WHOQOL-BREF) assesses quality of life across four domains (physical health, psychological, social relationships, and environment) with a total of 26 questions. The rating scale ranges from 1 to 5 and minimum and maximum values varies between domains (physical health: 7-35, psychological: 6-30, social relationships: 3-15, environment: 8-40). Higher scores denote higher quality of life. Reported here are results from the psychological domain. | Baseline to week 1 of 2x daily intervention |
| Beck Anxiety Inventory (BAI) | The Beck Anxiety Inventory (BAI) is a self-report instrument to measure the severity of anxiety and emotional distress. The BAI is a 21-item questionnaire with a 4-point rating scale (0-3), with a higher score reflecting greater anxiety. Total scores range from 0 to 63 with higher scores indicating higher anxiety. | Baseline to week 1 of 2x daily intervention |
| PROMIS Pain Interference | The PROMIS Pain Interference measures self-reported consequences of pain on relevant aspects of one's life, i.e., the extent to which pain hinders engagement with social, cognitive, emotional, physical, and recreational activities. This questionnaire has 8 items with ratings ranging from "not at all" to "very much". Total score minimum is 8 and the maximum is 40. Higher scores reflect higher interference of pain with level of functioning. | Baseline to week 1 of 2x daily intervention |
| Alcohol Urge Questionnaire (AUQ) | The Alcohol Urge Questionnaire (AUQ) is 8-item scale that measures cognitive preoccupation with alcohol on a 7-point rating scale ranging from "strongly disagree" to "strongly agree". Two items are reverse scored. Minimum score is 8 and maximum is 56. Higher scores reflect greater craving. | Baseline to week 1 of 2x daily intervention |
| Baseline to week 1 of 2x daily intervention |
| BG001 | Sham Cervical Transcutaneous Vagus Nerve Stimulation | Participants will be assigned to sham transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. Cervical transcutaneous vagus nerve stimulation (sham comparator): Sham nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that does not stimulate the vagus nerve. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | Sham Cervical Transcutaneous Vagus Nerve Stimulation | Participants will be assigned to sham transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. Cervical transcutaneous vagus nerve stimulation (sham comparator): Sham nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that does not stimulate the vagus nerve. |
|
|
| Primary | Measurement of Feasibility - Recruitment Goal (Data Reflects the Number of Participants Who Were Successfully Enrolled in the Study) | Treatment feasibility will be evaluated by meeting the proposed recruitment goal of 16 Veterans within 12 months. This aim was measured as the number of study participants who signed the study consent form, completed at least the baseline study visit, and were included in the study analyses. | More (19 subjects) than the initially proposed number of participants (16 subjects) were enrolled in the study. | Posted | Count of Participants | Participants | Baseline |
|
|
|
| Primary | Measurement of Feasibility - Treatment Adherence (Number of Times Subjects Self-administered nVNS/Sham Stimulation for 7 Days as Instructed) | Treatment adherence will be assessed via a daily treatment completion log, and calculated by dividing the total number of times subjects were instructed to self-administer the nVNS/sham stimulation (2x/day for 7 days = 14 times) by the number of times the subjects actually self-administered the stimulation. Treatment feasibility will be evaluated by meeting >75% treatment adherence during the 1-week interval. | 1 subject lost to FU | Posted | Mean | Standard Deviation | percentage of treatment administrations | Baseline to week 1 of 2x daily intervention |
|
|
|
| Primary | Measurement of Feasibility - Subject Retention (Number/Percentage of Subjects Who Return for a Follow-up Visit) | Treatment feasibility will be evaluated by meeting >75% subject retention at follow-up as measured by the number/percentage of subjects who return for a follow-up visit and complete primary outcome measures and return the device to the study team. | Posted | Count of Participants | Participants | Baseline to post treatment, up to 21 days post baseline |
|
|
|
| Primary | Measurement of Feasibility - Serious Adverse Side Effects | Treatment feasibility will be evaluated by no occurrence of serious adverse side effects (as documented in checklist/daily log, interview at study completion, or otherwise reported by the participant). | Number of serious adverse events | Posted | Number | Number of serious adverse events | Baseline to week 1 of 2x daily intervention |
|
|
|
| Secondary | Substance Use Recovery Evaluator (SURE) | The Substance Use Recovery Evaluator (SURE) assesses the following domains of AUD-related functional outcomes: self-care (mental and physical health), relationships, material resources (stability of housing and occupational resources), and outlook of life. The SURE has been developed for use in substance use disorder populations. The SURE is comprised of 21 items, rated on a 3-point scale, but scored using a 3-point scale. Scores range from 21-63. A higher score indicates better functional outcomes. | Posted | Mean | Standard Deviation | score on a scale | Baseline to week 1 of 2x daily intervention |
|
|
|
| Secondary | WHO Quality of Life Assessment (WHOQOL-BREF) - Psychological Domain | The WHO Quality of Life assessment (WHOQOL-BREF) assesses quality of life across four domains (physical health, psychological, social relationships, and environment) with a total of 26 questions. The rating scale ranges from 1 to 5 and minimum and maximum values varies between domains (physical health: 7-35, psychological: 6-30, social relationships: 3-15, environment: 8-40). Higher scores denote higher quality of life. Reported here are results from the psychological domain. | Posted | Mean | Standard Deviation | score on a scale | Baseline to week 1 of 2x daily intervention |
|
|
|
| Secondary | Beck Anxiety Inventory (BAI) | The Beck Anxiety Inventory (BAI) is a self-report instrument to measure the severity of anxiety and emotional distress. The BAI is a 21-item questionnaire with a 4-point rating scale (0-3), with a higher score reflecting greater anxiety. Total scores range from 0 to 63 with higher scores indicating higher anxiety. | Posted | Mean | Standard Deviation | score on a scale | Baseline to week 1 of 2x daily intervention |
|
|
|
| Secondary | PROMIS Pain Interference | The PROMIS Pain Interference measures self-reported consequences of pain on relevant aspects of one's life, i.e., the extent to which pain hinders engagement with social, cognitive, emotional, physical, and recreational activities. This questionnaire has 8 items with ratings ranging from "not at all" to "very much". Total score minimum is 8 and the maximum is 40. Higher scores reflect higher interference of pain with level of functioning. | Posted | Mean | Standard Deviation | score on a scale | Baseline to week 1 of 2x daily intervention |
|
|
|
| Secondary | Alcohol Urge Questionnaire (AUQ) | The Alcohol Urge Questionnaire (AUQ) is 8-item scale that measures cognitive preoccupation with alcohol on a 7-point rating scale ranging from "strongly disagree" to "strongly agree". Two items are reverse scored. Minimum score is 8 and maximum is 56. Higher scores reflect greater craving. | Posted | Mean | Standard Deviation | score on a scale | Baseline to week 1 of 2x daily intervention |
|
|
|
| Other Pre-specified | Neural Response to Heat Pain Stimuli (Measured as Sum of BOLD Beta Coefficients Over Time in Arbitrary Units) | Participants receive brief thermal stimuli (experienced temperature ranging from warm to hot) applied to the leg via a contact thermode during a functional magnetic resonance imaging scan. Neural activation will be measured using the general linear model (GLM) to estimate beta coefficients for the BOLD (blood-oxygen-level-dependent) signal in response to thermal stimulation. Activation in the brain region insula will be summarized by calculating the area under the beta response curve (arbitrary units) over the stimulus duration (i.e., time), reflecting the total magnitude of neural activation. BOLD signal and beta coefficients used to model neural response are in arbitrary units. The area under the curve is the cumulative scaled beta (i.e., cumulative percent signal change) that is most reflective of the activation attributable to the stimulus. Higher numbers indicate more neural activation in the insula in response to painful heat stimuli. | Two subjects did not participate in neuroimaging scans due to claustrophobia. | Posted | Mean | Standard Deviation | Arbitrary units | Baseline to week 1 of 2x daily intervention |
|
|
|
| 0 |
| 9 |
| 0 |
| 9 |
| 4 |
| 9 |
| EG001 | Sham Cervical Transcutaneous Vagus Nerve Stimulation | Participants will be assigned to sham transcutaneous vagus nerve stimulation, received once during each of the study visits and self-administered twice a day for a week. Cervical transcutaneous vagus nerve stimulation (sham comparator): Sham nVNS produces low-voltage electrical signal that generates sensations on the skin on upper anterior cervical area (overlying carotid artery) and that does not stimulate the vagus nerve. | 0 | 10 | 0 | 10 | 1 | 10 |
| Tingling sensation | Product Issues | Systematic Assessment |
|
| Muscle twitching | Product Issues | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Mild headache | Nervous system disorders | Systematic Assessment |
|
| Neck soreness | Product Issues | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D004327 | Drinking Behavior |
| D001519 | Behavior |