SBIR-STTR Award

Alcohol use disorder (AUD) is a major public health concern, affecting over 16 million Americans. AUD is a highly disabling disease associated with many physical and psychiatric co-morbidities, and excessive alcohol consumption is now the third leading preventable cause of death in the U.S. Current AUD interventions include pharmacologic treatment and behavioral therapies; however, these are not very effective, having high rates of relapse soon after initial successful treatment. A large evidence base shows that an exaggerated central nervous system response to alcohol-related cues is a key phenomenon in alcohol dependence and relapse. With long- term AUD, neutral cognitive or environmental cues can evoke a supraphysiological dopamine (DA) response in the mesolimbic circuit in the absence of the direct alcohol effect. The magnitude of this conditioned reward circuitry response has subsequently been hypothesized to be associated with craving, ultimately increasing the likelihood of relapse. Invasive neuromodulation techniques that target the mesolimbic circuitry in the mid-brain have demonstrated substantial promise in reducing craving and alcohol consumption in multiple case studies. However, the invasive surgical procedure as well as infection- and implant-related adverse events limit acceptability. Peripheral nerve stimulation, which may be a more acceptable therapy to patients, has also been shown to directly regulate the mesolimbic DA pathway and impede drug-induced effects. To take advantage of this craving regulatory circuit, TheraNova has developed Leo-S, a non-invasive, portable transcutaneous electrical nerve stimulation device for the treatment of AUD. By providing a safe, discreet, easy-to-use, and effective therapy that targets the mesolimbic circuit, Leo-S may substantially improve initial treatment outcomes as well as future relapse rates. Leo-S device has demonstrated early feasibility through two pilot studies in healthy human subjects. The overall goal of this Phase I proposal is to verify safety and patient acceptability for daily Leo-S use as an AUD treatment. In Specific Aim 1, a 20-patient study will be conducted to optimize the device design. Two skin-contacting electrode designs will be evaluated to maximize patient acceptability while providing consistent nerve stimulation. In Specific Aim 2, we will use the optimal design from Aim 1 to conduct a 25-patient, cross-over, home-use study. Patients will have a one-week control period with no treatment followed by two weeks of daily Leo-S treatment. Our primary endpoints will be device acceptability and safety for home- use. We will also evaluate the short-term treatment effectiveness for reducing alcohol craving and consumption. In addition, these studies will provide data on recruitment, attrition, and effect size that will be critical for powering a pivotal study to validate the long-term effects of Leo-S treatment on craving and alcohol consumption in Phase II. Our goal is to provide a therapy that, alone or in conjunction with current treatments, effectively reduces craving, prevents relapse, and promotes abstinence from excessive alcohol consumption. This will provide AUD patients with a much-needed therapy to help eliminate the consequences of prolonged AUD.

Public Health Relevance Statement:
Narrative Alcohol use disorder (AUD) is a major public health concern that affects over 16 million Americans and is now the third leading preventable cause of death in the United States. Current interventions include pharmacologic treatment and behavioral therapies; however, high rates of relapse soon after initial successful treatment are a common problem. This Phase I SBIR project proposes the development of a non-invasive transcutaneous electrical nerve stimulation device to provide a therapy that, alone or in conjunction with current treatments, effectively reduces craving, prevents relapse, and promotes abstinence from excessive alcohol consumption.

Project Terms:
Abstinence; Acupuncture Therapy; Adverse event; adverse outcome; Affect; afferent nerve; alcohol abuse therapy; Alcohol consumption; alcohol craving; alcohol cue; Alcohol dependence; alcohol effect; alcohol response; alcohol use disorder; American; base; Behavior Therapy; Case Study; Cause of Death; Clinical Research; Cognitive; Comorbidity; Consumption; cost; craving; Crime; Cues; Data; dependence relapse; design; Development; Device Designs; Devices; disabling disease; Dopamine; Dorsal; effective therapy; Effectiveness; Electrodes; Evaluation; evidence base; Future; Goals; Hand; Health Benefit; Healthcare; Heavy Drinking; Home environment; human subject; Implant; improved; Infection; innovation; Intervention; Location; Long-Term Effects; Midbrain structure; Nerve; Neuraxis; neuroregulation; new technology; Operative Surgical Procedures; Participant; Pathway interactions; Patients; Periodicity; Peripheral Nerve Stimulation; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Physiologic pulse; Pilot Projects; portability; prevent; primary endpoint; Productivity; Public Health; recruit; Relapse; response; reward circuitry; Safety; Signal Transduction; Skin; Small Business Innovation Research Grant; Structure of ulnar nerve; Surveys; System; targeted treatment; Techniques; Transcutaneous Electric Nerve Stimulation; Treatment Effectiveness; Treatment outcome; United States; usability; user-friendly; Work; Wrist

Excessive alcohol consumption is the third leading cause of death in the United States, and approximately 15million Americans suffer from alcohol use disorder (AUD). AUD also economically expensive, with $249 billionspent annually for costs related to healthcare, lost work productivity, and crime. Despite the high prevalence ofAUD and its severe consequences, less than 20% of those with AUD receive any treatment, mainly due to keydrawbacks of current treatment options. Guidelines for AUD treatment include pharmacotherapy, behavioralintervention, or both. Meta-analyses consistently demonstrate that first-line AUD medications (naltrexone andacamprosate) are only moderately effective, at best. AUD pharmacotherapies also have common side effectsthat limit acceptability to patients. Similar to medications, behavioral interventions, such as cognitive behavioraltherapy (CBT), provide only small/moderate treatment benefits. In addition, programs often require abstinence,which can be a barrier as many AUD patients prefer non-abstinent goals. Recent preclinical and clinical researchhas shown that acupuncture of a peripheral nerve pathway can significantly modulate craving-, reward-, andwithdrawal-related responses for drugs of abuse. We, thus, hypothesize that peripheral nerve stimulation can bean effective treatment for AUD through its direct effects on craving, reward, and withdrawal. Thus, TheraNovahas developed the Empower Neuromodulation System, a portable, easy-to-use transcutaneous electrical nervestimulation (TENS) device for non-invasive nerve stimulation as a treatment for AUD. The EmpowerNeuromodulation System consists of a small, wearable Controller and gel electrodes that are temporarilyadhered to the skin to stimulate the underlying nerve. Our Phase I clinical study with AUD patients demonstratedthat the Empower treatment significantly reduced alcohol consumption (mean reduction = 29%, p=0.026), alcoholcraving intensity (mean reduction 21%, p=0.001), and anxiety (mean reduction = 31%, p<0.001) (vs. baselineweek measurements) after only two weeks of treatment. While promising, this was a two-week, open-label study,so a longer, sham-controlled pivotal trial is needed to rigorously verify that Empower offers a comprehensiveAUD treatment. In Aim 1 of this proposal, we will first update the design of the Empower Neuromodulation Systemand conduct all bench testing required to support an FDA submission. Then, in Aim 2, we will conduct a multi-site, sham-controlled pivotal clinical trial to evaluate the safety, effectiveness, and acceptability of Empower asa treatment for AUD. The data obtained through this work will support FDA clearance, enablingcommercialization of the Empower Neuromodulation System as a comprehensive treatment for AUD.

Public Health Relevance Statement:
Narrative Approximately 15 million Americans suffer from alcohol use disorder (AUD), but current treatment options have low-to-moderate effectiveness and all suffer from one or more key drawbacks. In this Phase II SBIR, we propose further development of the Empower Neuromodulation System, a non-invasive, home-use neuromodulation treatment for AUD. The data obtained through this work will support FDA clearance, enabling commercialization of the Empower Neuromodulation System as a comprehensive treatment for AUD.

Project Terms: