Lemborexant Augmentation of Naltrexone for Alcohol Craving and Sleep

Lemborexant Augmentation of Naltrexone for Alcohol Craving and Sleep: A Randomized, Double-Blind, Placebo- Controlled Study

The purpose of this study to evaluate the effects of naltrexone plus lemborexant augmentation compared to naltrexone plus placebo on cue-induced and non-cued alcohol cravings in people with alcohol use disorder and insomnia. Our secondary goals are to evaluate the effects of lemborexant plus naltrexone combination on sleep quality using self-report questionnaires and actigraph data, depression, anxiety, and suicidal ideation.

Study Overview

• Status: Completed
• Conditions: Alcohol Use Disorder
• Intervention / Treatment: Drug: Lemborexant 10 mg; Drug: Naltrexone

Detailed Description

Alcohol is one of the most popular substances used worldwide for thousands of years. Globally, harmful alcohol use continues to be a major public health and economic burden. The World Health Organization global status report attributed harmful alcohol use to 3 million deaths in 2016.In the United States, alcohol is the most used substance by people over the age of 12, with alcohol use disorder (AUD) affecting 14.5 million people in this age group. Hazardous alcohol use is associated with emergency room visits, overdose, driving fatalities and chronic medical conditions such as liver disease, heart disease, and hypertension.

Pharmacological interventions for AUD have expanded over the past few decades, including FDA approved and off-label medications such as naltrexone that have demonstrated efficacy in reducing alcohol cravings, consumption, and likelihood of relapse. However, the significant variability in response to treatment fuels ongoing interest in novel pharmacotherapy for AUD. A common approach involves repurposing readily available medications based on our understanding of AUD pathophysiology. In this study, we focus on the orexin system, which has been implicated in behaviors such as feeding, sleep-wake cycle, motivation, and reward associated with food, sex and substances including alcohol. The brain neuropeptides orexin A and orexin B originate in the hypothalamus and project throughout the central nervous system, activating G-protein-coupled receptors orexin 1 and 2 (OX1R and OX2R). While both orexin receptors are involved in addictive behaviors, OX1R signaling has a stronger association with reward processes whereas OX2R promotes arousal. Chronic alcohol exposure may lead to neuroadaptations in the orexin system, as observed in studies showing a positive correlation between orexin levels and severity of alcohol dependence and distress during alcohol withdrawal. Moreover, multiple animal studies have demonstrated efficacy of orexin antagonists in reducing alcohol craving, self-administration, and reinstatement of alcohol use induced by cues and stress.

The orexin antagonist lemborexant is FDA approved for treatment of insomnia. Lemborexant acts on both OX1R and OX2R and has shown efficacy in sleep initiation and maintenance compared to placebo on polysomnography and patient-report. It has demonstrated long-term safety and effectiveness without physical dependence or rebound insomnia. Compared to suvorexant, another orexin antagonist, lemborexant has greater selectivity and stronger binding for orexin receptors. Suvorexant has secondary effects on the adenosine receptor and dopamine transporter whereas lemborexant only has weak binding to melatonin 1. These differences may increase risk of misuse for suvorexant more than lemborexant. In addition, Lemborexant's longer half-life (17-19h) may be advantageous for reduction of cravings during the day.

In people with AUD, insomnia is a common problem that is associated with alcohol craving and relapse. Standard treatment for AUD with naltrexone improves cravings and other AUD outcomes, but does not improve sleep. In some cases, naltrexone may have a detrimental effect on sleep. Lemborexant may be able to target both alcohol craving/urges and insomnia when added to standard treatment with naltrexone.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Thanh Thuy Truong, MD; Phone Number: 713-275-5251; Email: ttruong3@menninger.edu
• Study Contact Backup: Name: Nadine Obeid, MPH; Phone Number: 713-275-5674; Email: nobeid@menninger.edu

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77035
      • The Menninger Clinic
      • Contact: Thanh Truong, MD; Phone Number: 713-275-5251; Email: ttruong3@menninger.edu
      • Contact: Nadine Obeid, MPH; Phone Number: 713-275-5647; Email: nobeid@menninger.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Admission to The Menninger clinic
• Age 18-65 years
• diagnosis of alcohol use disorder using the DSM-5 criteria confirmed with SCID-5 and
• Diagnosis of insomnia using the DSM 5 criteria, confirmed with SCID-5

Exclusion Criteria:

• unstable medical conditions (e.g. liver enzymes (ALT and AST) more than 3 times normal)
• acute alcohol withdrawal
• another drug use disorder other than nicotine and cannabis
• use of either of the study medications, naltrexone or lemborexant, within the last 30 days
• Use of any opioid medication within the past 10 days
• Use of scheduled benzodiazepines and hypnotics
• Breathalyzer positive for alcohol
• Known sensitivity to naltrexone or lemborexant
• Pregnant or breastfeeding
• Diagnosis of narcolepsy. The presence of other psychiatric illnesses, use of other psychotropic medications, and stable medical conditions will not be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lemborexant plus Naltrexone; 10 milligrams of Lemborexant will be given daily at nighttime and 50 milligrams of Naltrexone will be given daily for a total of 4 weeks	Drug: Lemborexant 10 mg; 10 mg of Lemborexant; Other Names: Dayvigo; Drug: Naltrexone; 50 mg of Naltrexone; Other Names: Revia; Vivitrol
Placebo Comparator: Placebo plus Naltrexone; 10 milligrams of placebo will be given daily at nighttime and 50 milligrams of Naltrexone will be given daily for a total of 4 weeks	Drug: Naltrexone; 50 mg of Naltrexone; Other Names: Revia; Vivitrol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cue-induced Alcohol Cravings using the Alcohol Urge Questionnaire	Evaluate the effects of naltrexone plus lemborexant augmentation compared to naltrexone plus placebo on cue-induced alcohol cravings in people with alcohol use disorder and insomnia. Alcohol Urge Questionnaire (AUQ): an 8-item self-report questionnaire of present alcohol cravings. Each item is scored on a 1 to 7 scale (Strongly Disagree = 1 and Strongly Agree = 7). Items 2 and 7 are reverse scored. A total score is computed by averaging the item scores. Higher scores reflect greater craving. Participants will be given the AUQ shortly after going through a virtual reality scenario involving alcohol at baseline, end of week 2 and end of week 4.	4 Weeks after Randomization
Non-Cued Alcohol Cravings using the Penn Alcohol Craving Scale	Evaluate the effects of naltrexone plus lemborexant augmentation compared to naltrexone plus placebo on non-cued alcohol cravings in people with alcohol use disorder and insomnia. Penn Alcohol Craving Scale (PACS): The PACS is a 5-item questionnaire that measures alcohol craving in the past week. Scores range from 0-30, with higher scores indicating stronger cravings. The PACS will be given at baseline and weekly.	4 Weeks after Randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Quality Using the Pittsburgh sleep quality index	Pittsburgh sleep quality index (PSQI) is a 19-item self-rated questionnaire that assesses sleep quality and disturbances. Questions are rated from 0 = no difficulty to 3 = severe difficulty. The total scores range from 0 to 21 and a score >5 is considered a significant sleep disturbance.	4 weeks after randomization
Insomnia Severity using the Insomnia Severity Index	Insomnia Severity Index (ISI) is a 7-item questionnaire that measures insomnia severity. Scores 8 to 14 indicates subthreshold, 15 to 21 indicates moderately severe, 22 to 28 indicates severe clinical insomnia.	4 weeks after randomization
Daytime sleepiness using the Epworth Sleepiness Scale	Epworth Sleepiness Scale (ESS) is an 8-item questionnaire that asks the respondent to rate on a 4-point scale (0-3) their usual chances of having dozed off or fallen asleep while engaged in eight different activities. ESS scores of 11-24 represent increasing levels of excessive daytime sleepiness.	4 weeks after randomization
Actigraphy to measure Total Sleep Time	The ActiGraph wGT3X-BT will measure daily total sleep time (minutes)	4 weeks after randomization
Actigraphy to measure sleep latency	The ActiGraph wGT3X-BT will measure sleep latency (minutes)	4 weeks after randomization
Actigraphy to measure wake after sleep onset	The ActiGraph wGT3X-BT will measure wake after sleep onset (minutes)	4 weeks after randomization
Actigraphy to measure sleep efficiency	The ActiGraph wGT3X-BT will measure sleep efficiency, which is calculated by total time asleep divided by total time in bed x 100.	4 weeks after randomization
Anxiety Using the Generalized Anxiety Disorder scale	Generalized Anxiety Disorder scale (GAD-7): THE GAD-7 is a self-report questionnaire that measures symptoms of generalized anxiety disorder. The participant will be given the GAD-7 at screening, baseline and weekly. Using the threshold score of 10, the GAD-7 has a sensitivity of 89% and a specificity of 82% for GAD. A score of 10 or greater on the GAD-7 indicates GAD. Cut points of 5, 10, and 15 are interpreted as mild, moderate, and severe levels of anxiety, respectively.	4 weeks after randomization
Depression using the Patient Health Questionnaire	The Patient Health Questionnaire (PHQ-9): The PHQ-9 a self-report questionnaire that measures symptoms of depression. The participant will be given the PHQ-9 at screening, baseline and weekly. PHQ-9 score ≥10 had a sensitivity of 88% and a specificity of 88% for major depression. PHQ-9 scores of 5-9, 10-14, 15-19 and 20-27 represent mild, moderate, moderately severe, and severe depression, respectively.	4 weeks after randomization
Suicide Risk Using the Suicide Behavior Questionnaire-Revised	Suicide Behavior Questionnaire-Revised (SBQ-R): The SBQ-R is a 4-item questionnaire that assesses suicidal thoughts and behaviors. A score of 8 or higher indicates high risk of suicide.	4 weeks after randomization

Collaborators and Investigators

• Sponsor: Baylor College of Medicine

Publications and helpful links

General Publications

• Swift RM, Aston ER. Pharmacotherapy for alcohol use disorder: current and emerging therapies. Harv Rev Psychiatry. 2015 Mar-Apr;23(2):122-33. doi: 10.1097/HRP.0000000000000079.
• Zindel LR, Kranzler HR. Pharmacotherapy of alcohol use disorders: seventy-five years of progress. J Stud Alcohol Drugs Suppl. 2014;75 Suppl 17(Suppl 17):79-88.
• Ziolkowski M, Czarnecki D, Budzynski J, Rosinska Z, Zekanowska E, Goralczyk B. Orexin in Patients with Alcohol Dependence Treated for Relapse Prevention: A Pilot Study. Alcohol Alcohol. 2016 Jul;51(4):416-21. doi: 10.1093/alcalc/agv129. Epub 2015 Nov 22.
• von der Goltz C, Koopmann A, Dinter C, Richter A, Rockenbach C, Grosshans M, Nakovics H, Wiedemann K, Mann K, Winterer G, Kiefer F. Orexin and leptin are associated with nicotine craving: a link between smoking, appetite and reward. Psychoneuroendocrinology. 2010 May;35(4):570-7. doi: 10.1016/j.psyneuen.2009.09.005. Epub 2009 Oct 13.
• Moorman DE. The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders. Psychopharmacology (Berl). 2018 Jun;235(6):1663-1680. doi: 10.1007/s00213-018-4871-2. Epub 2018 Mar 6.
• Rosenberg R, Murphy P, Zammit G, Mayleben D, Kumar D, Dhadda S, Filippov G, LoPresti A, Moline M. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. JAMA Netw Open. 2019 Dec 2;2(12):e1918254. doi: 10.1001/jamanetworkopen.2019.18254. Erratum In: JAMA Netw Open. 2020 Apr 1;3(4):e206497. JAMA Netw Open. 2021 Aug 2;4(8):e2127643.
• Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, Dhadda S, Hong Q, Giorgi L, Satlin A. Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Sleep Med. 2017 Nov 15;13(11):1289-1299. doi: 10.5664/jcsm.6800.
• Yardley J, Karppa M, Inoue Y, Pinner K, Perdomo C, Ishikawa K, Filippov G, Kubota N, Moline M. Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial. Sleep Med. 2021 Apr;80:333-342. doi: 10.1016/j.sleep.2021.01.048. Epub 2021 Feb 1.

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2023
• Primary Completion (Actual): January 30, 2024
• Study Completion (Actual): January 30, 2024

Study Registration Dates

• First Submitted: July 6, 2022
• First Submitted That Met QC Criteria: July 12, 2022
• First Posted (Actual): July 14, 2022

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Hypnotics and Sedatives; Narcotic Antagonists; Alcohol Deterrents; Sleep Aids, Pharmaceutical; Orexin Receptor Antagonists; Naltrexone; Lemborexant
• Other Study ID Numbers: H-52091

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes