Orexin Receptor Antagonists as Modulators of Threat Sensitivity in Individuals With Alcohol Use Disorder

NCT05656534 | Completed Early Phase 1 Results FDA Drug

• 2 other identifiers: 2022H02651R21AA030097-01A1
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this double-blind clinical trial is to further explore if, how, and for whom orexin antagonism modifies brain-behavior stress targets in moderate to severe alcohol use disorder (AUD). The main questions it aims to answer are:

• Does an acute dose of suvorexant (SUV) and/or daily use of SUV modify brain-behavior targets of AUD dysfunction?
• Does daily SUV use change alcohol behavior and if so, is this change in behavior linked to brain-behavior change? Participants will be randomized to a treatment group (SUV or placebo) and protocol arm, electromyography (EMG) only or EMG+functional magnetic resonance imaging (fMRI). Participants will be asked to complete the following:
• Baseline lab visit(s) that include the psychophysiological stress paradigm (EMG only or EMG+fMRI, dependent upon randomization).
• Acute drug challenge where the participant will return to the lab to repeat the stress paradigm following administration of a single dose of either 10mg SUV or placebo.
• Medication trial where participants will be instructed to take 10mg capsules of SUV or placebo orally each night before bedtime for 4-weeks.
• Daily reports of medication adherence, side-effects, sleep, alcohol use, and mood will be collected via smartphones during the 4-week medication trial.
• Post-treatment lab visit(s) where participants will return to the lab at the end of the medication trial and complete the same stress paradigm from baseline (EMG only or EMG+fMRI, dependent upon randomization).

Conditions

Alcohol Use Disorder

Keywords

suvorexant; alcohol use disorder; electromyography; functional magnetic resonance imaging

Outcome Measures

Primary Outcomes (3)

• Startle Eyeblink Electromyographic (EMG) Response to Stress With an Acute Dose of Suvorexant

  Startle EMG responses were collected during the well-validated No-Predictable-Unpredictable threat paradigm. The task includes within-subjects conditions and raw EMG responses were averaged for each condition. To quantify the difference between threat and no-threat periods, we calculated a standardized residual score for unpredictable threat (U-threat) by saving the variance leftover (i.e., the amount of variability in a dependent variable \[DV\] that is not explained by an independent variable \[IV\]) in a simple linear regression, where the no-threat EMG startle average (IV) was entered to predict the U-threat EMG startle average (DV). The U-threat residual score was used as the primary variable. It has a mean of zero and higher scores reflect greater startle reactivity to U-threat. U-threat residual scores were calculated for the baseline session and the acute challenge.

  Change from baseline to 2 hours post-ingestion of an acute dose of suvorexant.

• Startle Eyeblink Electromyographic (EMG) Response to Stress With Daily Use of Suvorexant.

  Startle EMG responses were collected during the well-validated No-Predictable-Unpredictable threat paradigm. The task includes within-subjects conditions and raw EMG responses were averaged for each condition. To quantify the difference between threat and no-threat periods, we calculated a standardized residual score for unpredictable threat (U-threat) by saving the variance leftover (i.e., the amount of variability in a dependent variable \[DV\] that is not explained by an independent variable \[IV\]) in a simple linear regression, where the no-threat EMG startle average (IV) was entered to predict the U-threat EMG startle average (DV). The U-threat residual score was used as the primary variable. It has a mean of zero and higher scores reflect greater startle reactivity to U-threat.

  Change from baseline to post-treatment, up to 2 months.

• Percentage of Heavy Drinking Days During Daily Use of Suvorexant.

  Percentage of heavy drinking days (PHDD) was calculated each week for all four weeks of the trial. A heavy drinking day was defined using NIH criteria: 5+ drinks for males and 4+ drinks for females in a single day. We conducted a multilevel mixed model with PHDD from week 1 to 4 as the within-subjects variable and treatment arm as the between subjects variable.

  Change from baseline to post-treatment, over the course of 4 weeks.

Secondary Outcomes (1)

• Changes in Neural Activation During Unpredictable Stress Anticipation Following Daily Use of Suvorexant.

  Change from baseline to post-treatment, up to 2 months.

Study Arms (2)

Control

PLACEBO COMPARATOR

Individuals will take a placebo pill during the Acute Drug Challenge and daily for 28 days.

Other: Placebo

Suvorexant Treatment

EXPERIMENTAL

Individuals will take 10mg of suvorexant (Merck \& Co Inc.) during the Acute Drug Challenge and daily for 28 days.

Drug: Suvorexant

Interventions

Suvorexant DRUG

This study is a double-blind study. Participants will complete an initial screening visit and pre-treatment lab visits (EMG, fMRI). Suvorexant (SUV) will be placed in opaque capsules with dextrose filler. After the pre-treatment visits participants will take one pill of SUV at the Acute Drug Challenge under medical supervision. Ninety minutes post ingestion participants will complete an EMG. Laboratory assessments will occur during peak concentration, 2 hours post-ingestion. At the end of the visit, participants will be given a blister pack with 28 pills. Participants will be instructed to take one pill orally about 30 minutes prior to sleep time each night for 28 days. Participants will be provided education about common side effects. Participants will complete daily surveys to monitor side effects and potential drug-drug interactions. At the end of the 28 days, participants will complete post-treatment lab visits.

Also known as: Belsomra

Suvorexant Treatment

Placebo OTHER

This study is a double-blind study. Participants will complete an initial screening visit and pre-treatment lab visits (EMG, fMRI). The placebo pill will be identical in appearance to suvorexant but will contain only dextrose. Following the pre-treatment visits, participants will take one pill at the Acute Drug Challenge under medical supervision. Ninety minutes post ingestion participants will complete the EMG paradigm. At the end of the visit participants will be provided a blister pack with 28 pills. Participants will be instructed to take one pill orally about 30 minutes prior to sleep time each night for 28 days. Participants will be provided education about common side effects. Participants will complete daily surveys to monitor side. At the end of the 28 days, participants will complete post-treatment lab visits.

Control

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-65.
• Participant is able to give informed consent.
• Generally medically and physically healthy as confirmed by medical history.
• Meet DSM-5 diagnostic criteria for current moderate or severe AUD.
• Engage in heavy alcohol use defined as drinking equal or greater than 14 standard drinks per week if male and equal or greater than 7 standard drinks per week if female.

You may not qualify if:

• Clinically significant medical or neurological condition (e.g., liver disease, narcolepsy, complex sleep behaviors, severe hepatic impairment, COPD, severe obstructive sleep apnea).
• Current cognitive dysfunction (traumatic brain injury, mental retardation, organic mental syndrome, pervasive developmental disorder, or dementia).
• Current use of antihistamines, strong or moderate inhibitors of CYP3A liver enzymes, strong CYP3A inducers, or digoxin.
• Current or past DSM-5 diagnosis of mania, schizophrenia, psychosis, suicidality, major depressive disorder, or obsessive compulsive disorder.
• Current substance use disorder other than alcohol or mild cannabis use disorder.
• Treatment seeking for AUD.
• Recent psychotropic medication use in the past 2 months.
• Currently smokes 5 or more cigarettes (or electronic equivalent) per day.
• BMI equal or greater than 35.
• Engage in night-shift work.
• Lack of fluency in English.
• Presence of ferrous-containing metal in the body.
• Inability to tolerate small, enclosed spaces.
• Deafness in one or both ears.
• Currently pregnant (positive pregnancy test), lactating, or not agreeing to use birth control methods during the duration of the trial.

Sponsors & Collaborators

• Ohio State University: lead
• National Institute on Alcohol Abuse and Alcoholism (NIAAA): collaborator

Study Sites (1)

The Ohio State University

Columbus, Ohio, 43210, United States

Location

MeSH Terms

Conditions

Alcoholism

Interventions

suvorexant

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Results Point of Contact

• Title: Dr. Stephanie Gorka
• Organization: The Ohio State University

stephanie.gorka@osumc.edu

614-366-1027

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: December 11, 2022
• First Posted: December 19, 2022
• Study Start: November 29, 2022
• Primary Completion: August 1, 2024
• Study Completion: August 1, 2024
• Last Updated: October 30, 2025
• Results First Posted: October 30, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Time Frame: The data, as outlined above, will be submitted to the NIAAA Data Archive biannually per NIAAA requirements throughout the duration of the study.

Locations

US (1)