Non-Invasive Neuromodulation Device for the Treatment of Alcohol Use Disorder - Abstract
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.
