Non-invasive Vagal Nerve Stimulation in Alcohol Use Disorder

• ClinicalTrials.gov Identifier: NCT05226130
• Recruitment Status: Recruiting
• First Posted: February 7, 2022
• Last Update Posted: March 13, 2023
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Tracking Information

• First Submitted Date: December 27, 2021
• First Posted Date: February 7, 2022
• Last Update Posted Date: March 13, 2023
• Actual Study Start Date: May 2, 2022
• Estimated Primary Completion Date: October 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2022)

• Treatment Acceptability Questionnaire (TAQ) [ Time Frame: Baseline to week 1 of 2x daily intervention (measure only administered at at study completion, i.e., 1 week after baseline) ]
  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".
• Measurement of feasibility - Recruitment goal [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  Treatment feasibility will be evaluated by meeting the recruitment goal of 16 Veterans within 12 months as measured by consented subjects who completed the baseline study visit.
• Measurement of feasibility - Treatment adherence [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  Treatment feasibility will be evaluated by meeting >75% treatment adherence as documented in checklist/daily diary and interview) and measured as administering nVNS/sham stimulation twice a day for 7 days.
• Measurement of feasibility - Subject retention [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  Treatment feasibility will be evaluated by meeting >75% subject retention at follow-up as measured by subjects completing the follow-up study visit.
• Measurement of feasibility - Adverse side effects [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  Treatment feasibility will be evaluated by no serious adverse side effects (as documented in checklist/daily diary and interview).

Original Primary Outcome Measures (submitted: January 25, 2022)

• Treatment Acceptability Questionnaire (TAQ) [ Time Frame: At study completion (following 1 week of intervention) ]
  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".
• Measurement of feasibility - Recruitment goal [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  Treatment feasibility will be evaluated by meeting the recruitment goal of 16 Veterans within 12 months as measured by consented subjects who completed the baseline study visit.
• Measurement of feasibility - Treatment adherence [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  Treatment feasibility will be evaluated by meeting >75% treatment adherence as documented in checklist/daily diary and interview) and measured as administering nVNS/sham stimulation twice a day for 7 days.
• Measurement of feasibility - Subject retention [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  Treatment feasibility will be evaluated by meeting >75% subject retention at follow-up as measured by subjects completing the follow-up study visit.
• Measurement of feasibility - Adverse side effects [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  Treatment feasibility will be evaluated by no serious adverse side effects (as documented in checklist/daily diary and interview).

Current Secondary Outcome Measures (submitted: January 25, 2022)

• Substance Use Recovery Evaluator (SURE) [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  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.
• WHO Quality of Life assessment (WHOQOL-BREF) [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  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; score interpretation varies between items.
• Beck Anxiety Inventory (BAI) [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  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, with a higher score reflecting greater anxiety.
• PROMIS Pain Interference [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  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, rated on a 5-point scale, ranging from "not at all" to "very much". Higher scores reflect higher pain interference.
• Alcohol Urge Questionnaire (AUQ) [ Time Frame: Baseline to week 1 of 2x daily intervention ]
  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. Higher scores reflect greater craving.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: January 25, 2022)

Heat pain fMRI task [ Time Frame: Baseline to week 1 of 2x daily intervention ]

During this task, participants receive brief thermal stimuli (experienced temperature ranging from warm to hot) applied to the leg via a thermode. Neural activation will be measured using percent signal change with higher scores indicating greater activation.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Non-invasive Vagal Nerve Stimulation in Alcohol Use Disorder
• Official Title: Non-invasive Vagal Nerve Stimulation to Improve Functional Outcomes in Veterans With Alcohol Use Disorder
• Brief Summary: 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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).

Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:

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.

Primary Purpose: Treatment

• Condition: Alcohol Use Disorder

Intervention

• Device: 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.
• Device: 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.

Study Arms

• Active Comparator: 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.
  Intervention: Device: Cervical transcutaneous vagus nerve stimulation (active comparator)
• Placebo Comparator: 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.
  Intervention: Device: Cervical transcutaneous vagus nerve stimulation (sham comparator)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 25, 2022): 16
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 31, 2024
• Estimated Primary Completion Date: October 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Veteran
• Male subjects between 21 and 65 years of age
• Current DSM-5 diagnosis of AUD with at least one functional disability due to alcohol use, current alcohol craving, and current heavy drinking (>4 drinks on any day or >14 drinks per week)
• Able to forgo consumption of alcohol for 24 hours without any serious discomfort including nausea/vomiting, visual/auditory/tactile hallucinations, or non-essential tremor

Exclusion Criteria:

• Clinical Institute Withdrawal Assessment of Alcohol Scale (CiWA) score >=9 on the day of the scan (symptoms judged to be due to co-existing anxiety or headache disorders will not be counted toward the total).
• Currently or recently (within last 90 days) enrolled in abstinence-based treatment program.
• Evidence of a maladaptive pattern of substance use or abuse other than alcohol one month prior to screening visit.
• Severe mental illness, e.g., psychosis or bipolar disorder
• At risk for suicide or homicide
• History of neurological disorder that might be associated with cognitive dysfunction.
• History of head trauma involving loss of consciousness >24 hours
• Clinically significant uncontrolled/unstable medical illness or clinically significant surgery within 1 month of the screening visit.
• MRI-related exclusion criteria: cardiac pacemaker, metal fragments in eyes/skin/body, aortic/aneurysm clips, heart-valve replacement, copper intrauterine device, shunt (ventricular or spinal), neuro/bio-stimulators
• Vagus nerve stimulation related criteria: history of carotid endarterectomy, severe carotid artery disease (e.g., history of transient ischemic attack (TIA) or stroke], congestive heart failure, cardiac arrhythmia, known severe coronary artery disease or recent myocardial infarction (within 5 years), history of seizure or syncope (within past year), prior neck surgery.

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: 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.

• Ages: 21 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Ruth Klaming, PhD; (858) 642-3538; Ruth.Miller@va.gov

Contact: Imanuel R Lerman, MD MSc; (203) 640-8068; ilerman@mail.ucsd.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05226130
• Other Study ID Numbers: D3629-M
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: VA Office of Research and Development
• Original Responsible Party: Same as current
• Current Study Sponsor: VA Office of Research and Development
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ruth Klaming, PhD; VA San Diego Healthcare System, San Diego, CA

• PRS Account: VA Office of Research and Development
• Verification Date: March 2023